https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Matthew+J+LowryProteopedia - User contributions [en]2026-09-16T15:10:32ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=Montelukast&diff=2688550Montelukast2016-12-05T23:26:06Z<p>Matthew J Lowry: </p>
<hr />
<div><StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks the production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
<scene name='74/745011/Montelukast_alone/3'>Montelukast</scene> has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast is held in place in the <scene name='74/745011/Initial/5'>active site</scene> of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Ser100 and Val296 are indicated in pink. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A<sub>4</sub> (LTA<sub>4</sub>) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA<sub>4</sub> is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA<sub>4</sub> into LTB<sub>4</sub>, or LTC<sub>4</sub> synthase converts it into LTC<sub>4</sub> <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC<sub>4</sub> continuing the cascade to produce subsequent leukotrienes D<sub>4</sub> and E<sub>4</sub>.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC<sub>4</sub> is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD<sub>4</sub> and LTE<sub>4</sub>; leukotrienes C<sub>4</sub> and D<sub>4</sub> have equal ability to stimulate smooth muscle constriction in the airway, while E<sub>4</sub> is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB<sub>4</sub> Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB<sub>4</sub> pathway; once LTB<sub>4</sub> is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB<sub>4</sub> <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C<sub>4</sub>, D<sub>4</sub>, and E<sub>4</sub>. It is also thought that the amount of Montelukast needed to prevent production of LTB<sub>4</sub> would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=Montelukast&diff=2688546Montelukast2016-12-05T23:19:45Z<p>Matthew J Lowry: </p>
<hr />
<div><StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks the production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
<scene name='74/745011/Montelukast_alone/3'>Montelukast</scene> has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. <scene name='74/745011/Initial/5'>Ser100 and Val296</scene> are indicated in pink. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A<sub>4</sub> (LTA<sub>4</sub>) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA<sub>4</sub> is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA<sub>4</sub> into LTB<sub>4</sub>, or LTC<sub>4</sub> synthase converts it into LTC<sub>4</sub> <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC<sub>4</sub> continuing the cascade to produce subsequent leukotrienes D<sub>4</sub> and E<sub>4</sub>.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC<sub>4</sub> is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD<sub>4</sub> and LTE<sub>4</sub>; leukotrienes C<sub>4</sub> and D<sub>4</sub> have equal ability to stimulate smooth muscle constriction in the airway, while E<sub>4</sub> is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB<sub>4</sub> Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB<sub>4</sub> pathway; once LTB<sub>4</sub> is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB<sub>4</sub> <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C<sub>4</sub>, D<sub>4</sub>, and E<sub>4</sub>. It is also thought that the amount of Montelukast needed to prevent production of LTB<sub>4</sub> would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=Montelukast&diff=2688545Montelukast2016-12-05T23:18:40Z<p>Matthew J Lowry: New page: ==Montelukast== <StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'> == Function == Monte...</p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks the production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
<scene name='74/745011/Montelukast_alone/3'>Montelukast</scene> has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. <scene name='74/745011/Initial/5'>Ser100 and Val296</scene> are indicated in pink. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A<sub>4</sub> (LTA<sub>4</sub>) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA<sub>4</sub> is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA<sub>4</sub> into LTB<sub>4</sub>, or LTC<sub>4</sub> synthase converts it into LTC<sub>4</sub> <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC<sub>4</sub> continuing the cascade to produce subsequent leukotrienes D<sub>4</sub> and E<sub>4</sub>.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC<sub>4</sub> is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD<sub>4</sub> and LTE<sub>4</sub>; leukotrienes C<sub>4</sub> and D<sub>4</sub> have equal ability to stimulate smooth muscle constriction in the airway, while E<sub>4</sub> is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB<sub>4</sub> Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB<sub>4</sub> pathway; once LTB<sub>4</sub> is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB<sub>4</sub> <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C<sub>4</sub>, D<sub>4</sub>, and E<sub>4</sub>. It is also thought that the amount of Montelukast needed to prevent production of LTB<sub>4</sub> would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=Glut3&diff=2688541Glut32016-12-05T23:16:05Z<p>Matthew J Lowry: </p>
<hr />
<div>==Facilitated Glucose Transporter 3, Solute Carrier Family 2 (GLUT3/ SLC2A3) in Homo Sapiens==<br />
<StructureSection load='5c65' size='340' side='right' caption='Human glucose transporter complex with cholesterol derivative (PDB code [[5c65]])'><br />
== Function ==<br />
GLUT3 is one of fourteen facilitative sugar transporters, which use the glucose diffusion gradient to move across various plasma membranes to display various specificities, kinetics and tissue expression profiles <ref name="three">Long, W., & Cheeseman, C. I. (2015). Structure of, and functional insight into the GLUT family of membrane transporters. Cell Health and Cytoskeleton, 7, 167-183. doi:10.2147/CHC.S60484</ref>. Glucose transporters are approximately 500 amino acids in length and part of a growing superfamily of integral membrane glycoproteins that have 12 transmembrane (TM) helices. The transmembrane regions presumably create channels through which glucose can move<ref name="four">Kipmen-Korgun, D., Bilmen-Sarikcioglu, S., Altunbas, H., Demir, R., & Korgun, E. T. (2009). Type-2 diabetes down-regulates glucose transporter proteins and genes of the human blood leukocytes.Scandinavian Journal of Clinical and Laboratory Investigation, 69(3), 350-358.<br />
doi:10.1080/00365510802632163</ref>. GLUT3 is categorized as a Class I transporter due to its protein sequence and structural similarity to other glucose transporters grouped in Class I<ref name="three"/>. GLUT3 displays the highest affinity for glucose of all of the Class I glucose transporters and has a transport capacity five times greater than that of GLUT1 and GLUT4<ref name="five"> Simpson,I. A., Dwyer, D., Malide, D., Moley, K. H., Travis, A., & Vannucci, S. J. (2008). The facilitative glucose transporter GLUT3: 20 years of distinction. American Journal of Physiology - Endocrinology and Metabolism, 295(2), E242-E253. doi:10.1152/ajpendo.90388.2008</ref>. In humans, GLUT3 is found predominantly in brain tissue, highly and specifically expressed by neurons, and has some expression in peripheral tissues. For this reason GLUT3 is commonly known as the “neuronal glucose transporter”<ref name="five"/><ref name="six">Maher, F., Vannucci, S. J., & Simpson, I. A. (1994). Glucose transporter proteins in brain. FASEB Journal, 8(13), 1003-1011.</ref>. GLUT3 has a more restricted expression pathway, which represents specialized functions for the protein<ref name="seven">Xu, J., Lu, C., Wang, J., Zhang, R., Qian, X., & Zhu, H. (2015). Regulation of human trophoblast GLUT3 glucose transporter by mammalian target of rapamycin signaling. International Journal of Molecular Sciences, 16(6), 13815-13828. doi:10.3390/ijms160613815</ref>. GLUT3 has been found to play an important role in gestational development and maintaining the brain's structure. Defects in GLUT3 can cause fetal death as well as neurodegeneration, which can lead to diseases like Alzheimer’s<ref name="eight">Liu, Y., Liu, F., Iqbal, K., Grundke-Iqbal, I., & Gong, C. -. (2008). Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in alzheimer disease. FEBS Letters, 582(2), 359-364. doi:10.1016/j.febslet.2007.12.035</ref>.<br />
<br />
==Structure==<br />
GLUT3(<scene name='71/716527/5c65/1'>5c65</scene>) is a transport protein consisting of 481 amino acids and weighing 52,520 Daltons in its asymmetrical unit<ref name="nineteen">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/</ref>. This protein is an alpha-helical protein consisting of two chains, two different ligands and water<ref name="nineteen"/>. The structure was determined by X-Ray diffraction and was measured at a resolution of 2.65 Angstroms<ref name="twentytwo">http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c65</ref>. GLUT3 consists of 12 transmembrane segments (TMs) folded “into the N-terminal and C-terminal domains, each comprising ‘3+3’ inverted repeats”<ref name="nine"/> These TMs consist of four 3 repeated sections. [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F1.html Here] is a figure by Deng, D., et al. showing these repeated transmembrane segments<ref name="nine">Deng, D., Sun, P., Yan, C., Ke, M., Jiang, X., Xiong, L., . . . Yan, N. (2015). Molecular basis of ligand recognition and transport by glucose transporters. Nature, 526(7573), 391-396. doi:10.1038/nature14655</ref>. The protein consists of two different ligands, Y01 and 37X<ref name="eighteen">http://www.rcsb.org/pdb/explore.do?structureId=5C65</ref>. Octyl Glucose Neopentyl Glycol (<scene name='71/716528/37x/2'>37X</scene>) has a chemical formula of C<sub>27</sub>H<sub>52</sub>O<sub>12</sub> and a molecular weight of 569 Da. There are six 37X (501-506a) bound to chain A of 5c65. These ligands are kept in place by hydrogen bonds to arginine, proline, and serine and by van der Waals forces. Chain B has three 37X ligands attached to it (501-503b). These are attached through hydrogen bonds by arginine, proline, and serine as well as by van der Waals forces<ref name="twenty">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/bound/37X</ref>. To view 37X in 3D use [http://www.rcsb.org/pdb/explore/jmol.do?structureId=5C65&residueNr=37X JSmol]. Cholesterol hemisuccinate (<scene name='71/716528/Y01/1'>Y01</scene>) has a chemical formula of C<sub>31</sub>H<sub>50</sub>O<sub>4</sub> and has a molecular weight of 487 Da. One Y01 is attached to chain a and another Y01 is attached to chain b<ref name="twentyone">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/bound/Y01</ref>. To view Y01 in 3D use [http://www.rcsb.org/pdb/explore/jmol.do?structureId=5C65&residueNr=Y01 JSmol]. GLUT3 was also identified and analyzed in a complex with alpha & beta d-glucose. This model was reported with a resolution of 1.5 Å and was in an open-occluded state<ref name="nine"/>. The alpha and beta d glucose were coordinated in a <scene name='71/716528/Binding_pocket/8'>binding pocket</scene> by amino acids N315, E378, Q159, W368, Q280, Q281, N286. These are located on TM8 and TM10a and TM10b<ref name="nine"/>. A figure of this glucose coordination by Deng, D., et al. is available [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F2.html here]. GLUT3 structure was also determined when bound to maltose in an outward-open and an outward-occluded conformation. This was measure to a resolution of 2.6 Å and 2.4 Å respectively. A figure of this maltose coordination by Deng, D., et al. is available [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F3.html here]. To get a better view of the structure of the protein use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5C65 FirstGlance]. <br />
<br />
This is 5c65 shown with <scene name="/12/3456/Sample/1">colored groups</scene>. This is 5c65 shown as a <scene name="/12/3456/Sample/2">transparent representation</scene> of the protein.<br />
<br />
==Mechanism ==<br />
Multiple mechanistic theories have been proposed for facilitated glucose transporters. The simple carrier model was the earliest theory proposed by Widdas and contains four steps. First, the empty carrier opens to the cis side of the membrane for glucose to bind<ref name="three"/>. Then the substrate binding carrier translocates to the trans side of the membrane where it then releases glucose on that side. Last the empty carrier switches to the cis side. Multiple mechanistic theories, including the simple carrier model were proposed but all attempted to explain two key components of GLUT transporters, the asymmetry of the transport affinities and the trans-acceleration that occurs in the presence of hexose on the trans side. Trans acceleration or accelerated transport occurs when unidirectional uptake of sugar is stimulated by the presence of intracellular sugar<ref name="twelve">Naftalin RJ, Holman GD. Transport of sugars in human red cells. In: Ellory JC, Lew V, editors. \ Membrane Transport in Red Cells. New York, NY, USA: Academic Press; 1977.</ref>. After considerable research, two popular models remain for class 1 glut transporters. The two-site/fixed site transporter theory explains the asymmetry by having both substrate binding sites simultaneously available<ref name="thirteen">Carruthers, A., DeZutter, J., Ganguly, A., & Devaskar, S. U. (2009). Will the original glucose transporter isoform please stand up! American Journal of Physiology - Endocrinology and Metabolism, 297(4), E836-E848. doi:10.1152/ajpendo.00496.2009 </ref>. After glucose is bound, hexoses exchange between sites and speed the binding process. Although this method explains the asymmetry and the kinetics of class 1 glut transporters it is not known if all class 1 glut transporters undergo a trans-acceleration model<ref name="thirteen"/>. The alternating access model explains the mechanism for class 1 glut transporters that are symmetrical and follows three steps<ref name="fourteen">Jardetzky, O. (1966). Simple allosteric model for membrane pumps [27]. Nature, 211(5052), 969-970. doi:10.1038/211969a0</ref>. The transporter has a cavity for small substrates, and contains a substrate binding site. The transporter also has two different configurational openings to one cell membrane or the other. This mechanism differs from the two-site/fixed site transporter theory by assuming there is only one binding site available at a time, leading to four different conformation states. An empty outward open state, an occluded transporter state, a inward open state and finally another occluded state<ref name="fifteen">Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR, Iwata S. Structure and mechanism of the lactose permease of Escherichia coli. Science. 2003;301:610–615.</ref>. Trans-acceleration is only observed in a minority of class 1 glut transporters<ref name="sixteen">Caulfield MJ, Munroe PB, O’Neill D, et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 2008;5:1509–1523.</ref>. GLUT3 has been proven to be dependent on trans-acceleration. This method was discovered when hexose was found to be moving against its concentration gradient<ref name="three"/>. This movement is argued to support both the two-site transporter theory and the alternating access model. Geminate exchange, named by Naftalin et al, explains this movement with the idea that hexose could exchange freely between two binding sites within the carrier<ref name="twelve"/>. While other scientists argue that hexose could move from outward to inward without glucose binding<ref name="seventeen">Vollers, S. S., & Carruthers, A. (2012). Sequence determinants of GLUT1-mediated accelerated-exchange transport: Analysis by homology-scanning mutagenesis. Journal of Biological Chemistry, 287(51), 42533-42544.doi:10.1074/jbc.M112.369587</ref>.<br />
<br />
== Disease in Humans ==<br />
===Type 2 Diabetes===<br />
Higher glucose concentration, as seen in diabetics, influences GLUT expression in leukocytes. Patients with type 2 diabetes have decreased GLUT3 in granulocytes, lymphocytes, and monocytes. In addition, the level of transcripts that encode GLUT3 are reduced in diabetic patients. Decreased expression of GLUT3 and other GLUT isoforms could possibly impair immune function and increase susceptibility to infection in type 2 diabetes<ref name="four"/>.<br />
===Alzheimer's Disease===<br />
Alzheimer’s disease shows levels of impaired glucose uptake and metabolism, which leads to neurodegeneration via down-regulation of many other factors in the brain. GLUT3 is responsible for transporting glucose from extracellular space to neuronal tissue, specifically dendrites and axons. Decreased levels of GLUT3 in Alzheimer brain shows a positive correlation to decreased levels of N-acetylglucosamine, which is a derivative of glucose. The impaired presence of GLUT3 leads to hyperphosphorylation of the Tau protein, which normally stabilizes neuronal microtubules. Lastly there is a reduction in the transcription for factor hypoxia-inducible factor 1, which plays a role in glucose metabolism in the brain. The comparison between a normal healthy brain and an Alzheimer brain revealed that there was a 25-30% decrease in GLUT3 levels in the Alzheimer brain<ref name="eight"/>. <br />
===Huntington’s Disease===<br />
Huntington’s disease leads to decreased expression of GLUT3 in the plasma membrane. Increasing the expression of GLUT3 in a Huntington’s disease brain can delay the onset of the disease<ref name="ten">Vittori, A., Breda, C., Repici, M., Orth, M., Roos, R. A. C., Outeiro, T. F., . . . the REGISTRY investigators of the European Huntington's Disease Network. (2014). Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in huntington's disease. Human Molecular Genetics, 23(12), 3129-3137. doi:10.1093/hmg/ddu022</ref>. Rab11 is a protein that is involved with the regulation of transporter trafficking. It helps in the regulation of glucose transporters particularly the GLUT3 transporter. Its regulation is impaired by Huntington’s disease, which leads to the decreased cell surface expression of GLUT3 in the brain. The exact mechanism of Huntington’s disease is still unknown to this day<ref name="eleven">McClory, H., Williams, D., & Sapp, E. (2014). Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington’s disease mice. Acta Neuropathol Commun, 2, 1-9.</ref>.<br />
<br />
== 3D structure of sugar transporters ==<br />
<br />
See [[ABC transporter]]<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=Glut3&diff=2688539Glut32016-12-05T23:15:40Z<p>Matthew J Lowry: </p>
<hr />
<div>==Facilitated Glucose Transporter 3, Solute Carrier Family 2 (GLUT3/ SLC2A3) in Homo Sapiens==<br />
<StructureSection load='5c65' size='340' side='right' caption='Human glucose transporter complex with cholesterol derivative (PDB code [[5c65]])'><br />
== Function ==<br />
GLUT3 one of fourteen facilitative sugar transporters, which use the glucose diffusion gradient to move across various plasma membranes to display various specificities, kinetics and tissue expression profiles <ref name="three">Long, W., & Cheeseman, C. I. (2015). Structure of, and functional insight into the GLUT family of membrane transporters. Cell Health and Cytoskeleton, 7, 167-183. doi:10.2147/CHC.S60484</ref>. Glucose transporters are approximately 500 amino acids in length and part of a growing superfamily of integral membrane glycoproteins that have 12 transmembrane (TM) helices. The transmembrane regions presumably create channels through which glucose can move<ref name="four">Kipmen-Korgun, D., Bilmen-Sarikcioglu, S., Altunbas, H., Demir, R., & Korgun, E. T. (2009). Type-2 diabetes down-regulates glucose transporter proteins and genes of the human blood leukocytes.Scandinavian Journal of Clinical and Laboratory Investigation, 69(3), 350-358.<br />
doi:10.1080/00365510802632163</ref>. GLUT3 is categorized as a Class I transporter due to its protein sequence and structural similarity to other glucose transporters grouped in Class I<ref name="three"/>. GLUT3 displays the highest affinity for glucose of all of the Class I glucose transporters and has a transport capacity five times greater than that of GLUT1 and GLUT4<ref name="five"> Simpson,I. A., Dwyer, D., Malide, D., Moley, K. H., Travis, A., & Vannucci, S. J. (2008). The facilitative glucose transporter GLUT3: 20 years of distinction. American Journal of Physiology - Endocrinology and Metabolism, 295(2), E242-E253. doi:10.1152/ajpendo.90388.2008</ref>. In humans, GLUT3 is found predominantly in brain tissue, highly and specifically expressed by neurons, and has some expression in peripheral tissues. For this reason GLUT3 is commonly known as the “neuronal glucose transporter”<ref name="five"/><ref name="six">Maher, F., Vannucci, S. J., & Simpson, I. A. (1994). Glucose transporter proteins in brain. FASEB Journal, 8(13), 1003-1011.</ref>. GLUT3 has a more restricted expression pathway, which represents specialized functions for the protein<ref name="seven">Xu, J., Lu, C., Wang, J., Zhang, R., Qian, X., & Zhu, H. (2015). Regulation of human trophoblast GLUT3 glucose transporter by mammalian target of rapamycin signaling. International Journal of Molecular Sciences, 16(6), 13815-13828. doi:10.3390/ijms160613815</ref>. GLUT3 has been found to play an important role in gestational development and maintaining the brain's structure. Defects in GLUT3 can cause fetal death as well as neurodegeneration, which can lead to diseases like Alzheimer’s<ref name="eight">Liu, Y., Liu, F., Iqbal, K., Grundke-Iqbal, I., & Gong, C. -. (2008). Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in alzheimer disease. FEBS Letters, 582(2), 359-364. doi:10.1016/j.febslet.2007.12.035</ref>.<br />
<br />
==Structure==<br />
GLUT3(<scene name='71/716527/5c65/1'>5c65</scene>) is a transport protein consisting of 481 amino acids and weighing 52,520 Daltons in its asymmetrical unit<ref name="nineteen">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/</ref>. This protein is an alpha-helical protein consisting of two chains, two different ligands and water<ref name="nineteen"/>. The structure was determined by X-Ray diffraction and was measured at a resolution of 2.65 Angstroms<ref name="twentytwo">http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c65</ref>. GLUT3 consists of 12 transmembrane segments (TMs) folded “into the N-terminal and C-terminal domains, each comprising ‘3+3’ inverted repeats”<ref name="nine"/> These TMs consist of four 3 repeated sections. [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F1.html Here] is a figure by Deng, D., et al. showing these repeated transmembrane segments<ref name="nine">Deng, D., Sun, P., Yan, C., Ke, M., Jiang, X., Xiong, L., . . . Yan, N. (2015). Molecular basis of ligand recognition and transport by glucose transporters. Nature, 526(7573), 391-396. doi:10.1038/nature14655</ref>. The protein consists of two different ligands, Y01 and 37X<ref name="eighteen">http://www.rcsb.org/pdb/explore.do?structureId=5C65</ref>. Octyl Glucose Neopentyl Glycol (<scene name='71/716528/37x/2'>37X</scene>) has a chemical formula of C<sub>27</sub>H<sub>52</sub>O<sub>12</sub> and a molecular weight of 569 Da. There are six 37X (501-506a) bound to chain A of 5c65. These ligands are kept in place by hydrogen bonds to arginine, proline, and serine and by van der Waals forces. Chain B has three 37X ligands attached to it (501-503b). These are attached through hydrogen bonds by arginine, proline, and serine as well as by van der Waals forces<ref name="twenty">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/bound/37X</ref>. To view 37X in 3D use [http://www.rcsb.org/pdb/explore/jmol.do?structureId=5C65&residueNr=37X JSmol]. Cholesterol hemisuccinate (<scene name='71/716528/Y01/1'>Y01</scene>) has a chemical formula of C<sub>31</sub>H<sub>50</sub>O<sub>4</sub> and has a molecular weight of 487 Da. One Y01 is attached to chain a and another Y01 is attached to chain b<ref name="twentyone">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/bound/Y01</ref>. To view Y01 in 3D use [http://www.rcsb.org/pdb/explore/jmol.do?structureId=5C65&residueNr=Y01 JSmol]. GLUT3 was also identified and analyzed in a complex with alpha & beta d-glucose. This model was reported with a resolution of 1.5 Å and was in an open-occluded state<ref name="nine"/>. The alpha and beta d glucose were coordinated in a <scene name='71/716528/Binding_pocket/8'>binding pocket</scene> by amino acids N315, E378, Q159, W368, Q280, Q281, N286. These are located on TM8 and TM10a and TM10b<ref name="nine"/>. A figure of this glucose coordination by Deng, D., et al. is available [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F2.html here]. GLUT3 structure was also determined when bound to maltose in an outward-open and an outward-occluded conformation. This was measure to a resolution of 2.6 Å and 2.4 Å respectively. A figure of this maltose coordination by Deng, D., et al. is available [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F3.html here]. To get a better view of the structure of the protein use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5C65 FirstGlance]. <br />
<br />
This is 5c65 shown with <scene name="/12/3456/Sample/1">colored groups</scene>. This is 5c65 shown as a <scene name="/12/3456/Sample/2">transparent representation</scene> of the protein.<br />
<br />
==Mechanism ==<br />
Multiple mechanistic theories have been proposed for facilitated glucose transporters. The simple carrier model was the earliest theory proposed by Widdas and contains four steps. First, the empty carrier opens to the cis side of the membrane for glucose to bind<ref name="three"/>. Then the substrate binding carrier translocates to the trans side of the membrane where it then releases glucose on that side. Last the empty carrier switches to the cis side. Multiple mechanistic theories, including the simple carrier model were proposed but all attempted to explain two key components of GLUT transporters, the asymmetry of the transport affinities and the trans-acceleration that occurs in the presence of hexose on the trans side. Trans acceleration or accelerated transport occurs when unidirectional uptake of sugar is stimulated by the presence of intracellular sugar<ref name="twelve">Naftalin RJ, Holman GD. Transport of sugars in human red cells. In: Ellory JC, Lew V, editors. \ Membrane Transport in Red Cells. New York, NY, USA: Academic Press; 1977.</ref>. After considerable research, two popular models remain for class 1 glut transporters. The two-site/fixed site transporter theory explains the asymmetry by having both substrate binding sites simultaneously available<ref name="thirteen">Carruthers, A., DeZutter, J., Ganguly, A., & Devaskar, S. U. (2009). Will the original glucose transporter isoform please stand up! American Journal of Physiology - Endocrinology and Metabolism, 297(4), E836-E848. doi:10.1152/ajpendo.00496.2009 </ref>. After glucose is bound, hexoses exchange between sites and speed the binding process. Although this method explains the asymmetry and the kinetics of class 1 glut transporters it is not known if all class 1 glut transporters undergo a trans-acceleration model<ref name="thirteen"/>. The alternating access model explains the mechanism for class 1 glut transporters that are symmetrical and follows three steps<ref name="fourteen">Jardetzky, O. (1966). Simple allosteric model for membrane pumps [27]. Nature, 211(5052), 969-970. doi:10.1038/211969a0</ref>. The transporter has a cavity for small substrates, and contains a substrate binding site. The transporter also has two different configurational openings to one cell membrane or the other. This mechanism differs from the two-site/fixed site transporter theory by assuming there is only one binding site available at a time, leading to four different conformation states. An empty outward open state, an occluded transporter state, a inward open state and finally another occluded state<ref name="fifteen">Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR, Iwata S. Structure and mechanism of the lactose permease of Escherichia coli. Science. 2003;301:610–615.</ref>. Trans-acceleration is only observed in a minority of class 1 glut transporters<ref name="sixteen">Caulfield MJ, Munroe PB, O’Neill D, et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 2008;5:1509–1523.</ref>. GLUT3 has been proven to be dependent on trans-acceleration. This method was discovered when hexose was found to be moving against its concentration gradient<ref name="three"/>. This movement is argued to support both the two-site transporter theory and the alternating access model. Geminate exchange, named by Naftalin et al, explains this movement with the idea that hexose could exchange freely between two binding sites within the carrier<ref name="twelve"/>. While other scientists argue that hexose could move from outward to inward without glucose binding<ref name="seventeen">Vollers, S. S., & Carruthers, A. (2012). Sequence determinants of GLUT1-mediated accelerated-exchange transport: Analysis by homology-scanning mutagenesis. Journal of Biological Chemistry, 287(51), 42533-42544.doi:10.1074/jbc.M112.369587</ref>.<br />
<br />
== Disease in Humans ==<br />
===Type 2 Diabetes===<br />
Higher glucose concentration, as seen in diabetics, influences GLUT expression in leukocytes. Patients with type 2 diabetes have decreased GLUT3 in granulocytes, lymphocytes, and monocytes. In addition, the level of transcripts that encode GLUT3 are reduced in diabetic patients. Decreased expression of GLUT3 and other GLUT isoforms could possibly impair immune function and increase susceptibility to infection in type 2 diabetes<ref name="four"/>.<br />
===Alzheimer's Disease===<br />
Alzheimer’s disease shows levels of impaired glucose uptake and metabolism, which leads to neurodegeneration via down-regulation of many other factors in the brain. GLUT3 is responsible for transporting glucose from extracellular space to neuronal tissue, specifically dendrites and axons. Decreased levels of GLUT3 in Alzheimer brain shows a positive correlation to decreased levels of N-acetylglucosamine, which is a derivative of glucose. The impaired presence of GLUT3 leads to hyperphosphorylation of the Tau protein, which normally stabilizes neuronal microtubules. Lastly there is a reduction in the transcription for factor hypoxia-inducible factor 1, which plays a role in glucose metabolism in the brain. The comparison between a normal healthy brain and an Alzheimer brain revealed that there was a 25-30% decrease in GLUT3 levels in the Alzheimer brain<ref name="eight"/>. <br />
===Huntington’s Disease===<br />
Huntington’s disease leads to decreased expression of GLUT3 in the plasma membrane. Increasing the expression of GLUT3 in a Huntington’s disease brain can delay the onset of the disease<ref name="ten">Vittori, A., Breda, C., Repici, M., Orth, M., Roos, R. A. C., Outeiro, T. F., . . . the REGISTRY investigators of the European Huntington's Disease Network. (2014). Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in huntington's disease. Human Molecular Genetics, 23(12), 3129-3137. doi:10.1093/hmg/ddu022</ref>. Rab11 is a protein that is involved with the regulation of transporter trafficking. It helps in the regulation of glucose transporters particularly the GLUT3 transporter. Its regulation is impaired by Huntington’s disease, which leads to the decreased cell surface expression of GLUT3 in the brain. The exact mechanism of Huntington’s disease is still unknown to this day<ref name="eleven">McClory, H., Williams, D., & Sapp, E. (2014). Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington’s disease mice. Acta Neuropathol Commun, 2, 1-9.</ref>.<br />
<br />
== 3D structure of sugar transporters ==<br />
<br />
See [[ABC transporter]]<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Montelukast&diff=2688535User:Matthew J Lowry/Montelukast2016-12-05T23:13:52Z<p>Matthew J Lowry: New page: ==Montelukast== <StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'> == Function == Monte...</p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks the production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
<scene name='74/745011/Montelukast_alone/3'>Montelukast</scene> has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. <scene name='74/745011/Initial/5'>Ser100 and Val296</scene> are indicated in pink. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A<sub>4</sub> (LTA<sub>4</sub>) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA<sub>4</sub> is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA<sub>4</sub> into LTB<sub>4</sub>, or LTC<sub>4</sub> synthase converts it into LTC<sub>4</sub> <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC<sub>4</sub> continuing the cascade to produce subsequent leukotrienes D<sub>4</sub> and E<sub>4</sub>.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC<sub>4</sub> is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD<sub>4</sub> and LTE<sub>4</sub>; leukotrienes C<sub>4</sub> and D<sub>4</sub> have equal ability to stimulate smooth muscle constriction in the airway, while E<sub>4</sub> is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB<sub>4</sub> Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB<sub>4</sub> pathway; once LTB<sub>4</sub> is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB<sub>4</sub> <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C<sub>4</sub>, D<sub>4</sub>, and E<sub>4</sub>. It is also thought that the amount of Montelukast needed to prevent production of LTB<sub>4</sub> would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2688528User:Matthew J Lowry/Sandbox 12016-12-05T23:06:54Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks the production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
<scene name='74/745011/Montelukast_alone/3'>Montelukast</scene> has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. <scene name='74/745011/Initial/5'>Ser100 and Val296</scene> are indicated in pink. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A<sub>4</sub> (LTA<sub>4</sub>) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA<sub>4</sub> is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA<sub>4</sub> into LTB<sub>4</sub>, or LTC<sub>4</sub> synthase converts it into LTC<sub>4</sub> <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC<sub>4</sub> continuing the cascade to produce subsequent leukotrienes D<sub>4</sub> and E<sub>4</sub>.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC<sub>4</sub> is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD<sub>4</sub> and LTE<sub>4</sub>; leukotrienes C<sub>4</sub> and D<sub>4</sub> have equal ability to stimulate smooth muscle constriction in the airway, while E<sub>4</sub> is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB<sub>4</sub> Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB<sub>4</sub> pathway; once LTB<sub>4</sub> is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB<sub>4</sub> <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C<sub>4</sub>, D<sub>4</sub>, and E<sub>4</sub>. It is also thought that the amount of Montelukast needed to prevent production of LTB<sub>4</sub> would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2688526User:Matthew J Lowry/Sandbox 12016-12-05T23:04:08Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks the production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
<scene name='74/745011/Montelukast_alone/3'>Montelukast</scene> has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. <scene name='74/745011/Initial/5'>Ser100 and Val296</scene> are indicated in pink. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A<sub>4</sub> (LTA<sub>4</sub>) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA<sub>4</sub> is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA<sub>4</sub> into LTB<sub>4</sub>, or LTC<sub>4</sub> synthase converts it into LTC<sub>4</sub> <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC<sub>4</sub> continuing the cascade to produce subsequent leukotrienes D<sub>4</sub> and E<sub>4</sub>.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC<sub>4</sub> is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD<sub>4</sub> and LTE<sub>4</sub>; leukotrienes C<sub>4</sub> and D<sub>4</sub> have equal ability to stimulate smooth muscle constriction in the airway, while E<sub>4</sub> is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB<sub>4</sub> Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB<sub>4</sub> pathway; once LTB<sub>4</sub> is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C<sub>4</sub>, D<sub>4</sub>, and E<sub>4</sub>. It is also thought that the amount of Montelukast needed to prevent production of LTB<sub>4</sub> would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2688501User:Matthew J Lowry/Sandbox 12016-12-05T22:40:20Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks the production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
<scene name='74/745011/Montelukast_alone/3'>Montelukast</scene> has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. <scene name='74/745011/Initial/5'>Ser100 and Val296</scene> are indicated in pink. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2688337User:Matthew J Lowry/Sandbox 12016-12-05T05:20:21Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
<scene name='74/745011/Montelukast_alone/3'>Montelukast</scene> has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. <scene name='74/745011/Initial/5'>Ser100 and Val296</scene> are indicated in pink. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2688334User:Matthew J Lowry/Sandbox 12016-12-05T04:23:18Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
<scene name='74/745011/Montelukast_alone/3'>Montelukast</scene> has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (<scene name='74/745011/Initial/3'>MTK</scene>) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Ser100 and Val296 are indicated in pink Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2688329User:Matthew J Lowry/Sandbox 12016-12-05T03:33:51Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
<scene name='74/745011/Montelukast_alone/2'>Montelukast</scene> has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (<scene name='74/745011/Initial/3'>MTK</scene>) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Ser100 and Val296 are indicated in pink Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2688328User:Matthew J Lowry/Sandbox 12016-12-05T03:30:15Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
<scene name='74/745011/Montelukast_alone/1'>Montelukast</scene> has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (<scene name='74/745011/Initial/3'>MTK</scene>) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Ser100 and Val296 are indicated in pink Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2688280User:Matthew J Lowry/Sandbox 12016-12-04T23:21:48Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (<scene name='74/745011/Initial/3'>MTK</scene>) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Ser100 and Val296 are indicated in pink Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2688279User:Matthew J Lowry/Sandbox 12016-12-04T23:18:30Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (<scene name='74/745011/Initial/3'>MTK</scene>) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687509User:Matthew J Lowry/Sandbox 12016-11-16T19:58:58Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNI' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (<scene name='74/745011/Initial/2'>MTK</scene>) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687507User:Matthew J Lowry/Sandbox 12016-11-16T19:53:52Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNi' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (<scene name='74/745011/Initial/2'>MTK</scene>) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
To view 2NNI colored by group click <scene name="/12/3456/Sample/1">here</scene>. To see a transparent view of the protein click <scene name="/12/3456/Sample/2">here</scene> of the protein.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687504User:Matthew J Lowry/Sandbox 12016-11-16T19:50:14Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNi' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (<scene name='74/745011/Initial/2'>MTK</scene>) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687503User:Matthew J Lowry/Sandbox 12016-11-16T19:39:55Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNi' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with Montelukast.' scene='74/745011/Initial/1'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI-MTK</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (“MTK” scene zoom) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687500User:Matthew J Lowry/Sandbox 12016-11-16T19:35:08Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNi' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with many different ligands, but most notably Montelukast. (PDB entry [[2NNI]])'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural Highlights ==<br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8)(<scene name='74/745011/Initial/1'>2NNI-MTK</scene>). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (“MTK” scene zoom) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687498User:Matthew J Lowry/Sandbox 12016-11-16T19:30:39Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNi' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with many different ligands, but most notably Montelukast. (PDB entry [[2NNI]])'><br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural highlights ==<br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (“MTK” scene zoom) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687496User:Matthew J Lowry/Sandbox 12016-11-16T19:20:36Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='2NNi' size='350' side='right' caption='Cytochrome P450 2C8 in Humans complexed with many different ligands, but most notably Montelukast. (PDB entry [[2NNI]])'><br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural highlights ==<br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (“MTK” scene zoom) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687491User:Matthew J Lowry/Sandbox 12016-11-16T18:51:52Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (“MTK” scene zoom) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name="fourteen">Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name="fifteen">Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name="fifteen"/>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name="fourteen"/>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name="fifteen"/>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name="fourteen"/>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name="fifteen"/>. It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name="sixteen">Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name="sixteen"/>.<br />
<br />
<br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687456User:Matthew J Lowry/Sandbox 12016-11-16T15:11:17Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name="three">Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (“MTK” scene zoom) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name="three" />.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
<br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687158User:Matthew J Lowry/Sandbox 12016-11-15T01:52:55Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name=“three”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (“MTK” scene zoom) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="twelve"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="twelve"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“thirteen>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
<br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687157User:Matthew J Lowry/Sandbox 12016-11-15T01:48:24Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name=“three”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (“MTK” scene zoom) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="thirteen"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="thirteen"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
<br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687154User:Matthew J Lowry/Sandbox 12016-11-15T01:41:29Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“one”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“two”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name=“three”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“four”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="five">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="six">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="seven">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="eight">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="nine">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="ten">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="eleven"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (“MTK” scene zoom) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="twelve">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="thirteen"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="thirteen"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687148User:Matthew J Lowry/Sandbox 12016-11-15T01:35:20Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“twelve”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of asthma and asthma associated allergic rhinitis<ref name=“thirteen”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks the leukotriene cascade that is responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, this can lead to leukotrienes in the upper airway that act as inflammatory mediators producing the symptoms of allergic rhinitis <ref name=“sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, alleviating allergic symptoms by decreasing airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“fourteen”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="three">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="four">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="five">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="six">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="seven">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="eight">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="nine"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (“MTK” scene zoom) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="ten">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="ten"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="ten"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687144User:Matthew J Lowry/Sandbox 12016-11-15T01:29:39Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“twelve”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of the diseases, especially for asthma and asthma associated allergic rhinitis<ref name=“thirteen”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks leukotriene D4 and cysteinyl-leukotrienes that are responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, having leukotrienes in the upper airway as inflammatory mediators of allergic signs and symptoms<ref name=“sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, improving allergic symptoms of airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“fourteen”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="three">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="four">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="five">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="six">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="seven">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="eight">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="nine"> http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nni</ref>. Montelukast (“MTK” scene zoom) is held in place in the active site of CYP2C8 by hydrogen bonds between the side chain of Ser100 and the oxygens carboxyl group of Montelukast (resonance allows H-bond to either oxygens), and Val296 and the tertiary alcohol in Montelukast<ref name="ten">http://cdn.rcsb.org//poseview/NN/2NNI/MTK/2NNI_MTK.png</ref>. Residue Thr107 helps stabilize the polarity induced by the Chlorine <ref name="ten"/>. Hydrophobic interactions from amino acids like Alanine, Isoleucine, and Phenylalanine throughout the active site also help stabilize the interaction <ref name="ten"/>. The binding pocket can be three-dimensionally visualized using [http://www.rcsb.org/pdb/explore/jmol.do?structureId=2NNI&residueNr=MTK JSmol].<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687134User:Matthew J Lowry/Sandbox 12016-11-15T01:09:36Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
Montelukast is a cysteinyl leukotriene receptor antagonist that blocks production of leukotrienes and prevents them from binding to their receptors. Leukotrienes often cause many pulmonary dysfunctions and inflammatory illnesses such as asthma, peptic ulcers, and ischemia or reperfusion <ref name=“twelve”>Bentli, R., Ciftci, O., Cetin, A., and Otlu, A. (2016) Anti-inflammatory Montelukast prevents toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Oxidative stress, histological alterations in liver, and serum cytokine levels. Toxicology and Industrial Health, 32(5), 769-776. doi: 10.1177/0748233713505894</ref>. Montelukast is known for its effectiveness in the pathophysiological mechanisms of the diseases, especially for asthma and asthma associated allergic rhinitis<ref name=“thirteen”>Cylllyl, A., Kara, A., Ozdemir, T., Ogus, C. , and Gulkesen K. (2003) Effects of oral montelukast on airway function in acute asthma. Respiratory Medicine, 97(5), 533-536. doi: 10.1053/rmed.2003.1479</ref>. Montelukast suppresses the activation of eosinophils, which are associated with increased asthma severity. It specifically targets and blocks leukotriene D4 and cysteinyl-leukotrienes that are responsible for bronchoconstriction and sensory activation in the inflammatory pathway of asthma. Allergic rhinitis is often associated with asthma, having leukotrienes in the upper airway as inflammatory mediators of allergic signs and symptoms<ref name=“sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>. Montelukast reduces the release of inflammatory cytokines from airway cells and concentration of exhaled nitric oxide, improving allergic symptoms of airway hyperresponsiveness and bronchoconstriction. Due to its efficacy and safety, it can work as a monotherapy for those who do not respond well to inhaled corticosteroids, but it can also be prescribed with other drugs such as inhaled or oral corticosteroids, antihistamines, and beta-2 agonists to maximize its effects<ref name=“fourteen”>Paggiaro, P., Bacci, E. (2011) Montelukast in Asthma: A Review of its Efficacy and Place in Therapy. Therapeutic Advances in Chronic Disease, 2(1), 47-58. doi: 10.1177/ 2040622310383343</ref>. <br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="three">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="four">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="five">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="six">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="seven">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="eight">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="nine">http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=2NNI</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687112User:Matthew J Lowry/Sandbox 12016-11-14T21:00:34Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="three">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="four">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="five">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="six">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="seven">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 51% alpha helices and 9% beta sheets<ref name="eight">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>. The structure was determined using the method of X-ray diffraction with a resolution of 2.8 Angstroms<ref name="nine">http://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=2NNI</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687110User:Matthew J Lowry/Sandbox 12016-11-14T20:52:13Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="three">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="four">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="five">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="six">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="seven">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 53% alpha helices and 9% beta sheets<ref name="eight">Kabsch, W., & Sander, C. (1983, December). Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers, 22(12), 2577-2637. doi:10.1002/bip.360221211</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687041User:Matthew J Lowry/Sandbox 12016-11-14T01:33:12Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="three">https://www3.rcsb.org/ligand/MTK</ref>. The primary target for Montelukast is Cysteinyl Leukotriene Receptor 1 (CysLTR1) which contains 337 amino acids with a molecular weight of 38,541 Da <ref name="four">http://www.uniprot.org/uniprot/Q9Y271#sequences</ref>. It has 4 extracellular domains, 4 cytoplasmic domains, and 7 helical transmembrane domains <ref name="five">http://www.rcsb.org/pdb/protein/Q9Y271</ref>. Because no three-dimensional model was found for this protein on the PDB, Bandaru, S., et al used a multitude of programs to predict the structure of the protein <ref name="six">Bandaru, S., Marri, V. K., Kasera, P., Kovuri, P., Girdhar, A., Mittal, D. R., . . . Nayarisseri, A. (2014). Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist. Bioinformation, 10(10), 652-657. doi:10.6026/97320630010652</ref>. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248348/figure/F1/ Figure 1] of their paper provides an image of their prediction. Though this provides a model for the CysLTR1 protein there is still no model for the complexing of Montelukast with its target protein.<br />
<br />
Montelukast, like any drug, can also bind to non-target proteins. One of these proteins is Cytochrome P450 2C8 (CYP2C8). This protein is made of 490 amino acids and has a molecular weight of 55,825 Da <ref name="seven">http://www.uniprot.org/uniprot/P10632#sequences</ref>. The peptide chain of Cytochrome P450 2C8 consists of 53% alpha helices and 9% beta sheets<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687032User:Matthew J Lowry/Sandbox 12016-11-14T00:58:04Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="twelve">https://www3.rcsb.org/ligand/MTK</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
===LTB4 Pathway===<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687031User:Matthew J Lowry/Sandbox 12016-11-14T00:56:56Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="twelve">https://www3.rcsb.org/ligand/MTK</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
===5-lipoxygenase Pathway===<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687028User:Matthew J Lowry/Sandbox 12016-11-14T00:52:33Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="twelve">https://www3.rcsb.org/ligand/MTK</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>. It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1)<ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687026User:Matthew J Lowry/Sandbox 12016-11-14T00:51:27Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="twelve">https://www3.rcsb.org/ligand/MTK</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
== Mechanism ==<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687025User:Matthew J Lowry/Sandbox 12016-11-14T00:35:48Z<p>Matthew J Lowry: </p>
<hr />
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You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="twelve">https://www3.rcsb.org/ligand/MTK</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>.It accomplishes this by preventing the binding of receptors to a receptor site involved in the 5-lipoxygenase pathway, or more commonly known as the leukotriene cascade. Leukotrienes are better known for their role in producing inflammation, hyper responsiveness, bronchoconstriction, and increased smooth muscle contraction of the airways; they are able to produce these effects by binding to the cysteinyl leukotriene 1 receptor (CysLT1) . <ref name=”sixteen”>Nayak, A. (2004). A review of montelukast in the treatment of asthma and allergic rhinitis. Expert Opinion on Pharmacotherapy, 5:3, 679-686. doi:10.1517/14656566.5.3.679</ref>.<br />
<br />
All leukotrienes involved in the 5-lipoxygenase pathway are synthesized from the fatty acid arachidonic acid<ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.; this acid is converted into the intermediate 5-hydroperoxyeicosatetraenioc acid (5-HPETE) by 5-lipoxygenase, and then 5-lipoxygenase quickly converts this into leukotriene A4 (LTA4) <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.LTA4 is a very unstable leukotriene and quickly follows one of two pathways: either its epoxide hydrolase catalyzes the conversion of LTA4 into LTB4, or LTC4 synthase converts it into LTC4 <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Each of these leukotrienes precedes their own pathway with LTC4 continuing the cascade to produce subsequent leukotrienes D4 and E4.<br />
<br />
Once synthesized in the cytosol of cells within lung tissue, LTC4 is carried by a transmembrane transporter to the extracellular space where it initiates the production of LTD4 and LTE4; leukotrienes C4 and D4 have equal ability to stimulate smooth muscle constriction in the airway, while E4 is not as strong of a muscle constrictor <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>. Each of these leukotrienes can bind to a CysLT receptor producing symptoms associated with asthma and also leading to increased edema formation, mucus secretion, and a decrease in mucus clearance <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>. Montelukast acts as an antagonist by blocking the leukotrienes from binding at the CysLT receptor therefore, preventing the previously discussed symptoms from occurring; it is easy to think of Montelukast as a key that fits into a lock, but does not turn it. <br />
<br />
Less information is known about the specifics of how Montelukast may affect the LTB4 pathway; once LTB4 is synthesized from arachidonic acid it is also carried to the extracellular space by a transmembrane transporter; once in the extracellular space it binds to the B leukotriene receptor, known as BLT <ref name=”seventeen”>Drazen, J., Elliot, I., & O’Byrne, P. (1999). Treatment of Asthma with Drugs Modifying the Leukotriene Pathway. The New England Journal of Medicine, 340, 197-206. doi:10.1056/NEJM199901213400306</ref>.This leukotriene is a strong neutrophil-chemo-attracting compound that can cause neutrophilic adhesion, mucus generation, and can aid in increasing inflammation seen during asthma <ref name=”eighteen”>Wenzel, S.E. (1997). Arachidonic Acid Metabolites: Mediators of Inflammation in Asthma. Pharmacotherapy, 17, 3S-12S. doi:10.1002/j.1875-9114.1997tbo3696.x</ref>.It is hypothesized that Montelukast may inhibit 5-lipooxygenase in neutrophils, monocytes, and macrophages possibly preventing the production of LTB4 <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.This mechanism for Montelukast would also be distinct from the mechanism used in the cascade involving leukotriene’s C4, D4, and E4. It is also thought that the amount of Montelukast needed to prevent production of LTB4 would need to be greater than that needed to prevent the CysLT cascade <ref name=”nineteen”>Tintinger, G., Feldman, C., Theron, A., and Anderson, R. (2010) Montelukast:more than a cysteinyl leukotriene receptor antagonist? The Scientific World Journal, 10, 2403-2413. doi:10.1100/tsw.2010.229.</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687024User:Matthew J Lowry/Sandbox 12016-11-14T00:27:14Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="twelve">https://www3.rcsb.org/ligand/MTK</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
== Mechanism ==<br />
Montelukast is a leukotriene receptor antagonist that uses a very specific dual mechanism of action where it acts as both a bronchodilator and an anti-inflammatory<ref name=“fifteen”>Diamant, Z., Mantzouranis, E., & Bjermer, L. (2009). Montelukast in the treatment of asthma and beyond. Expert Reviews, 5, 639-658. doi:10.1586/eci.09.62</ref>.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687023User:Matthew J Lowry/Sandbox 12016-11-14T00:17:05Z<p>Matthew J Lowry: </p>
<hr />
<div>This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="twelve">https://www3.rcsb.org/ligand/MTK</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
== Mechanism ==<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687022User:Matthew J Lowry/Sandbox 12016-11-14T00:14:59Z<p>Matthew J Lowry: </p>
<hr />
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You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="three">https://www3.rcsb.org/ligand/MTK</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
== Mechanism ==<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2687021User:Matthew J Lowry/Sandbox 12016-11-14T00:01:46Z<p>Matthew J Lowry: </p>
<hr />
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You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
Montelukast has the chemical formula of C<sub>35</sub>H<sub>36</sub>ClNO<sub>3</sub>S with a molecular weight of 586.187 Da <ref name="one">https://www3.rcsb.org/ligand/MTK</ref>.<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
== Mechanism ==<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2686972User:Matthew J Lowry/Sandbox 12016-11-13T04:36:30Z<p>Matthew J Lowry: </p>
<hr />
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You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
== Mechanism ==<br />
<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2686719User:Matthew J Lowry/Sandbox 12016-11-06T23:37:55Z<p>Matthew J Lowry: </p>
<hr />
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<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
== Mechanism ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2686704User:Matthew J Lowry/Sandbox 12016-11-04T20:20:26Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<Structure load='2nni' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><br />
== Mechanism ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2686703User:Matthew J Lowry/Sandbox 12016-11-04T20:18:58Z<p>Matthew J Lowry: </p>
<hr />
<div>==Montelukast==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Mechanism ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=File:Fileformat%3Dsdf%26get3d%3Dtrue.png&diff=2683660File:Fileformat=sdf&get3d=true.png2016-10-25T01:22:17Z<p>Matthew J Lowry: </p>
<hr />
<div></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=File:Montelukast_fileformat%3Dsdf%26get3d%3Dtrue.jpg&diff=2683659File:Montelukast fileformat=sdf&get3d=true.jpg2016-10-25T01:12:37Z<p>Matthew J Lowry: </p>
<hr />
<div></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2683658User:Matthew J Lowry/Sandbox 12016-10-25T00:19:04Z<p>Matthew J Lowry: </p>
<hr />
<div>==Your Heading Here (maybe something like 'Structure')== 2<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
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== Disease ==<br />
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== Relevance ==<br />
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== Structural highlights ==<br />
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== Mechanism ==<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowryhttps://proteopedia.org/index.php?title=User:Matthew_J_Lowry/Sandbox_1&diff=2683657User:Matthew J Lowry/Sandbox 12016-10-25T00:15:38Z<p>Matthew J Lowry: New page: ==Your Heading Here (maybe something like 'Structure')== 2 <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> This is a default text for y...</p>
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<div>==Your Heading Here (maybe something like 'Structure')== 2<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''Matthew J Lowry/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
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== Function ==<br />
Hi<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Matthew J Lowry