https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Stacey+Shantz 2026-09-14T11:59:24Z User contributions MediaWiki 1.43.8 https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1062352 2010-03-30T17:42:21Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='1yr2 at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.&lt;ref name=&quot;Shan2&quot;&gt;PMID:15738423&lt;/ref&gt;<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|left|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages between the domains shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain&lt;ref name=&quot;Besedin&quot;&gt;PMID:12658988&lt;/ref&gt;.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding.&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%).&lt;ref name=&quot;Gass&quot;&gt;PMID:17160352&lt;/ref&gt; The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.&lt;ref name=&quot;Shan2&quot;/&gt;<br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The initial theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter.&lt;ref name=&quot;Shan1&quot;&gt;PMID:15245330&lt;/ref&gt; This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> Another proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on small peptides of less than 30 amino acids.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP].&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> Structural data for ''Myxococcus xanthus'' determined by &lt;ref name=&quot;Shan2&quot;/&gt; shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies.&lt;ref name=&quot;Besedin&quot;/&gt; PEPs have also been linked to several neurological disorders due to high activity in the brain and a proposed role in the degradation of neuropeptides.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating foods containing [http://en.wikipedia.org/wiki/Prolamin prolamins].<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade proline rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this therapy would be to to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.&lt;ref name=&quot;Ehren2&quot;&gt;PMID:19621078&lt;/ref&gt;<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].&lt;ref name=&quot;Ehren1&quot;&gt;PMID:18836204&lt;/ref&gt;<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> ==References==<br /> &lt;References/&gt;</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1062148 2010-03-29T21:10:48Z

<p>Stacey Shantz: /* Celiac Disease */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='1yr2 at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.&lt;ref name=&quot;Shan2&quot;&gt;PMID:15738423&lt;/ref&gt;<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages between the domains shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain&lt;ref name=&quot;Besedin&quot;&gt;PMID:12658988&lt;/ref&gt;.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding.&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%).&lt;ref name=&quot;Gass&quot;&gt;PMID:17160352&lt;/ref&gt; The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.&lt;ref name=&quot;Shan2&quot;/&gt;<br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The initial theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter.&lt;ref name=&quot;Shan1&quot;&gt;PMID:15245330&lt;/ref&gt; This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> Another proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on small peptides of less than 30 amino acids.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP].&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> Structural data for ''Myxococcus xanthus'' determined by &lt;ref name=&quot;Shan2&quot;/&gt; shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies.&lt;ref name=&quot;Besedin&quot;/&gt; PEPs have also been linked to several neurological disorders due to high activity in the brain and a proposed role in the degradation of neuropeptides.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating foods containing [http://en.wikipedia.org/wiki/Prolamin prolamins].<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade proline rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this therapy would be to to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.&lt;ref name=&quot;Ehren2&quot;&gt;PMID:19621078&lt;/ref&gt;<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].&lt;ref name=&quot;Ehren1&quot;&gt;PMID:18836204&lt;/ref&gt;<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> ==References==<br /> &lt;References/&gt;</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1062146 2010-03-29T21:08:16Z

<p>Stacey Shantz: /* Pharmaceutical Possibilities */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='1yr2 at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.&lt;ref name=&quot;Shan2&quot;&gt;PMID:15738423&lt;/ref&gt;<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages between the domains shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain&lt;ref name=&quot;Besedin&quot;&gt;PMID:12658988&lt;/ref&gt;.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding.&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%).&lt;ref name=&quot;Gass&quot;&gt;PMID:17160352&lt;/ref&gt; The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.&lt;ref name=&quot;Shan2&quot;/&gt;<br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The initial theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter.&lt;ref name=&quot;Shan1&quot;&gt;PMID:15245330&lt;/ref&gt; This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> Another proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on small peptides of less than 30 amino acids.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP].&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> Structural data for ''Myxococcus xanthus'' determined by &lt;ref name=&quot;Shan2&quot;/&gt; shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies.&lt;ref name=&quot;Besedin&quot;/&gt; PEPs have also been linked to several neurological disorders due to high activity in the brain and a proposed role in the degradation of neuropeptides.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating foods containing [http://en.wikipedia.org/wiki/Prolamin prolamins].<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade proline rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this therapy would be to to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.&lt;ref name=&quot;Ehren2&quot;&gt;PMID:19621078&lt;/ref&gt;<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].&lt;ref name=&quot;Ehren1&quot;&gt;PMID:19621078&lt;/ref&gt;<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> ==References==<br /> &lt;References/&gt;</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1062142 2010-03-29T21:02:51Z

<p>Stacey Shantz: /* Pharmaceutical Possibilities */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='1yr2 at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.&lt;ref name=&quot;Shan2&quot;&gt;PMID:15738423&lt;/ref&gt;<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages between the domains shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain&lt;ref name=&quot;Besedin&quot;&gt;PMID:12658988&lt;/ref&gt;.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding.&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%).&lt;ref name=&quot;Gass&quot;&gt;PMID:17160352&lt;/ref&gt; The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.&lt;ref name=&quot;Shan2&quot;/&gt;<br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The initial theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter.&lt;ref name=&quot;Shan1&quot;&gt;PMID:15245330&lt;/ref&gt; This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> Another proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on small peptides of less than 30 amino acids.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP].&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> Structural data for ''Myxococcus xanthus'' determined by &lt;ref name=&quot;Shan2&quot;/&gt; shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies.&lt;ref name=&quot;Besedin&quot;/&gt; PEPs have also been linked to several neurological disorders due to high activity in the brain and a proposed role in the degradation of neuropeptides.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].&lt;ref name=&quot;Ehren1&quot;&gt;PMID:19621078&lt;/ref&gt;<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> ==References==<br /> &lt;References/&gt;</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1062141 2010-03-29T20:58:56Z

<p>Stacey Shantz: /* Inhibition */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='1yr2 at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.&lt;ref name=&quot;Shan2&quot;&gt;PMID:15738423&lt;/ref&gt;<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages between the domains shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain&lt;ref name=&quot;Besedin&quot;&gt;PMID:12658988&lt;/ref&gt;.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding.&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%).&lt;ref name=&quot;Gass&quot;&gt;PMID:17160352&lt;/ref&gt; The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.&lt;ref name=&quot;Shan2&quot;/&gt;<br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The initial theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter.&lt;ref name=&quot;Shan1&quot;&gt;PMID:15245330&lt;/ref&gt; This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> Another proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on small peptides of less than 30 amino acids.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP].&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> Structural data for ''Myxococcus xanthus'' determined by &lt;ref name=&quot;Shan2&quot;/&gt; shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies.&lt;ref name=&quot;Besedin&quot;/&gt; PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].&lt;ref name=&quot;Ehren1&quot;&gt;PMID:19621078&lt;/ref&gt;<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> ==References==<br /> &lt;References/&gt;</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1062138 2010-03-29T20:57:35Z

<p>Stacey Shantz: /* Binding Mechanism */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='1yr2 at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.&lt;ref name=&quot;Shan2&quot;&gt;PMID:15738423&lt;/ref&gt;<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages between the domains shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain&lt;ref name=&quot;Besedin&quot;&gt;PMID:12658988&lt;/ref&gt;.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding.&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%).&lt;ref name=&quot;Gass&quot;&gt;PMID:17160352&lt;/ref&gt; The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.&lt;ref name=&quot;Shan2&quot;/&gt;<br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The initial theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter.&lt;ref name=&quot;Shan1&quot;&gt;PMID:15245330&lt;/ref&gt; This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> Another proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on small peptides of less than 30 amino acids.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP].&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies.&lt;ref name=&quot;Besedin&quot;/&gt; PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].&lt;ref name=&quot;Ehren1&quot;&gt;PMID:19621078&lt;/ref&gt;<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> ==References==<br /> &lt;References/&gt;</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1062137 2010-03-29T20:50:34Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='1yr2 at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.&lt;ref name=&quot;Shan2&quot;&gt;PMID:15738423&lt;/ref&gt;<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages between the domains shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain&lt;ref name=&quot;Besedin&quot;&gt;PMID:12658988&lt;/ref&gt;.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding.&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%).&lt;ref name=&quot;Gass&quot;&gt;PMID:17160352&lt;/ref&gt; The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.&lt;ref name=&quot;Shan2&quot;/&gt;<br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The first theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter.&lt;ref name=&quot;Shan1&quot;&gt;PMID:15245330&lt;/ref&gt; This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> A newer proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on peptides of less than 30 residues.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP].&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies.&lt;ref name=&quot;Besedin&quot;/&gt; PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].&lt;ref name=&quot;Ehren1&quot;&gt;PMID:19621078&lt;/ref&gt;<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> ==References==<br /> &lt;References/&gt;</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1062136 2010-03-29T20:49:58Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='1yr2 at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.&lt;ref name=&quot;Shan2&quot;&gt;PMID:15738423&lt;/ref&gt;<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages between the domains shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain&lt;ref name=&quot;Besedin&quot;&gt;PMID:12658988&lt;/ref&gt;.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding.&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%).&lt;ref name=&quot;Gass&quot;&gt;PMID:17160352&lt;/ref&gt; The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.&lt;ref name=&quot;Shan2&quot;/&gt;<br /> <br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The first theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter.&lt;ref name=&quot;Shan1&quot;&gt;PMID:15245330&lt;/ref&gt; This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> A newer proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on peptides of less than 30 residues.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP].&lt;ref name=&quot;Besedin&quot;/&gt;<br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies.&lt;ref name=&quot;Besedin&quot;/&gt; PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides.&lt;ref name=&quot;Gass&quot;/&gt;<br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].&lt;ref name=&quot;Ehren1&quot;&gt;PMID:19621078&lt;/ref&gt;<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> ==References==<br /> &lt;References/&gt;</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1061396 2010-03-26T14:49:45Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='1yr2 at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues [1].<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages between the domains shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain [2].<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding [2].<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%) [3]. The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.<br /> <br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The first theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter [4]. This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> A newer proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge [3].<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on peptides of less than 30 residues.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [1] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [2] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [3] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [4] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1061158 2010-03-26T04:00:19Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues [1].<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages between the domains shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain [2].<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding [2].<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%) [3]. The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.<br /> <br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The first theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter [4]. This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> A newer proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge [3].<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on peptides of less than 30 residues.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [1] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [2] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [3] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [4] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=File:1yr2_ribbon2.png&diff=1061157 2010-03-26T03:57:21Z

<p>Stacey Shantz: uploaded a new version of &quot;Image:1yr2 ribbon2.png&quot;: Image of 1yr2 in ribbon format with linkages between domains highlighted.</p> <hr /> <div>SwissPDB image of 1yr2 structural domains and domain linkages in ribbon form.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1061139 2010-03-26T03:22:24Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues [1].<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain [2].<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding [2].<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%) [3]. The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.<br /> <br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The first theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter [4]. This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> A newer proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge [3].<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on peptides of less than 30 residues.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [1] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [2] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [3] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [4] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1061137 2010-03-26T03:21:58Z

<p>Stacey Shantz: /* Structure */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain [2].<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding [2].<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%) [3]. The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.<br /> <br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The first theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter [4]. This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> A newer proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge [3].<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on peptides of less than 30 residues.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [1] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [2] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [3] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [4] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1061136 2010-03-26T03:21:29Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å [1]' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in green and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain[2].<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding [2].<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%) [3]. The catalytic site contains a catalytic triad of Ser-Asp-His and lies in a cavity near the interface to the β-propeller domain.<br /> <br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The first theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter [4]. This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> A newer proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge [3].<br /> <br /> Both mechanistic binding theories account for the observed activity of PEP as being limited to acting on peptides of less than 30 residues.<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [1] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [2] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [3] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [4] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1061128 2010-03-26T03:03:19Z

<p>Stacey Shantz: /* Binding Mechanism */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding [].<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%) [].<br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The first theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter. This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> A newer proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''Sphingomonas capsulata'' clearly shows the β-propeller in an open configuration connected to the catalytic domain by two peptide strands on the same side of the enzyme forming a hinge [].<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1061125 2010-03-26T02:59:58Z

<p>Stacey Shantz: /* Binding Mechanism */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding [].<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%) [].<br /> <br /> === Binding Mechanism ===<br /> From observed interactions between the β-propeller and catalytic domains several possible substrate binding mechanism have been proposed.<br /> <br /> The first theory of substrate binding was that the substrate would be able to travel through the central channel in the β-propeller domain to the active site. This theory was proved less likely as the central channel is only 4Å wide in its relaxed state compared to the medium length peptides catalyzed by PEP which are 6-12Å in diameter. This theory is still possible as a conformational change could allow the much larger substrate to travel through the β-propeller domain.<br /> <br /> A newer proposed mechanism of substrate binding is that the β-propeller domain acts as a gate to the active site and that the whole domain moves during a conformational change. This theory has gathered support as a structure for the PEP of ''<br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1061118 2010-03-26T02:48:42Z

<p>Stacey Shantz: /* Catalytic Domain */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding [].<br /> <br /> === Catalytic Domain ===<br /> The catalytic domain mainly consists of an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold] which is a series of 8 strands connected by helices in a fold common to many enzymes. The catalytic domain was found to be much more conserved than the β-propeller domain(~50%) [].<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1061101 2010-03-26T02:25:26Z

<p>Stacey Shantz: /* β-Propeller Domain */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a major role in substrate binding [].<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1061100 2010-03-26T02:24:34Z

<p>Stacey Shantz: /* Structure */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state. It has been found that this domain is roughly 2% conserved indicating that it likely doesnt play a large role in substrate binding []. <br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1061094 2010-03-26T02:12:03Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|300x300px|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state.<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060984 2010-03-25T22:47:01Z

<p>Stacey Shantz: /* Neurological Disorders */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state.<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> As well as having a proposed role in the degradation of neuropeptides PEPs have also been linked to several specific neurological disorders. It has been found that patients suffering from depression had decreased PEP activity and those suffering from psychosis have increased PEP activity showing the importance of maintaining a balanced level of PEP activity in the brain. PEP inhibitors are a current point of research in hopes of finding ways to balance brain PEP activity.<br /> <br /> == References ==<br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060975 2010-03-25T22:28:55Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state.<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> Initial classification of prolyl endopeptidases as [http://en.wikipedia.org/wiki/Serine_protease serine proteases] was due to their inhibition by [http://en.wikipedia.org/wiki/Diisopropyl_fluorophosphate DFP]. <br /> <br /> Structural data for ''Myxococcus xanthus'' PEP in [X] shows that a bound inhibitor causes the β-propeller domain to become tightly associated with the catalytic domain and subsequently block the active site to inhibit catalysis.<br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==<br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060962 2010-03-25T22:20:30Z

<p>Stacey Shantz: /* β-Propeller Domain */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets with connecting peptide strands which form a tight lid over the active site located on the catalytic domain. The β-propeller domain is cylindrical in structure and contains a very tight central channel through its core that is roughly 4Å in diameter in the resting state.<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==<br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060946 2010-03-25T22:01:03Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets forming a tight lid over the active site located on the catalytic domain. This propeller domain is proposed to be very important in allowing the binding of subtrate as well as the inability of PEPs to hydrolyze peptide chains longer than 30 amino acids.<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> <br /> == Function ==<br /> Although the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] [5].<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==<br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.<br /> <br /> [5] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060944 2010-03-25T21:59:14Z

<p>Stacey Shantz: /* Function */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets forming a tight lid over the active site located on the catalytic domain. This propeller domain is proposed to be very important in allowing the binding of subtrate as well as the inability of PEPs to hydrolyze peptide chains longer than 30 amino acids.<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> <br /> == Function ==<br /> Althought the physiological function of PEPs are not entirely understood there are several proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla CITE has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==<br /> [] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.<br /> <br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060941 2010-03-25T21:57:27Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets forming a tight lid over the active site located on the catalytic domain. This propeller domain is proposed to be very important in allowing the binding of subtrate as well as the inability of PEPs to hydrolyze peptide chains longer than 30 amino acids.<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> <br /> == Function ==<br /> Althought the physiological function of PEPs are not entirely understood there are several main proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many other peptidases cannot cleave proline residues.<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla CITE has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==<br /> [] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.<br /> <br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060936 2010-03-25T21:55:42Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets forming a tight lid over the active site located on the catalytic domain. This propeller domain is proposed to be very important in allowing the binding of subtrate as well as the inability of PEPs to hydrolyze peptide chains longer than 30 amino acids.<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> Althought the physiological function of PEPs are not entirely understood there are several main proposed functions based on their activity and localization. <br /> <br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> PEPs may also have a more general role in the degradation of peptides as PEP activity is found in most major organs and many peptidases cannot cleave proline residues.<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla CITE has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==<br /> [] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.<br /> <br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060927 2010-03-25T21:36:43Z

<p>Stacey Shantz: /* References */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets forming a tight lid over the active site located on the catalytic domain. This propeller domain is proposed to be very important in allowing the binding of subtrate as well as the inability of PEPs to hydrolyze peptide chains longer than 30 amino acids.<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla CITE has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==<br /> [] Ehren J, Govindarajan S, Morón B, Minshull J, Khosla C. Protein engineering of improved prolyl endopeptidases for celiac sprue therapy. Protein Eng. Des. Sel. 2008 Oct 4; 21(12)699-707.<br /> <br /> [] Besedin DV, Rudenskaya GN. Proline-Specific Endopeptidases. Russ. J. Bioorg. Chem. 2002 Feb 28; 29(1)1-17.<br /> <br /> [] Gass J, Khosla C. Biomedicine and Diseases: Review Prolyl Endopeptidases. Cell. Mol. Life Sci. 2007; 64 345-55.<br /> <br /> [] Shan L, Mathews II, Khosla C. Structural and mechanistic analysis of two prolyl endopeptidases: Role of interdomain dynamics in catalysis and specificity. PNAS. 2005 Mar 8; 102(10)3599-604.<br /> <br /> [] Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue. Biochem. J. 2008; 383 311-18.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060914 2010-03-25T20:59:16Z

<p>Stacey Shantz: /* Celiac Disease */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets forming a tight lid over the active site located on the catalytic domain. This propeller domain is proposed to be very important in allowing the binding of subtrate as well as the inability of PEPs to hydrolyze peptide chains longer than 30 amino acids.<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> Research by Ehren, Govindarajan, Morón, Minshull, and Khosla CITE has shown the ability to engineer the prolyl endopeptidase of ''Sphingomonas capsulata'' to increase the activity of this PEP under simulated gastric conditions showing the relevance of PEPs as a potential therapeutic agent for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease].<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060912 2010-03-25T20:53:15Z

<p>Stacey Shantz: /* β-Propeller Domain */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets forming a tight lid over the active site located on the catalytic domain. This propeller domain is proposed to be very important in allowing the binding of subtrate as well as the inability of PEPs to hydrolyze peptide chains longer than 30 amino acids.<br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060906 2010-03-25T20:32:28Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> The β-propeller domain is made up of repeated antiparallel β-sheets forming a tight lid over the active site located on the catalytic domain. This propelleer domain is thought to be very important in the binding of subtrate as well as the inability of PEPs to hydrolyze peptide chains longer than 30 amino acids.<br /> <br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060904 2010-03-25T20:27:40Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic(bottom) and β-propeller domains(top) with peptide linkages shown in red and blue]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060903 2010-03-25T20:26:21Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the C-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic( and β-propeller domains(]]<br /> Prolyl endopeptidases are relatively large enzymes(75 kDa) and contain two distinct domains: a catalytic domain and a β-propeller domain.<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060902 2010-03-25T20:23:16Z

<p>Stacey Shantz: /* Celiac Disease */</p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> === Binding Mechanism ===<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic( and β-propeller domains(]]<br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine once the acidity is decreased.<br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060898 2010-03-25T20:19:01Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> === Binding Mechanism ===<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic( and β-propeller domains(]]<br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of certain proteins such as gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins] that are rich in proline residues and known to be resistant to many proteases.<br /> <br /> There is currently no cure for [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease] and the main treatment is to simply avoid eating [http://en.wikipedia.org/wiki/Prolamin prolamin] containing foods.<br /> <br /> Prolyl endopeptidases are a promising therapeutic agent due to their ability to degrade the protein rich [http://en.wikipedia.org/wiki/Prolamin prolamins] and inhibit the inflammatory reaction. An early idea for treatment is to orally administer certain microbial PEPs which could directly degrade [http://en.wikipedia.org/wiki/Prolamin prolamins] in the intestine and reduce the auto-immune response. The key for this possibility is to be able to protect the PEPs from being degraded by gastric acids while allowing them to be able to be functional in the small intestine.<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060896 2010-03-25T20:10:31Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> === Binding Mechanism ===<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic( and β-propeller domains(]]<br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to the consumption of gluten and other [http://en.wikipedia.org/wiki/Prolamin prolamins] found in wheat and wheat subspecies. The symptoms of CD are due to an auto-immune inflammatory reaction that occurs in the small intestine due to [http://en.wikipedia.org/wiki/Prolamin prolamins]. [http://en.wikipedia.org/wiki/Prolamin Prolamins] are rich in proline residues and known to be resistant to many proteases<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060892 2010-03-25T20:05:48Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> === Binding Mechanism ===<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic( and β-propeller domains(]]<br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> [http://en.wikipedia.org/wiki/Coeliac_disease Celiac Disease](CD) is a genetic disorder marked by diarrhea, fatigue, weight loss, and villous atrophy due to consuming gluten and other prolamins. <br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060891 2010-03-25T20:03:28Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides](vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptides] which supports PEPs being involved in the degradation of [http://en.wikipedia.org/wiki/Neuropeptides neuropeptide] transmitters.<br /> <br /> === Binding Mechanism ===<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic( and β-propeller domains(]]<br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060890 2010-03-25T20:02:29Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degredation of neuropeptides due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several neuropeptides(vasopressin, β-endorphin, thyroliberin). The distribution of PEP in the brain has been found to be similar to that of certain receptors of neuropeptides which supports PEPs being involved in the degradation of neuropeptide transmitters.<br /> <br /> === Binding Mechanism ===<br /> [[Image:1yr2_ribbon2.png|thumb|alt=Alt text|Catalytic( and β-propeller domains(]]<br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> Both human and microbial PEP have been the focus of research into their viability as therapeutic agents for several diseases. The ability of PEPs to cleave internal proline peptide bonds is of interest in the treatment of Celiac Disease which is caused by a reaction to gluten, a proline rich protein found in wheat and wheat subspecies. CITE BESEDIN PEPs have also been linked to several neurological disorders due to high activity in the brain and proposed role in the degradation of neuropeptides. <br /> <br /> === Celiac Disease ===<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=File:1yr2_ribbon2.png&diff=1060874 2010-03-25T19:24:30Z

<p>Stacey Shantz: SwissPDB image of 1yr2 structural domains and domain linkages in ribbon form.</p> <hr /> <div>SwissPDB image of 1yr2 structural domains and domain linkages in ribbon form.</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060861 2010-03-25T18:15:21Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degredation of neuropeptides due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several neuropeptides(vasopressin, β-endorphin, thyroliberin).<br /> <br /> === Binding Mechanism ===<br /> [[Image:1yr2_hing.png|thumb|alt=Alt text|Peptide chains connecting the catalytic and β-propeller domains]]<br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> <br /> === Celiac Disease ===<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060860 2010-03-25T18:11:59Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata at 1.80Å' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degredation of neuropeptides due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several neuropeptides(vasopressin, β-endorphin, thyroliberin).<br /> <br /> === Binding Mechanism ===<br /> [[Image:1yr2_hing.png]]<br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> <br /> === Celiac Disease ===<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060668 2010-03-24T20:02:44Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> PEPs are thought to have a role in the degredation of neuropeptides due to the high concentration of PEPs in the brain and the fact that PEPs have been shown to degrade several neuropeptides(vasopressin, β-endorphin, thyroliberin).<br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> <br /> === Celiac Disease ===<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060666 2010-03-24T19:56:21Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues.<br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> <br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> <br /> === Celiac Disease ===<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060665 2010-03-24T19:55:33Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues. Proline residues are often stable to proteases due to their unique structure and even PEPs require a trans peptide bond preceeding proline for hydrolysis to occur. <br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> <br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> <br /> === Celiac Disease ===<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060663 2010-03-24T19:51:02Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases which cleave peptide bonds on the c-terminal side of internal proline residues. <br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> === Domain Interface ===<br /> <br /> <br /> == Function ==<br /> <br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> <br /> === Celiac Disease ===<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060659 2010-03-24T19:39:01Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases known to have a role in the degradation of neuropeptides and peptide hormones. PEPs are large enzymes (75kDa) that cleave after proline residues in the peptide chain. <br /> <br /> == Structure ==<br /> <br /> === β-Propeller Domain ===<br /> <br /> <br /> === Catalytic Domain ===<br /> <br /> <br /> == Function ==<br /> <br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> <br /> === Celiac Disease ===<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060658 2010-03-24T19:37:36Z

<p>Stacey Shantz: </p> <hr /> <div>&lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata' /&gt;<br /> <br /> Prolyl endopeptidases (PEPs) are a class of serine proteases known to have a role in the degradation of neuropeptides and peptide hormones. PEPs are large enzymes (75kDa) that cleave after proline residues in the peptide chain. <br /> <br /> == Structure ==<br /> <br /> <br /> <br /> <br /> <br /> <br /> == Function ==<br /> <br /> <br /> === Binding Mechanism ===<br /> <br /> <br /> === Inhibition ===<br /> <br /> <br /> == Pharmaceutical Possibilities ==<br /> <br /> === Celiac Disease ===<br /> <br /> <br /> === Neurological Disorders ===<br /> <br /> <br /> <br /> == References ==</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060648 2010-03-24T18:54:59Z

<p>Stacey Shantz: </p> <hr /> <div>== Prolyl Endopeptidases ==<br /> <br /> &lt;applet load='1yr2' size='300' frame='true' align='right' caption='Prolyl endopeptidase of Sphingomonas capsulata' /&gt;</div>

Stacey Shantz https://proteopedia.org/index.php?title=Prolyl_Endopeptidase&diff=1060637 2010-03-24T17:14:42Z

<p>Stacey Shantz: </p> <hr /> <div>== Prolyl Endopeptidases ==<br /> <br /> &lt;applet load='1yr2' size='300' frame='true' align='right' caption='Insert caption here' /&gt;<br /> <br /> hello</div>

Stacey Shantz