Sandbox Reserved 918: Difference between revisions
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# Histidine, via hydrogen bond with asparatate, becomes more [http://en.wikipedia.org/wiki/Electronegativity electronegative] and therefore readily accepts the hydrogen from the hydroxyl group on serine, making it [http://en.wikipedia.org/wiki/Nucleophile nucleophilic]. [[Image:Serine_protease_mechanism_by_snellios.png|right|thumb|150px|<font size=".8"><div style="text-align: center;"> General [http://en.wikipedia.org/wiki/File:Serine_protease_mechanism_by_snellios.png arrow pushing mechanism] for serine proteases. </div></font>]] | # Histidine, via hydrogen bond with asparatate, becomes more [http://en.wikipedia.org/wiki/Electronegativity electronegative] and therefore readily accepts the hydrogen from the hydroxyl group on serine, making it [http://en.wikipedia.org/wiki/Nucleophile nucleophilic]. [[Image:Serine_protease_mechanism_by_snellios.png|right|thumb|150px|<font size=".8"><div style="text-align: center;"> General [http://en.wikipedia.org/wiki/File:Serine_protease_mechanism_by_snellios.png arrow pushing mechanism] for serine proteases. </div></font>]] | ||
# The nucleophilic serine attacks the [http://en.wikipedia.org/wiki/Carbonyl carbonyl] carbon, generating a [http://goldbook.iupac.org/T06289.html tetrahedral intermediate] (as seen in the [http://en.wikipedia.org/wiki/Arrow_pushing arrow pushing mechanism]). | # The nucleophilic serine attacks the [http://en.wikipedia.org/wiki/Carbonyl carbonyl] carbon, generating a [http://goldbook.iupac.org/T06289.html tetrahedral intermediate] (as seen in the [http://en.wikipedia.org/wiki/Arrow_pushing arrow pushing mechanism]). | ||
# The peptide bond is cleaved and the electrons from it move to attack the hydrogen on the histidine. This half of the substrate now dissociates, leaving the other half still bound to serine. | # The peptide bond is cleaved and the electrons from it move to attack the hydrogen on the histidine. This half of the substrate now dissociates, leaving the other half still covalently bound to serine. | ||
# Histidine then deprotonates a water molecule, forming a nucleophilic [http://en.wikipedia.org/wiki/Hydroxide hydroxide group] that attacks the serine-bound carbonyl carbon. | # Histidine then deprotonates a water molecule, forming a nucleophilic [http://en.wikipedia.org/wiki/Hydroxide hydroxide group] that attacks the serine-bound carbonyl carbon. | ||
# As the electrons move from the oxygen back down to reform the double bond, serine [http://en.wikipedia.org/wiki/Dissociation_(chemistry) dissociates] as a leaving group and the other half of the substrate dissociates from the enzyme. | # As the electrons move from the oxygen back down to reform the double bond, serine [http://en.wikipedia.org/wiki/Dissociation_(chemistry) dissociates] as a leaving group and the other half of the substrate dissociates from the enzyme. | ||
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In addition to the glutamates holding the substrate in close proximity, and the catalytic triad using acid base chemistry to cleave the peptide bond, there is a tyrosine, <scene name='57/573132/1x70_activesitetyr/3'>Tyr547</scene>, which is depicted in orange and notably only 4.08 [http://en.wikipedia.org/wiki/Angstrom angstroms] away from the substrate, [http://en.wikipedia.org/wiki/Sitagliptin Sitagliptin]. Based off of the crystal structure, this tyrosine is believed to stabilize the tetrahedral intermediate, another important function in enzymatic processes. <ref name="Gorrell"/> The active site in its entirety is considered to contain residues 39-51 and 501-766 and is known as the <scene name='57/573132/1x70_alphabetaprop/1'>α/β-hydrolase domain</scene> | In addition to the glutamates holding the substrate in close proximity, and the catalytic triad using acid base chemistry to cleave the peptide bond, there is a tyrosine, <scene name='57/573132/1x70_activesitetyr/3'>Tyr547</scene>, which is depicted in orange and notably only 4.08 [http://en.wikipedia.org/wiki/Angstrom angstroms] away from the substrate, [http://en.wikipedia.org/wiki/Sitagliptin Sitagliptin]. Based off of the crystal structure, this tyrosine is believed to stabilize the tetrahedral intermediate, another important function in enzymatic processes. <ref name="Gorrell"/> The active site in its entirety is considered to contain residues 39-51 and 501-766 and is known as the <scene name='57/573132/1x70_alphabetaprop/1'>α/β-hydrolase domain</scene> | ||
Lastly, the | Lastly, the <scene name='57/573132/1x70_basic_dimer/1'>homodimerization</scene> (colored by monomer) of DPP IV is critical to the catalytic function. Though whole domains play key roles in the formation of this dimer, single residues like (<scene name='57/573132/1x70_his750/1'>His750</scene>) have also been shown to be key to formation of the dimer. If [http://en.wikipedia.org/wiki/Point_mutation point mutated] to glutamate, the dimer will not form. The [http://en.wikipedia.org/wiki/Ionic_bonding ionic] interaction of the histidine with the opposing chain are changed from electrostatically positive to a repulsive effect thus eliminating the ability to dimerize. <ref name="Gorrell"/> | ||
===Propeller Domain=== | ===Propeller Domain=== | ||
