Sandbox Reserved 918: Difference between revisions
No edit summary |
No edit summary |
||
| (33 intermediate revisions by 2 users not shown) | |||
| Line 11: | Line 11: | ||
'''Dipeptidyl Peptidase IV''' (commonly abbreviated as '''DPP IV''' or '''CD26''') is a regulatory [http://en.wikipedia.org/wiki/Protease protease] and binding [http://en.wikipedia.org/wiki/Glycoprotein glycoprotein] that carries out numerous functions in humans. DPP IV, discovered by V.K. Hopsu-Havu and G.G. Glenner in homogenized rat liver tissue<ref name="regpeps">PMID: 10588446</ref>, was originally believed to serve a specific role in breaking [http://en.wikipedia.org/wiki/2-Naphthylamine 2-Naphthylamine] off of [http://brenda-enzymes.org/php/ligand_flatfile.php4?brenda_ligand_id=228740 Gly-Pro-2-napthylamide], hence its original name glycylproline napthylamidase. However, further research into the specificity of DPP IV showed that it serves a more generic function as a [http://en.wikipedia.org/wiki/Hydrolase hydrolase] (a serine [http://en.wikipedia.org/wiki/Exopeptidase exopeptidase]), primarily cleaving N-terminal Xaa-Pro bonds, but also capable of cleaving N-terminal Xaa-Ala bonds. DPP IV is the founding member of the DPP-IV and/or structure homologue (DASH) family, who all share this serine protease catalysis of post-proline peptide bonds. <ref> PMID: 16186403</ref> These penultimate [http://en.wikipedia.org/wiki/Proline prolines] of the [http://en.wikipedia.org/wiki/N-terminus N-terminus] are known for their ability to resist attacks from most proteases and also induce a [http://en.wikipedia.org/wiki/Conformational_change conformational change] in their respective proteins, making DPP IV a unique protease for its ability to cleave this site.<ref name="Gorrell"/> | '''Dipeptidyl Peptidase IV''' (commonly abbreviated as '''DPP IV''' or '''CD26''') is a regulatory [http://en.wikipedia.org/wiki/Protease protease] and binding [http://en.wikipedia.org/wiki/Glycoprotein glycoprotein] that carries out numerous functions in humans. DPP IV, discovered by V.K. Hopsu-Havu and G.G. Glenner in homogenized rat liver tissue<ref name="regpeps">PMID: 10588446</ref>, was originally believed to serve a specific role in breaking [http://en.wikipedia.org/wiki/2-Naphthylamine 2-Naphthylamine] off of [http://brenda-enzymes.org/php/ligand_flatfile.php4?brenda_ligand_id=228740 Gly-Pro-2-napthylamide], hence its original name glycylproline napthylamidase. However, further research into the specificity of DPP IV showed that it serves a more generic function as a [http://en.wikipedia.org/wiki/Hydrolase hydrolase] (a serine [http://en.wikipedia.org/wiki/Exopeptidase exopeptidase]), primarily cleaving N-terminal Xaa-Pro bonds, but also capable of cleaving N-terminal Xaa-Ala bonds. DPP IV is the founding member of the DPP-IV and/or structure homologue (DASH) family, who all share this serine protease catalysis of post-proline peptide bonds. <ref> PMID: 16186403</ref> These penultimate [http://en.wikipedia.org/wiki/Proline prolines] of the [http://en.wikipedia.org/wiki/N-terminus N-terminus] are known for their ability to resist attacks from most proteases and also induce a [http://en.wikipedia.org/wiki/Conformational_change conformational change] in their respective proteins, making DPP IV a unique protease for its ability to cleave this site.<ref name="Gorrell"/> | ||
DPP IV also serves as a binding glycoprotein on the membrane of cells, binding ligands such as [http://en.wikipedia.org/wiki/Adenosine_deaminase adenosine deaminase] with high affinity.<ref name="Gorrell"/> Though this interaction currently has no known significance | DPP IV also serves as a binding glycoprotein on the membrane of cells, binding ligands such as [http://en.wikipedia.org/wiki/Adenosine_deaminase adenosine deaminase] with high affinity.<ref name="Gorrell"/> Though this interaction currently has no known significance, DPP IV and its ability to catalyze N-terminal prolines gives it a unique specificity and target for pharmaceutical companies. <ref name="regpeps">PMID: 10588446</ref> | ||
---- | ---- | ||
| Line 18: | Line 18: | ||
<StructureSection load='1X70' size='350' frame='true' align='right' caption='Biological Dimer of DPP IV' scene='57/573132/1x70_basic_dimer/1'> | <StructureSection load='1X70' size='350' frame='true' align='right' caption='Biological Dimer of DPP IV' scene='57/573132/1x70_basic_dimer/1'> | ||
===Binding Pocket=== | ===Binding Pocket=== | ||
The specificity of the DPP IV for proline from other amino acids can be seen in the <scene name='57/573132/1x70_basic_dimer_bindingpocket/1'>binding pocket</scene> <scene name='57/573132/1x70_basic_dimer_bindingzoomed/2'>(zoomed binding pocket)</scene> where two glutamates, <scene name='57/573132/1x70_glutamates/ | The specificity of the DPP IV for proline from other amino acids can be seen in the <scene name='57/573132/1x70_basic_dimer_bindingpocket/1'>binding pocket</scene> <scene name='57/573132/1x70_basic_dimer_bindingzoomed/2'>(zoomed binding pocket)</scene> where two glutamates, <scene name='57/573132/1x70_glutamates/6'>Glu205-Glu206</scene> orient the substrate allowing only small residues like proline or alanine to fit. The substrate shown here, <scene name='57/573132/1x70_sitagliptin/3'>Sitagliptin</scene>, is a common drug used to inhibit DPP IV. The [http://en.wikipedia.org/wiki/Glutamic_acid glutamates] form a [http://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) salt bridge] with the N-terminus, positioning the substrate so that only two amino acids can fit into position for hydrolysis. <ref name="Gorrell">PMID: 15584901</ref> Examples of DPP IV substrates with alanine or proline at their N-terminus are: | ||
{| class="wikitable" style="text-align:center; width:550px; height:200px;" | {| class="wikitable" style="text-align:center; width:550px; height:200px;" | ||
|+ | |+ | ||
| Line 44: | Line 44: | ||
===Active Site=== | ===Active Site=== | ||
These substrates, along with many others, are cleaved by DPP IV | These substrates, along with many others, are cleaved by DPP IV using an active site containing a [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] composed of <scene name='57/573132/1x70_catalytictriad/3'>Ser630, His740, and Asp708</scene>. This Serine-Histidine-Asparatate motif, best known in the enzyme [http://en.wikipedia.org/wiki/Chymotrypsin chymotrypsin], uses acid-base chemistry to facilitate the binding, cleaving, and release of the given substrate.<ref name="Gorrell"/> The mechanism of the reaction is as follows: | ||
<div style="text-align: left;"> | <div style="text-align: left;"> | ||
# Substrate binds to enzyme and carbonyl carbon is positioned by [http://en.wikipedia.org/wiki/Active_site active site]. | # Substrate binds to enzyme and carbonyl carbon is positioned by [http://en.wikipedia.org/wiki/Active_site active site]. | ||
# Histidine, via hydrogen bond with asparatate, becomes more [http://en.wikipedia.org/wiki/Electronegativity electronegative] and therefore readily accepts the hydrogen from the | # 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 more [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. | ||
| Line 56: | Line 56: | ||
</div> | </div> | ||
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/ | 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/5'>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 oxyanion intermediate, another important function in enzymatic processes. <ref name="Tyrosine">PMID: 15175333</ref> 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. The hydrolase domain and the propeller domain are involved in the dimerization of DPP IV. Residues like <scene name='57/573132/1x70_dimerizationaa/1'>Phe713, Trp734, and Tyr735</scene> provide hydrophobic interactions that are essential for forming the dimer. <ref name="Chien">PMID: 16752891</ref> Though whole domains play key roles in the formation of this dimer, single residues like <scene name='57/573132/1x70_his750/2'>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] interactions 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=== | ||
Though DPP IV's primary function is as a hydrolase, it also serves as a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] glycoprotein on the surface of cells. A specific domain, the <scene name='57/573132/1x70_8bladed/2'>8-bladed β-propeller domain</scene>, works in binding the most well known DPP IV ligand, [http://en.wikipedia.org/wiki/Adenosine_deaminase adenosine deaminase] (or ADA). ADA can bind to either the monomer or dimer of DPP IV because each monomer contains the 8-bladed propeller domain. ADA actually binds to the lower side of this domain, at the fourth and fifth propeller. Adenosine deaminase works to deaminate adenosine into [http://en.wikipedia.org/wiki/Inosine inosine], an important function in [http://en.wikipedia.org/wiki/Purine_metabolism purine metabolism], however it's most important role in humans deals with the immune system. ADA is a well understood enzyme that is highly conserved across numerous species in the body, yet it's binding to DPP IV is not completely understood | Though DPP IV's primary function is as a hydrolase, it also serves as a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] glycoprotein on the surface of cells. A specific domain, the <scene name='57/573132/1x70_8bladed/2'>8-bladed β-propeller domain</scene>, works in binding the most well known DPP IV ligand, [http://en.wikipedia.org/wiki/Adenosine_deaminase adenosine deaminase] (or ADA). The 8-bladed β-propeller of DPP IV is unique among the more common 7-bladed propellers of other leucocyte surface molecules.<ref name="Gorrell"/> ADA can bind to either the monomer or dimer of DPP IV because each monomer contains the 8-bladed propeller domain. ADA actually binds to the lower side of this domain, with three important residues being <scene name='57/573132/1x70_8bladed_lower/2'>Val341, Thr440, and Lys441</scene>, at the fourth and fifth propeller. Adenosine deaminase works to deaminate adenosine into [http://en.wikipedia.org/wiki/Inosine inosine], an important function in [http://en.wikipedia.org/wiki/Purine_metabolism purine metabolism]<ref name="regpeps"/>, however it's most important role in humans deals with the immune system.<ref name="Gorrell"/> ADA is a well understood enzyme that is highly conserved across numerous species in the body<ref name="Gorrell"/>, yet it's binding to DPP IV is not completely understood, especially the biological importance of the interaction. One theory is that binding ADA to the DPP IV glycoprotein inhibits its catalytic function, increasing the concentration of extracellular adenosine which plays a role in [http://en.wikipedia.org/wiki/T_cell T-cell] proliferation. <ref name="Gorrell"/> | ||
</StructureSection> | </StructureSection> | ||
===Medical Relevancy=== | ===Medical Relevancy=== | ||
DPP IV is found in diverse tissue types and is involved in various biological functions. The activity of DPP IV has been studied in fields like immunology, endocrinology, and the biology of cancers. <ref name="Gorrell"/> The ability of DPP IV to inactivate [http://en.wikipedia.org/wiki/Incretin incretins] glucagon-like-peptide-1 (GLP-1) and glucose-dependent [http://www.merriam-webster.com/medical/insulinotropic insulinotropic] polypeptide (GIP) have made it a | DPP IV is found in diverse tissue types and is involved in various biological functions. The activity of DPP IV has been studied in fields like immunology, endocrinology, and the biology of cancers. <ref name="Gorrell"/> The ability of DPP IV to inactivate [http://en.wikipedia.org/wiki/Incretin incretins] glucagon-like-peptide-1 (GLP-1) and glucose-dependent [http://www.merriam-webster.com/medical/insulinotropic insulinotropic] polypeptide (GIP) have made it a potential drug target for the treatment of [http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 Type II Diabetes]. GLP-1 and GIP promote glucose uptake, decrease the gastric emptying rate and inhibit glucagon secretion. These actions are all desired when it comes to treating Type II diabetes, but the problem is that DPP IV inactivates GLP-1 and GIP very rapidly (the half-lives of GLP-1 and GIP are less than two minutes). <ref> PMID: 17160910</ref> [http://en.wikipedia.org/wiki/Dipeptidyl_peptidase-4_inhibitor DPP IV inhibitors] prevent DPP IV from inactivating GLP-1 and GIP, which results in improved glucose tolerance, improved pancreatic islet cell function, and a decrease in blood glucose levels. The decrease in blood glucose is associated with increased levels of active circulating GLP-1 and a reduction of glucagon. <ref> PMID: 12892317</ref> <scene name='57/573132/1x70_sitagliptin/3'>Sitagliptin</scene>, also known as Januvia, is a DPP IV inhibitor that's in the incretin mimetic class. It was approved by the FDA for the treatment of type II diabetes in 2006. When given to control subjects, Sitagliptin increases plasma concentrations of GLP-1. Sitagliptin was approved to be used in combination with [http://en.wikipedia.org/wiki/Metformin metformin] in 2007. <ref> PMID: 17160910</ref> A study done by Williams-Herman et. al showed that initial combination therapy with metformin and sitagliptin resulted in lower blood glucose concentrations at each metformin dose studied than mono therapy of metformin. A majority of the patients in the combination therapy group maintained the desired blood glucose concentration of <7% at the end of the two-year trial period. <ref> PMID: 20415693</ref> This is noteworthy because it's more difficult for people to meet their glycemic goals long term as the disease progresses. Sitagliptin was approved to be administered with [http://en.wikipedia.org/wiki/Sulfonylurea sulfonylureas] in 2008, which are insulin-secreting agents. Combination therapy of these two drugs requires close monitoring and adjustment of the sulfonylurea dose to prevent hypoglycemia <ref name="Scheen"> PMID: 20690781</ref>. Statins, like simvastatin, which help lower cholesterol levels, are also frequently prescribed to patients with Type II diabetes in addition to DPP IV inhibitors like sitagliptin. <ref name="Scheen"/> | ||
===References=== | ===References=== | ||
{{reflist}} | {{reflist}} | ||