Sandbox Reserved 918: Difference between revisions

'''Dipeptidyl Peptidase IV''' (commonly abbreviated as '''DPP IV''') 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 making it a prime candidate for medicinal and pharmaceutical research. 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 eventually 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]), breaking  N-terminal Xaa-Pro bonds (though it can also catalyze alanine 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] of their respective proteins. Also, DPP IV 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 has no known significance as of yet, DPP IV and its ability to catalyze N-terminal prolines gives it a unique specificity and target for pharmaceutical companies to take advantage of. <ref name="regpeps">PMID: 10588446</ref>

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/1'>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 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 and there is no known reason as to why it occurs. 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"/>

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 well-studied protein because of its potential as a 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 rapidly (the half-lives of GLP-1 and GIP are less than two minutes). <ref> PMID: 17160910</ref> DPP IV inhibitors prevent DPP IV from inactivating GLP-1 and GIP, which results in improved glucose tolerance and 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/2'>Sitagliptin</scene>, also known as Januvia, is a DPP IV inhibitor that's well on its way to being approved for use in a plethora of countries. When given to control subjects, Sitagliptin increases plasma concentrations of GLP-1. Sitagliptin might be used in the future to help manage type II diabetes in combination with [http://www.drugs.com/metformin.html metformin]. <ref> PMID: 17160910</ref>