Sandbox Reserved 918: Difference between revisions

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/2'>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:

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>