Sitagliptin: Difference between revisions

Dipeptidyl Peptidase-4 (DPP-4) is an antigenic membrane serine exopeptidase that cleaves proline dipeptides form the N-terminal end of protein substrates. DPP-4 plays a major role in [[Carbohydrate Metabolism|glucose metabolism]] as it is responsible for the degradation of incretins, most notably Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIp). Incretins are a group of gastrointestinal hormones that stimulate insulin biosynthesis and inhibit glucagon secretion after consuming high glucose meals. Since [[Diabetes]] is typically caused by a deficiency in [[insulin]] secretion or by increased hepatic glucose production, preventing incretin degradation is a viable treatment for diabetics. Sitagliptin is a <scene name='Sitagliptin/Dpp4/2'>competitive inhibitor of DPP-4</scene>. By inhibiting DPP-4 and subsequently preventing the enzymatic degradation of GLP-1 and GIP, these incretins are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas, resulting in controlled blood-glucose levels.<ref>PMID:17073841</ref> The active site of DPP-4 consists of a <scene name='Sitagliptin/Hdryo/1'>hydrophobic "S1" pocket</scene> and several <scene name='Sitagliptin/Hbond/1'>hydrogen bonding residues</scene>, ideal for binding terminal dipeptides. Sitagliptin binds to the active site of DPP-4 with great specificity (DPP-4 [[Pharmacokinetics#Inhibitory_Concentration_.28IC50.29|IC₅₀]]: 18 nM vs. >50,000 nM for other DPPs), situating its trifluorophenyl moiety within the S1 hydrophobic pocket, forming four hydrogen bond interactions with residues Tyr 662, Glu 205, & Glu 206, and burying its trifluoro group within a a very tight pocket formed by residues Ser 209 and Arg 358.<ref>PMID:15634008</ref>