Mechanism of Gly-Pro-pNA cleavage catalyzed by dipeptidyl peptidase-IV and its inhibition by saxagliptin (BMS-477118)
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- 作者：Young B. Kim ; Lisa M. Kopcho ; Mark S. Kirby ; Lawrence G. Hamann ; Carolyn A. Weigelt ; William J. Metzler and Jovita Marcinkeviciene
- 关键词：Serine protease ; Human DPP-IV ; Diabetes ; GLP-1 ; Mechanism of inhibition ; Dipeptide cleavage ; Saxagliptin ; Covalent intermediate
- 刊名：Archives of Biochemistry and Biophysics
- 出版年：2006
- 出版时间：1 January 2006
- 年：2006
- 卷：445
- 期：1
- 页码：9-18
- 全文大小：243 K
文摘
Dipeptidyl peptidase-IV (DPP-IV) is a serine protease with a signature Asp-His-Ser motif at the active site. Our pH data suggest that Gly-Pro-pNA cleavage catalyzed by DPP-IV is facilitated by an ionization of a residue with a pK of 7.2 ± 0.1. By analogy to other serine proteases this pK is suggestive of His-Asp assisted Ser addition to the P1 carbonyl carbon of the substrate to form a tetrahedral intermediate. Solvent kinetic isotope effect studies yielded a D2Okcat/Km