Catalytic properties and inhibition of proline-specific dipeptidyl peptidases II, IV and VII

Abstract

There is currently intense interest in the emerging group of proline-specific dipeptidases, and their roles in the regulation of biological processes. Dipeptidyl peptidase IV (DPP-IV) is involved in glucose metabolism by contributing to the regulation of glucagon family peptides and has emerged as a potential target for the treatment of metabolic diseases. Two other proline-specific dipeptidases, DPP-VII (also known as quiescent cell proline dipeptidase) and DPP-II, have unknown functions and have recently been suggested to be identical proteases based on a sequence comparison of human DPP-VII and rat DPP-II (78% identity) [Araki, Li, Yamamoto, Haneda, Nishi, Kikkawa and Ohkubo (2001) J. Biochem. 129, 279-288; Fukasawa, Fukasawa, Higaki, Shiina, Ohno, Ito, Otogoto and Ota (2001) Biochem. J. 353, 283-290]. To facilitate the identification of selective substrates and inhibitors for these enzymes, a complete biochemical profile of these enzymes was obtained. The pH profiles, substrate specificities as determined by positional scanning, Michaelis-Menten constants and inhibition profiles for DPP-VII and DPP-II were shown to be virtually identical, strongly supporting the hypothesis that they are the same protease. In addition, substrate specificities, catalytic constants and IC(50) values were shown to be markedly different from those of DPP-IV. Selective DPP-IV and DPP-VII substrates were identified and they can be used to design selective inhibitors and probe further into the biology of these enzymes.

Degradation of Incretins and Modulation of Blood Glucose Levels by Periodontopathic Bacterial Dipeptidyl Peptidase 4

“…Together with the present and previous observations of PgDPP4, including the kinetic parameters of enzymatic reactions, optimal pH, inhibitor profiles, and substrate preference for Pro and less for Ala (15,18,31), our results led us to conclude that the enzymatic properties of bacterial DPP4 substantially resemble those of the human entity (28,38). In fact, the present findings revealed release of the N-terminal dipeptide from the incretin peptides GLP-1 and GIP by bacterial DPP4.…”

Cathepsin H Is an Additional Convertase of Pro-granzyme B

“…Other than CatC, two proteases that fit these criteria are DPPII and CatH. DPPII is a serine dipeptidase with a strong preference for Pro at the P1 residue, making it unlikely to activate proGrB, as the dipeptide typically cleaved from proGrB is Gly-Glu (21,22). CatH is the only other known cathepsin with aminopeptidase activity and, as a monopeptidase, would have to sequentially remove the two amino acids of the proGrB pro-dipeptide.…”

Current and prospective applications of non-proteinogenic amino acids in profiling of proteases substrate specificity

“…This approach resulted in the selection of ABPs for granzyme A and B that are very specifi c toward proteases investigated in cell-based experiments (Mahrus and Craik , 2005 ). The application of PS-SCL libraries aided in the discovery of differences between closely related proline-specifi c dipeptidases (DPP-II, -IV, and -VII), and this information was employed for drug design of dipeptidyl peptidase IV, involved diabetes type II (Leiting et al , 2003 ). Substrate specifi city data obtained for both proteinogenic and non-proteinogenic amino acids were also used by Drag and colleagues to design optimal phosphonate inhibitors of human and pig APN Grzywa et al , 2010 ).…”