title: 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.
authors.affiliation: Department of Metabolic Disorders, Merck Research Laboratories, Mail code RY50G-236, P.O. Box 2000, Rahway, NJ 07065, USA. barbara_leiting@merck.com
authors.forename: Barbara
authors.initials: B
authors.lastname: Leiting
authors.forename: KellyAnn D
authors.initials: KD
authors.lastname: Pryor
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wu
authors.forename: Frank
authors.initials: F
authors.lastname: Marsilio
authors.forename: Reshma A
authors.initials: RA
authors.lastname: Patel
authors.forename: Charles S
authors.initials: CS
authors.lastname: Craik
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Ellman
authors.forename: Richard T
authors.initials: RT
authors.lastname: Cummings
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
mesh_terms: D001483:Base Sequence; D002384:Catalysis; D003001:Cloning, Molecular; D017931:DNA Primers; D004151:Dipeptides / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010920:Placenta / Q000201:enzymology; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011392:Proline; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D017931:DNA Primers; D004151:Dipeptides; D011994:Recombinant Proteins; D011392:Proline; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100151:dipeptidyl peptidase II; D018819:Dipeptidyl Peptidase 4