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 IC50 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.
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April 2003
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Research Article|
April 15 2003
Catalytic properties and inhibition of proline-specific dipeptidyl peptidases II, IV and VII
Barbara LEITING;
Barbara LEITING
1
∗Department of Metabolic Disorders, Merck Research Laboratories, Mail code RY50G-236, P.O. Box 2000, Rahway, NJ 07065, U.S.A.
1To whom correspondence should be addressed (e-mail barbara_leiting@merck.com).
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KellyAnn D. PRYOR;
KellyAnn D. PRYOR
∗Department of Metabolic Disorders, Merck Research Laboratories, Mail code RY50G-236, P.O. Box 2000, Rahway, NJ 07065, U.S.A.
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Joseph K. WU;
Joseph K. WU
∗Department of Metabolic Disorders, Merck Research Laboratories, Mail code RY50G-236, P.O. Box 2000, Rahway, NJ 07065, U.S.A.
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Frank MARSILIO;
Frank MARSILIO
∗Department of Metabolic Disorders, Merck Research Laboratories, Mail code RY50G-236, P.O. Box 2000, Rahway, NJ 07065, U.S.A.
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Reshma A. PATEL;
Reshma A. PATEL
∗Department of Metabolic Disorders, Merck Research Laboratories, Mail code RY50G-236, P.O. Box 2000, Rahway, NJ 07065, U.S.A.
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Charles S. CRAIK;
Charles S. CRAIK
†Department of Pharmaceutical Chemistry, University of California, 513 Parnassus Avenue, San Francisco, CA 94143-0446, U.S.A.
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Jonathan A. ELLMAN;
Jonathan A. ELLMAN
‡Department of Chemistry, University of California, Berkeley, CA 94720, U.S.A.
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Richard T. CUMMINGS;
Richard T. CUMMINGS
∗Department of Metabolic Disorders, Merck Research Laboratories, Mail code RY50G-236, P.O. Box 2000, Rahway, NJ 07065, U.S.A.
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Nancy A. THORNBERRY
Nancy A. THORNBERRY
∗Department of Metabolic Disorders, Merck Research Laboratories, Mail code RY50G-236, P.O. Box 2000, Rahway, NJ 07065, U.S.A.
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Publisher: Portland Press Ltd
Received:
October 21 2002
Revision Received:
January 10 2003
Accepted:
January 15 2003
Accepted Manuscript online:
January 15 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 371 (2): 525–532.
Article history
Received:
October 21 2002
Revision Received:
January 10 2003
Accepted:
January 15 2003
Accepted Manuscript online:
January 15 2003
Citation
Barbara LEITING, KellyAnn D. PRYOR, Joseph K. WU, Frank MARSILIO, Reshma A. PATEL, Charles S. CRAIK, Jonathan A. ELLMAN, Richard T. CUMMINGS, Nancy A. THORNBERRY; Catalytic properties and inhibition of proline-specific dipeptidyl peptidases II, IV and VII. Biochem J 15 April 2003; 371 (2): 525–532. doi: https://doi.org/10.1042/bj20021643
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