Mapping of the active site of rat kidney γ-glutamyl transpeptidase using activated esters and their amide derivatives

被引:17
作者
Castonguay, R [1 ]
Lherbet, C [1 ]
Keillor, JW [1 ]
机构
[1] Univ Montreal, Dept Chim, Montreal, PQ H3C 3J7, Canada
基金
加拿大自然科学与工程研究理事会;
关键词
D O I
10.1016/S0968-0896(02)00165-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The enzyme gamma-glutamyl transpeptidase (GGT), implicated in many physiological processes, catalyses the transfer of a gamma-glutamyl from a donor substrate to an acyl acceptor substrate, usually an amino acid or a peptide. In order to investigate which moieties of the donor substrate are necessary for recognition by GGT, the structure of the well-recognized substrate L-gamma-glutamyl-p-nitroanilide was modified. Several activated esters and their amide derivatives were synthesized and used as substrates. Kinetic (K-m and and V-max) inhibition constants (K-i) were measured and reveal that almost the entire gamma-glutamyl moiety is necessary for recognition in the binding site of the donor substrate. The implied presence of certain complementary amino acids in this substrate binding site will allow the more rational design of various substrate analogues and inhibitors. (C) 2002 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:4185 / 4191
页数:7
相关论文
共 19 条
[1]  
ALLISON RD, 1985, METHOD ENZYMOL, V113, P419
[2]   INTERCONVERSION OF LEUKOTRIENES CATALYZED BY PURIFIED GAMMA-GLUTAMYL-TRANSFERASE TRANSPEPTIDASE - CONCOMITANT FORMATION OF LEUKOTRIENE D4 AND GAMMA-GLUTAMYL-TRANSFERASE AMINO-ACIDS [J].
ANDERSON, ME ;
ALLISON, RD ;
MEISTER, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1982, 79 (04) :1088-1091
[3]   THE DONOR SPECIFICITY AND KINETICS OF THE HYDROLYSIS REACTION OF GAMMA-GLUTAMYL-TRANSFERASE [J].
COOK, ND ;
UPPERTON, KP ;
CHALLIS, BC ;
PETERS, TJ .
BIOCHIMICA ET BIOPHYSICA ACTA, 1987, 914 (03) :240-245
[4]  
Del Bello B, 1999, FASEB J, V13, P69
[5]  
Fersht A., 1985, ENZYME STRUCTURE MEC
[6]  
GAGNON P, 2000, THESIS U MONTREAL
[7]  
GARDELL SJ, 1979, J BIOL CHEM, V254, P4942
[8]  
GASTONGUAY R, 2000, THESIS U MONTREAL
[9]   APOPTOSIS IN HUMAN LYMPHOBLASTOID-CELLS INDUCED BY ACIVICIN, A SPECIFIC GAMMA-GLUTAMYL-TRANSFERASE INHIBITOR [J].
GRABER, R ;
LOSA, GA .
INTERNATIONAL JOURNAL OF CANCER, 1995, 62 (04) :443-448
[10]   SELECTIVE-INHIBITION OF GAMMA-GLUTAMYL-CYCLE ENZYMES BY SUBSTRATE ANALOGS [J].
GRIFFITH, OW ;
MEISTER, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1977, 74 (08) :3330-3334