A mechanism of drug action revealed by structural studies of enoyl reductase

被引：218

作者：

Baldock, C

Rafferty, JB

Sedelnikova, SE

Baker, PJ

Stuitje, AR

Slabas, AR

Hawkes, TR

Rice, DW

机构：

[1] UNIV SHEFFIELD,DEPT MOL BIOL & BIOTECHNOL,KREBS INST BIOMOL RES,SHEFFIELD S10 2TN,S YORKSHIRE,ENGLAND

[2] VRIJE UNIV AMSTERDAM,BIOCTR AMSTERDA,INST MOL BIOL STUDIES IMBW,DEPT GENET,NL-1081 HV AMSTERDAM,NETHERLANDS

[3] UNIV DURHAM,DEPT BIOL SCI,DURHAM DH1 3LE,ENGLAND

[4] ZENECA AGROCHEM,JEALOTTS HILL RES STN,DEPT EXPLORATORY PLANT SCI,BRACKNELL RG12 6EY,BERKS,ENGLAND

来源：

SCIENCE | 1996年 / 274卷 / 5295期

关键词：

D O I：

10.1126/science.274.5295.2107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Enoyl reductase (ENR), an enzyme involved in fatty acid biosynthesis, is the target for antibacterial diazaborines and the front-line antituberculosis drug isoniazid. Analysis of the structures of complexes of Escherichia coli ENR with nicotinamide adenine dinucleotide and either thienodiazaborine or benzodiazaborine revealed the formation of a covalent bond between the 2' hydroxyl of the nicotinamide ribose and a boron atom in the drugs to generate a tight, noncovalently bound bisubstrate analog. This analysis has implications for the structure-based design of inhibitors of ENR, and similarities to other oxidoreductases suggest that mimicking this molecular linkage may have generic applications in other areas of medicinal chemistry.

引用

页码：2107 / 2110

页数：4

共 30 条

[1]

[Anonymous], ACTA CRYSTALLOGR D

[2]

BALDOCK C, IN PRESS ACTA CRYSTA

[3] INHA, A GENE ENCODING A TARGET FOR ISONIAZID AND ETHIONAMIDE IN MYCOBACTERIUM-TUBERCULOSIS [J].

BANERJEE, A ;

DUBNAU, E ;

QUEMARD, A ;

BALASUBRAMANIAN, V ;

UM, KS ;

WILSON, T ;

COLLINS, D ;

DELISLE, G ;

JACOBS, WR .

SCIENCE, 1994, 263 (5144) :227-230

[4] SEQUENCES OF THE ENVM GENE AND OF 2 MUTATED ALLELES IN ESCHERICHIA-COLI [J].

BERGLER, H ;

HOGENAUER, G ;

TURNOWSKY, F .

JOURNAL OF GENERAL MICROBIOLOGY, 1992, 138 :2093-2100

[5]

BERGLER H, 1994, J BIOL CHEM, V269, P5493

[6]

BOLIN JT, 1982, J BIOL CHEM, V257, P13650

[7] Mechanism-based inhibition of human steroid 5 alpha-reductase by finasteride: Enzyme-catalyzed formation of NADP-dihydrofinasteride, a potent bisubstrate analog inhibitor [J].

Bull, HG ;

GarciaCalvo, M ;

Andersson, S ;

Baginsky, WF ;

Chan, HK ;

Ellsworth, DE ;

Miller, RR ;

Stearns, RA ;

Bakshi, RK ;

Rasmusson, GH ;

Tolman, RL ;

Myers, RW ;

Kozarich, JW ;

Harris, GS .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1996, 118 (10) :2359-2365

[8] CRYSTAL-STRUCTURES OF ESCHERICHIA-COLI DIHYDROFOLATE-REDUCTASE - THE NADP+ HOLOENZYME AND THE FOLATE-NADP+ TERNARY COMPLEX - SUBSTRATE BINDING AND A MODEL FOR THE TRANSITION-STATE [J].

BYSTROFF, C ;

OATLEY, SJ ;

KRAUT, J .

BIOCHEMISTRY, 1990, 29 (13) :3263-3277

[9]

Cole Stewart T., 1994, Trends in Microbiology, V2, P411, DOI 10.1016/0966-842X(94)90621-1

[10]

Cowtan K., 1994, JOINT CCP4 ESF EACBM, V31, P34

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