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

Clair Baldock; John B. Rafferty; Svetlana E. Sedelnikova; Patrick J. Baker; Antoine R. Stuitje; Antoni R. Slabas; Timothy R. Hawkes; David W. Rice

doi:10.1126/science.274.5295.2107

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

Clair Baldock, John B. Rafferty, Svetlana E. Sedelnikova, Patrick J. Baker, Antoine R. Stuitje, Antoni R. Slabas, Timothy R. Hawkes, David W. Rice

Research output: Contribution to journal › Article › peer-review

Abstract

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 coil 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.

Original language	English
Pages (from-to)	2107-2110
Number of pages	3
Journal	Science
Volume	274
Issue number	5295
DOIs	https://doi.org/10.1126/science.274.5295.2107
Publication status	Published - 20 Dec 1996

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1126/science.274.5295.2107

Cite this

@article{617e676c040c4035bd557af4f98131be,

title = "A mechanism of drug action revealed by structural studies of Enoyl reductase",

abstract = "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 coil 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.",

author = "Clair Baldock and Rafferty, {John B.} and Sedelnikova, {Svetlana E.} and Baker, {Patrick J.} and Stuitje, {Antoine R.} and Slabas, {Antoni R.} and Hawkes, {Timothy R.} and Rice, {David W.}",

year = "1996",

month = dec,

day = "20",

doi = "10.1126/science.274.5295.2107",

language = "English",

volume = "274",

pages = "2107--2110",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science (A A A S)",

number = "5295",

}

TY - JOUR

T1 - A mechanism of drug action revealed by structural studies of Enoyl reductase

AU - Baldock, Clair

AU - Rafferty, John B.

AU - Sedelnikova, Svetlana E.

AU - Baker, Patrick J.

AU - Stuitje, Antoine R.

AU - Slabas, Antoni R.

AU - Hawkes, Timothy R.

AU - Rice, David W.

PY - 1996/12/20

Y1 - 1996/12/20

N2 - 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 coil 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.

AB - 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 coil 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.

U2 - 10.1126/science.274.5295.2107

DO - 10.1126/science.274.5295.2107

M3 - Article

C2 - 8953047

SN - 0036-8075

VL - 274

SP - 2107

EP - 2110

JO - Science

JF - Science

IS - 5295

ER -

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

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this