Mechanism-based Inactivation by Aromatization of the Transaminase BioA Involved in Biotin Biosynthesis in Mycobaterium tuberculosis

被引：32

作者：

Shi, Ce ^{[1
]}

Geders, Todd W. ^{[2
]}

Park, Sae Woong ^{[3
]}

Wilson, Daniel J. ^{[1
]}

Boshoff, Helena I. ^{[4
]}

Abayomi, Orishadipe ^{[4
]}

Barry, Clifton E., III ^{[4
]}

Schnappinger, Dirk ^{[3
]}

Finzel, Barry C. ^{[2
]}

Aldrich, Courtney C. ^{[1
]}

机构：

[1] Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA

[2] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA

[3] Weill Cornell Med Coll, Dept Microbiol & Immunol, New York, NY 10065 USA

[4] NIAID, TB Res Sect, Bethesda, MD 20892 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2011年 / 133卷 / 45期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

AMINOBUTYRIC-ACID AMINOTRANSFERASE; MYCOBACTERIUM-TUBERCULOSIS; ASPARTATE-AMINOTRANSFERASE; AROMATICITY INDEX; INHIBITION; SYNTHASE; AMICLENOMYCIN; ENZYME; SUBSTRATE; PRODUCTS;

D O I：

10.1021/ja204036t

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

BioA catalyzes the second step of biotin biosynthesis, and this enzyme represents a potential target to develop new antitubercular agents. Herein we report the design, synthesis, and biochemical characterization of a mechanism-based inhibitor (1) featuring a 3,6-dihydropyrid-2-one heterocycle that covalently modifies the pyridoxal S'-phosphate (PLP) cofactor of BioA through aromatization. The structure of the PLP adduct was confirmed by MS/MS and X-ray crystallography at 1.94 angstrom resolution. Inactivation of BioA by 1 was time- and concentration-dependent and protected by substrate. We used a conditional knock-down mutant of M. tuberculosis to demonstrate the antitubercular activity of 1 correlated with BioA expression, and these results provide support for the designed mechanism of action.

引用

页码：18194 / 18201

页数：8

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