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

共 62 条

[61] A continuous fluorescence displacement assay for BioA: An enzyme involved in biotin biosynthesis
Wilson, Daniel J.
Shi, Ce
Duckworth, Benjamin P.
Muretta, Joseph M.
Manjunatha, Ujjini
Sham, Yuk Y.
Thomas, David D.
Aldrich, Courtney C.
[J]. ANALYTICAL BIOCHEMISTRY, 2011, 416 (01) : 27 - 38
[62] Evaluating the Sensitivity of Mycobacterium tuberculosis to Biotin Deprivation Using Regulated Gene Expression
Park, Sae Woong
Klotzsche, Marcus
Wilson, Daniel J.
Boshoff, Helena I.
Eoh, Hyungjin
Manjunatha, Ujjini
Blumenthal, Antje
Rhee, Kyu
Barry, Clifton E., III
Aldrich, Courtney C.
Ehrt, Sabine
Schnappinger, Dirk
[J]. PLOS PATHOGENS, 2011, 7 (09)

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