Mechanism-based Inactivation by Aromatization of the Transaminase BioA Involved in Biotin Biosynthesis in Mycobaterium tuberculosis
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- 作者：Ce Shi ; Todd W. Geders ; Sae Woong Park ; Daniel J. Wilson ; Helena I. Boshoff ; Orishadipe Abayomi ; Clifton E. Barry ; III ; Dirk Schnappinger ; Barry C. Finzel ; Courtney C. Aldrich
- 刊名：Journal of the American Chemical Society
- 出版年：2011
- 出版时间：November 16, 2011
- 年：2011
- 卷：133
- 期：45
- 页码：18194-18201
- 全文大小：946K
- 年卷期：v.133,no.45(November 16, 2011)
- ISSN：1520-5126
文摘
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 5鈥?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 脜 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.