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J Am Chem Soc. 2011 Nov 16;133(45):18194-201. doi: 10.1021/ja204036t. Epub 2011 Oct 24.

Mechanism-based inactivation by aromatization of the transaminase BioA involved in biotin biosynthesis in Mycobaterium tuberculosis.

Author information

1
Academic Health Center, University of Minnesota, Minnesota 55455, United States.

Abstract

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'-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 Å 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.

PMID:
21988601
PMCID:
PMC3222238
DOI:
10.1021/ja204036t
[Indexed for MEDLINE]
Free PMC Article

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