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

Ce Shi, Todd W. Geders, Sae Woong Park, Daniel Wilson, Helena I. Boshoff, Orishadipe Abayomi, Clifton E. Barry, Dirk Schnappinger, Barry C Finzel, Courtney Aldrich

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)18194-18201
Number of pages8
JournalJournal of the American Chemical Society
Volume133
Issue number45
DOIs
StatePublished - Nov 16 2011

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