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

作者：Shi Ce; Geders Todd W; Park Sae Woong; Wilson Daniel J; Boshoff Helena I; Abayomi Orishadipe; Barry Clifton E III; Schnappinger Dirk; Finzel Barry C; Aldrich Courtney C^*

来源：Journal of the American Chemical Society, 2011, 133(45): 18194-18201.

DOI：10.1021/ja204036t

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.

• 出版日期2011-11-16