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

doi:10.1021/ja204036t

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

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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 language	English (US)
Pages (from-to)	18194-18201
Number of pages	8
Journal	Journal of the American Chemical Society
Volume	133
Issue number	45
DOIs	https://doi.org/10.1021/ja204036t
State	Published - Nov 16 2011

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Shi, C., Geders, T. W., Park, S. W., Wilson, D., Boshoff, H. I., Abayomi, O., Barry, C. E., Schnappinger, D., Finzel, B. C., & Aldrich, C. (2011). Mechanism-based inactivation by aromatization of the transaminase BioA involved in biotin biosynthesis in mycobaterium tuberculosis. Journal of the American Chemical Society, 133(45), 18194-18201. https://doi.org/10.1021/ja204036t

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

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 {\AA} 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.",

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AU - Shi, Ce

AU - Geders, Todd W.

AU - Park, Sae Woong

AU - Wilson, Daniel

AU - Boshoff, Helena I.

AU - Abayomi, Orishadipe

AU - Barry, Clifton E.

AU - Schnappinger, Dirk

AU - Finzel, Barry C

AU - Aldrich, Courtney

PY - 2011/11/16

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AB - 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.

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

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