3tft

Publication Abstract from PubMed

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 A 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.

Mechanism-based Inactivation by Aromatization of the Transaminase BioA Involved in Biotin Biosynthesis in Mycobaterium tuberculosis.,Shi C, Geders TW, Park SW, Wilson DJ, Boshoff HI, Abayomi O, Barry CE, Schnappinger D, Finzel BC, Aldrich CC J Am Chem Soc. 2011 Nov 16;133(45):18194-201. Epub 2011 Oct 24. PMID:21988601^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.