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 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.
authors: Academic Health Center, University of Minnesota, Minnesota 55455, United States.
authors: Ce
authors: C
authors: Shi
authors: Todd W
authors: TW
authors: Geders
authors: Sae Woong
authors: SW
authors: Park
authors: Daniel J
authors: DJ
authors: Wilson
authors: Helena I
authors: HI
authors: Boshoff
authors: Orishadipe
authors: O
authors: Abayomi
authors: Clifton E
authors: CE
authors: Barry
authors: Dirk
authors: D
authors: Schnappinger
authors: Barry C
authors: BC
authors: Finzel
authors: Courtney C
authors: CC
authors: Aldrich
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D001710:Biotin / Q000096:biosynthesis*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000637:Transaminases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D011728:Pyridones; D001710:Biotin; D000637:Transaminases; C102100:BioA protein, bacteria