Unknown

Dataset Information

0

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.

SUBMITTER: Shi C 

PROVIDER: S-EPMC3222238 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

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

Shi Ce C   Geders Todd W TW   Park Sae Woong SW   Wilson Daniel J DJ   Boshoff Helena I HI   Abayomi Orishadipe O   Barry Clifton E CE   Schnappinger Dirk D   Finzel Barry C BC   Aldrich Courtney C CC  

Journal of the American Chemical Society 20111024 45

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. Inact  ...[more]

Similar Datasets

Unknown Structure-Based Optimization of Pyridoxal 5'-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis.
| S-EPMC5590679 | biostudies-literature
Unknown Design and synthesis of potential mechanism-based inhibitors of the aminotransferase BioA involved in biotin biosynthesis.
| S-EPMC3448953 | biostudies-literature
Unknown A continuous fluorescence displacement assay for BioA: an enzyme involved in biotin biosynthesis.
| S-EPMC3135573 | biostudies-literature
Unknown Inhibition of Mycobacterium tuberculosis transaminase BioA by aryl hydrazines and hydrazides.
| S-EPMC4020011 | biostudies-literature
Unknown Target-based identification of whole-cell active inhibitors of biotin biosynthesis in Mycobacterium tuberculosis.
| S-EPMC4305006 | biostudies-literature
Unknown Fragment-based exploration of binding site flexibility in Mycobacterium tuberculosis BioA.
| S-EPMC4687966 | biostudies-literature
Unknown Peroxisomes are involved in biotin biosynthesis in Aspergillus and Arabidopsis.
| S-EPMC3162405 | biostudies-literature
Unknown Identification of Mycobacterium tuberculosis BioA inhibitors by using structure-based virtual screening.
| S-EPMC5935190 | biostudies-literature
Unknown Mechanism-based inhibitors of MenE, an acyl-CoA synthetase involved in bacterial menaquinone biosynthesis.
| S-EPMC2628629 | biostudies-literature
Unknown Structural characterization of the Mycobacterium tuberculosis biotin biosynthesis enzymes 7,8-diaminopelargonic acid synthase and dethiobiotin synthetase .
| S-EPMC3503319 | biostudies-literature