For COVID-19 vaccine updates, please review our information guide. For patient eligibility and scheduling availability, please visit VaccineTogetherNY.org.

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

TitleMechanism-based inactivation by aromatization of the transaminase BioA involved in biotin biosynthesis in Mycobaterium tuberculosis.
Publication TypeJournal Article
Year of Publication2011
AuthorsShi C, Geders TW, Park SWoong, Wilson DJ, Boshoff HI, Abayomi O, Barry CE, Schnappinger D, Finzel BC, Aldrich CC
JournalJ Am Chem Soc
Volume133
Issue45
Pagination18194-201
Date Published2011 Nov 16
ISSN1520-5126
KeywordsAntitubercular Agents, Bacterial Proteins, Biocatalysis, Biotin, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Mycobacterium tuberculosis, Pyridones, Stereoisomerism, Structure-Activity Relationship, Transaminases
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.

DOI10.1021/ja204036t
Alternate JournalJ Am Chem Soc
PubMed ID21988601
PubMed Central IDPMC3222238
Grant ListR01 AI091790-01 / AI / NIAID NIH HHS / United States
AI091790 / AI / NIAID NIH HHS / United States
/ / Intramural NIH HHS / United States
/ / Wellcome Trust / United Kingdom
R01 AI091790 / AI / NIAID NIH HHS / United States

Weill Cornell Medicine Microbiology and Immunology 1300 York Avenue, Box 62 New York, NY 10065 Phone: (212) 746-6505 Fax: (212) 746-8587