期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-20224-x
关键词
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资金
- Bill and Melinda Gates Foundation [OPP1024021, OPP1158806]
- Intramural Research Program of NIH, NIAID
- South African Medical Research Council
- National Research Foundation
- Swiss National Science Foundation (SNSF) [P2ZHP2_164947]
- Marie Curie Research Grants Scheme, EU H2020 Framework Programme (H2020-MSCA-IF-2017) [789607]
- NHMRC Overseas Biomedical Fellowship [1016357]
- Bill and Melinda Gates Foundation HIT-TB [OPP1024021]
- MRC-CinC [MC_PC_14099]
- Wellcome Trust [200814_Z_16_Z: RG83114]
- Marie Curie Actions (MSCA) [789607] Funding Source: Marie Curie Actions (MSCA)
- Bill and Melinda Gates Foundation [OPP1158806, OPP1024021] Funding Source: Bill and Melinda Gates Foundation
- Swiss National Science Foundation (SNF) [P2ZHP2_164947] Funding Source: Swiss National Science Foundation (SNF)
Coenzyme A (CoA) is a crucial factor in various metabolic pathways and cellular processes, particularly in prokaryotes such as Mycobacterium tuberculosis. The biosynthesis of CoA involves five steps, with the second and third steps catalyzed by a bifunctional protein CoaBC in most prokaryotes. The researchers identified inhibitors of M. tuberculosis CoaB through a high-throughput screen and discovered a cryptic allosteric binding site within the enzyme.
Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB. The bifunctional enzyme CoaBC catalyses the second and third step in the Coenzyme A (CoA) biosynthesis pathway and is of interest as a M. tuberculosis drug target. Here, the authors present the full-length crystal structure of Mycobacterium smegmatis CoaBC, which is regulated by CoA and CoA thioesters and forms a dodecamer and by performing a high-throughput screen they identify selective inhibitors of M. tuberculosis CoaB that bind to an allosteric site within CoaB.
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