Journal
ACS CHEMICAL BIOLOGY
Volume 7, Issue 10, Pages 1653-1658Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb300112x
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Funding
- National Institutes of Health [AI070219, F32 AI084326]
- Intrmural Research Program of the NIAID, NIH
- University of Minnesota Office of the Vice President for Research
- Medical School
- College of Biological Science, NIH, NSF
- Minnesota Medical Foundation
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MbtA is an adenylating enzyme from Mycobacterium tuberculosis that catalyzes the first step in the biosynthesis of the mycobactins. A bisubstrate inhibitor of MbtA (Sal-AMS) was previously described that displays potent antitubercular activity under iron-replete as well as iron-deficient growth conditions. This finding is surprising since mycobactin biosynthesis is not required under iron-replete conditions and suggests off-target inhibition of additional biochemical pathways. As a first step toward a complete understanding of the mechanism of action of Sal-AMS, we have designed and validated an activity-based probe (ABP) for studying Sal-AMS inhibition in M. tuberculosis. This probe labels pure MbtA as well as MbtA in mycobacterial lysate, and labeling can be completely inhibited by preincubation with Sal-AMS. Furthermore, this probe provides a prototypical core scaffold for the creation of ABPs to profile any of the other 66 adenylating enzymes in Mtb or the multitude of adenylating enzymes in other pathogenic bacteria.
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