Journal
CHEMBIOCHEM
Volume 15, Issue 4, Pages 575-586Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201300748
Keywords
hydrazine; reversible covalent inhibitors; transaminase; tuberculosis; X-ray crystal structures
Funding
- Minnesota Department of Employment and Economic Development [SPAP-06-0014-P-FY07]
- National Institutes of Health [AI091790]
- Hauptman-Woodward Medical Research Institute
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7,8-Diaminopelargonic acid synthase (BioA) of Mycobacterium tuberculosis is a recently validated target for therapeutic intervention in the treatment of tuberculosis (TB). Using biophysical fragment screening and structural characterization of compounds, we have identified a potent aryl hydrazine inhibitor of BioA that reversibly modifies the pyridoxal-5-phosphate (PLP) cofactor, forming a stable quinonoid. Analogous hydrazides also form covalent adducts that can be observed crystallographically but are incapable of inactivating the enzyme. In the X-ray crystal structures, small molecules induce unexpected conformational remodeling in the substrate binding site. We compared these conformational changes to those induced upon binding of the substrate (7-keto-8-aminopelargonic acid), and characterized the inhibition kinetics and the X-ray crystal structures of BioA with the hydrazine compound and analogues to unveil the mechanism of this reversible covalent modification.
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