Article
The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance.
Proceedings of the National Academy of Sciences of the United States of America - 25 Nov 2003
Rawat Richa, Whitty Adrian, Tonge Peter J
Abstract excerpt
Isoniazid (INH), a frontline antitubercular drug, inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. Here, we report that the INH-NAD adduct is a slow, tight-binding competitive inhibitor of InhA. Demonstration that the adduct binds to WT InhA by a two-step enzyme inhibition mechanism, with initial, weak binding (K(-1) = 16 +/- 11 nM) followed...
Topics
- Antitubercular Agents
- Bacterial Proteins
- Drug Resistance, Bacterial
- Enzyme Inhibitors
- Isoniazid
- Kinetics
- Mutation
- Mycobacterium tuberculosis
- NAD
- Oxidoreductases
- Thermodynamics