[The mechanism of action of isoniazid. A chemical model of activation].
The antituberculosis drug isoniazid (INH) is quickly oxidized by stoichiometric amounts of manganese(III)-pyrophosphate. In the presence of the nicotinamide coenzyme, the INH oxidation produced the formation of INH-NAD(H) adducts which are potential competitive inhibitors of the enoyl-acyl carrier protein reductase InhA, an INH target in the biosynthetic pathway for mycolic acids. Manganese(III)-pyrophosphate is an efficient alternative oxidant to mimick the activity of the Mycobacterium tuberculosis KatG catalase-peroxidase and will be useful for further mechanistic studies of INH activation and for structural investigations on reactive INH species and resulting InhA inhibitors.
Bernadou
J
J
Service de Chimie Thérapeutique, Faculté des Sciences Pharmaceutiques, 35, chemin des Maraîchers, F/31062 Toulouse.
Nguyen
M
M
Meunier
B
B
D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001711:Biotransformation; D002374:Catalase / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D007538:Isoniazid / Q000737:chemistry / Q000494:pharmacology*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D009243:NAD / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism
D000995:Antitubercular Agents; D009243:NAD; D002374:Catalase; D009195:Peroxidase; D007538:Isoniazid
Connaissances actuelles sur le mécanisme d'action de l'isoniazide. Apport d'un modèle chimique d'activation.