上商充通大￥ Shanghai Jiao Tong University N-NH2 Isoniazid 异烟肼
Shanghai Jiao Tong University Isoniazid 异烟肼
上游充通大￥ Isoniazid Shanghai Jiao Tong University Discovered in 1912 1951,found to be effective against tuberculosis Never used on its own because resistance develops quickly
Shanghai Jiao Tong University Isoniazid Discovered in 1912 1951, found to be effective against tuberculosis Never used on its own because resistance develops quickly
上浒文通大学 Mechanism of isoniazid Shanghai Jiao Tong University Prodrug Activated by bacterial catalase(过氧化氢酶)- peroxidase(过氧化物酶)enzyme called KatG KatG couples the isonicotinic acyl with NADH 胺腺嘌呤二核苷酸，辅酶) Form isonicotinic acyl-NADH complex Complex binds tightly to ketoenoylreductase 醇还原酶) Blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase (acyl carrier protein) the process inhibits the synthesis of mycolic acid 枝菌酸)，required for the mycobaterial cell wall.. AcpM:acyl carrier protein (JBC,2003,278(23):20647-54)
Shanghai Jiao Tong University Mechanism of isoniazid Prodrug Activated by bacterial catalase（过氧化氢酶）- peroxidase（过氧化物酶） enzyme called KatG KatG couples the isonicotinic acyl with NADH（烟酰 胺腺嘌呤二核苷酸，辅酶 I） Form isonicotinic acyl-NADH complex Complex binds tightly to ketoenoylreductase（酮烯 醇还原酶） Blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase （acyl carrier protein) the process inhibits the synthesis of mycolic acid（分 枝菌酸）, required for the mycobaterial cell wall. AcpM: acyl carrier protein (JBC, 2003, 278(23):20647-54)
Isoniazid N-acetyl isoniazid (pro-drug) (major metabolite) H NN 8-cH .N-NH2 H NAT2 ------Renal excretion AcCoA CoA In host In bacillus KatG C=O spontaneous NH2 C=O Nicotinoyl radical ('activated”drug) NH2 Nicotinoyl-NAD adduct (inhibitor of InhA) NAD+ Nicotinoyl-NADP adduct NADP+ (inhibitor of DHFR)
Shanghai Jiao Tong University
上浒充通大睾 Mechanism of action Shanghai Jiao Tong University NADH H*NAD* S-ACP S-ACP Reaction catalyzed by the enoyl-ACP reductase(InhA) NH2 isoniazid ethionamide InhA catalyzes the NADH-dependent reduction of 2-trans- enoyl-ACP's and is involved in the biosynthesis of mycolic acid,a critical component of the mycobacterial cell wall.This enzyme is the target for the anti-tubercular drugs isoniazid and ethionamide(乙硫异烟胺)
Shanghai Jiao Tong University Mechanism of action InhA catalyzes the NADH-dependent reduction of 2-transenoyl-ACP’s and is involved in the biosynthesis of mycolic acid, a critical component of the mycobacterial cell wall. This enzyme is the target for the anti-tubercular drugs isoniazid and ethionamide （乙硫异烟胺）