Enoyl-acyl carrier protein reductase [NADH] (Mycobacterium tuberculosis) (InhA)

Enoyl-acyl carrier protein reductase [NADH] (commonly called InhA) is an essential enzyme in Mycobacterium tuberculosis, functioning as the NADH-dependent enoyl-ACP reductase of the fatty acid synthase II (FAS-II) system. InhA catalyzes the reduction step in the elongation cycle of long-chain fatty acids, specifically mycolic acids, which are vital components of the mycobacterial cell wall and central to bacterial viability and pathogenicity. It is the validated primary target of the first-line antitubercular drug isoniazid and the second-line drug ethionamide. Inhibition of InhA impairs mycolic acid synthesis, thus compromising cell wall integrity and leading to cell death. Drug resistance often arises through mutations in the inhA gene or the mycobacterial catalase-peroxidase gene katG, which is required to activate prodrugs like isoniazid. Several direct InhA inhibitors that do not require bioactivation have been developed to address resistance, including compounds like NITD-916 and novel 4-hydroxy-2-pyridones. InhA remains a key therapeutic target for new antitubercular agents, especially in the context of multidrug-resistant tuberculosis.

Other names

ENRNADH-dependent enoyl-ACP reductaseFatty acid synthase II enoyl reductaseFAS-II enoyl-ACP reductase2-trans-enoyl-ACP reductaseEC 1.3.1.9

Inhibition of NADH-dependent reduction of 2-trans-enoyl-ACP, blocking mycolic acid synthesis Isoniazid forms a covalent adduct with NAD that binds and inhibits InhA (prodrug activation required) Ethionamide/prothionamide similarly form inhibitory adducts with NAD attached to InhA Direct competitive or slow tight binding inhibition of the enzyme active site (NITD-916, PT70, others)