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

Enoyl-[acyl-carrier-protein] reductase [NADH], commonly known as InhA, is a vital enzyme in the Fatty Acid Synthase II (FAS-II) system of Mycobacterium tuberculosis (Source: UniProt P9WGR1). It catalyzes the NADH-dependent reduction of long-chain trans-2-enoyl-ACP substrates, a rate-limiting step in the biosynthesis of mycolic acids, which are high-molecular-weight alpha-branched, beta-hydroxy fatty acids that constitute the primary permeability barrier of the mycobacterial cell wall (Source: PubMed: 22461516). As an essential enzyme for bacterial viability, InhA is the primary molecular target for the frontline antitubercular drug isoniazid and the second-line drug ethionamide (Source: PubMed: 15522310). These drugs are prodrugs that require activation to form adducts with NAD, which then bind tightly to the InhA active site, effectively halting cell wall synthesis and leading to bacterial cell death (Source: PubMed: 10411891). Resistance to these treatments frequently occurs through mutations in the inhA promoter or the katG activator gene, highlighting the need for novel direct-binding InhA inhibitors that do not require activation (Source: PubMed: 28253452).

Other names

Enoyl-ACP reductaseNADH-dependent enoyl-ACP reductase2-trans-enoyl-ACP reductaseInhA

InhA inhibitors block the reduction of long-chain trans-2-enoyl-ACP to acyl-ACP in the FAS-II pathway, thereby preventing the synthesis of mycolic acids required for the mycobacterial cell wall (Source: PubMed: 15522310). Frontline drugs like isoniazid are activated by the KatG enzyme to form an INH-NAD covalent adduct that occupies the NADH binding site of InhA, while direct inhibitors bind the enzyme without requiring bacterial activation (Source: PubMed: 28253452).