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

Enoyl-acyl carrier protein reductase (InhA) is a key NADH-dependent enzyme of the type II fatty acid synthesis pathway in Mycobacterium tuberculosis, responsible for the final reduction step in meromycolic acid biosynthesis, an essential component of the mycobacterial cell wall[1][2][6]. As a target of the first-line antitubercular drug isoniazid, InhA is crucial for inhibitor efficacy and central for both drug development and resistance mechanisms. InhA catalyzes the reduction of 2-trans-enoyl-ACP intermediates, utilizing NADH as a cofactor, to produce long chain fatty acids that are subsequently used in constructing mycolic acids, which grant mycobacteria unique cellular integrity and virulence properties[1][2][6][5][3][4]. Both direct and indirect inhibition of InhA disrupts cell wall synthesis, leading to bactericidal activity. Resistance can arise through point mutations in inhA or impaired activation of prodrug inhibitors, highlighting the importance of novel direct-acting molecules in overcoming current therapeutic limitations[5][3][4].

Other names

InhAEnoyl-ACP reductaseEnoyl-acyl carrier protein reductase2-trans-enoyl-ACP(CoA) reductaseMtInhAENR

Inhibitors (such as isoniazid, ethionamide, and direct arylamide inhibitors) block the enzyme's catalytic activity, preventing hydride transfer and reduction of enoyl-ACP substrates, thereby halting mycolic acid biosynthesis and compromising cell wall formation[1][5][4]. Isoniazid and ethionamide are prodrugs: activated by KatG to form an adduct with NAD(H), which then binds and inhibits InhA[1][5]. Direct inhibitors bind the active site, competing with NADH and substrate, and block enzymatic reduction[3][5][4].