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

Mycobacterium tuberculosis enoyl-[acyl-carrier-protein] reductase, commonly known as InhA, is a vital enzyme within the Type II fatty acid biosynthesis (FAS-II) system of M. tuberculosis [1]. It catalyzes the NADH-dependent reduction of long-chain trans-2-enoyl-acyl carrier proteins, which is a rate-limiting step in the synthesis of mycolic acids [1, 3]. Mycolic acids are high-molecular-weight alpha-branched, beta-hydroxy fatty acids that constitute a major and essential component of the mycobacterial cell wall, providing a permeability barrier against many antibiotics [3, 4]. InhA is the primary target for the frontline antibiotic isoniazid (INH) and the second-line drug ethionamide [2, 4]. These drugs act as prodrugs that, upon activation by bacterial enzymes like KatG or EthA, form covalent adducts with NAD; these adducts then bind to the active site of InhA with high affinity, inhibiting its activity and leading to bacterial cell death [3, 4]. Due to its essentiality and the lack of a human homolog, InhA remains a focal point for the development of new antitubercular agents, especially those that can bypass the need for activation to overcome resistance [4]. Sources: [1] UniProt (P9WGR1); [2] PubChem (Isoniazid); [3] PubMed (PMID: 7832855); [4] PubMed (PMID: 28254952).

Other names

InhAEnoyl-ACP reductaseNADH-dependent enoyl-ACP reductase2-trans-enoyl-ACP reductaseFabI

Inhibition of the NADH-dependent reduction of long-chain trans-2-enoyl-ACP substrates in the FAS-II pathway, leading to the disruption of mycolic acid biosynthesis and bacterial cell wall collapse.