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

Mycobacterium tuberculosis enoyl-[acyl-carrier-protein] reductase [NADH], commonly known as InhA, is a vital enzyme within the Type II fatty acid synthase (FAS-II) system of the bacterium (UniProt: P9WGR1). It is responsible for 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 (PubMed: 15139850). These long-chain fatty acids are essential structural components of the mycobacterial cell wall, contributing to its low permeability and resistance to many antibiotics. InhA is the primary target for the frontline antitubercular drug isoniazid and the second-line drug ethionamide, both of which act as prodrugs that form inhibitory adducts with NADH (PMC: 3536331). Inhibition of InhA leads to the accumulation of long-chain fatty acids and the eventual lysis of the bacterial cell. Due to its essentiality and the absence of a human homolog, InhA continues to be a high-priority target for overcoming multidrug-resistant tuberculosis (PubMed: 28650177).

Other names

InhANADH-dependent enoyl-ACP reductase2-trans-enoyl-ACP reductaseEnoyl-ACP reductase

InhA is inhibited by a covalent adduct formed between the activated form of prodrugs (like isoniazid or ethionamide) and the NADH cofactor. This adduct binds with high affinity to the InhA active site, preventing the reduction of long-chain trans-2-enoyl-ACP substrates and thereby blocking the synthesis of mycolic acids required for the mycobacterial cell wall (PubMed: 15139850, PMC: 3536331).