Beta-hydroxyacyl-ACP dehydratase HadA (HadA)

Beta-hydroxyacyl-ACP dehydratase HadA is a critical enzyme subunit within the Fatty Acid Synthase II (FAS-II) system of Mycobacterium tuberculosis [1, 2]. It functions as part of a heterodimeric complex, typically HadAB or HadBC, where it plays a vital role in the biosynthesis of mycolic acids—long-chain fatty acids essential for the structural integrity and virulence of the mycobacterial cell wall [1, 3]. While the HadB subunit provides the catalytic residues, HadA contributes to the substrate-binding channel, facilitating the dehydration of beta-hydroxyacyl-ACP to trans-2-enoyl-ACP [3, 6]. This enzyme complex is the target of several anti-tubercular agents, including the clinical drugs isoxyl and thiacetazone, as well as various flavonoids like butein [3, 9, 12]. These inhibitors typically act by occluding the substrate binding site or through covalent modification following prodrug activation [3, 7]. Resistance to these drugs is frequently associated with specific point mutations in the HadA or HadC subunits, making them important markers for monitoring therapeutic efficacy and drug resistance in tuberculosis patients [7, 12].

Other names

(3R)-hydroxyacyl-ACP dehydratase HadABeta-hydroxyacyl-acyl carrier protein dehydratase HadARv0635HadA subunit of the HadABC complex

Inhibition of mycolic acid biosynthesis by blocking the dehydration of beta-hydroxyacyl-ACP to trans-2-enoyl-ACP within the FAS-II elongation cycle.