Beta-hydroxyacyl-ACP dehydratase HadB (HadB)

Beta-hydroxyacyl-ACP dehydratase HadB is a critical enzyme in the Mycobacterium tuberculosis Type II Fatty Acid Synthase (FAS-II) system, where it forms essential heterodimeric complexes with HadA or HadC [1, 5]. These complexes, HadAB and HadBC, catalyze the dehydration of (3R)-hydroxyacyl-ACP to trans-2-enoyl-ACP, a key step in the biosynthesis of mycolic acids which are vital components of the mycobacterial cell wall [2, 3]. HadB provides the catalytic His-Asp dyad necessary for the reaction, while its partners influence substrate chain-length specificity [1, 5]. This enzyme complex is the primary target of anti-tubercular prodrugs such as Isoxyl and Thiacetazone, which, upon activation by the monooxygenase EtaA, inhibit the dehydratase activity and disrupt cell wall integrity [4]. Flavonoids like butein and fisetin have also been shown to inhibit the complex by occluding the substrate from the active site [1]. Due to its essentiality for bacterial survival and the absence of a human homolog, HadB is a significant target for the development of novel antibiotics against both drug-sensitive and multi-drug-resistant tuberculosis [1, 3].

Other names

(3R)-hydroxyacyl-ACP dehydratase HadB3-hydroxyacyl-ACP dehydratase HadBRv0636HadB subunit of the (3R)-hydroxyacyl-ACP dehydratase complex

Inhibition of the (3R)-hydroxyacyl-ACP dehydratase activity within the HadAB or HadBC complex, preventing the dehydration of beta-hydroxyacyl-ACP to trans-2-enoyl-ACP in the FAS-II pathway, thereby blocking mycolic acid synthesis [1, 4, 5].