(3R)-hydroxyacyl-ACP dehydratase HadAB complex (HadAB)

The (3R)-hydroxyacyl-ACP dehydratase HadAB complex is a critical heterodimeric enzyme in Mycobacterium tuberculosis, composed of the HadA and HadB subunits. It plays an essential role in the Type II Fatty Acid Synthase (FAS-II) system by catalyzing the dehydration of (3R)-hydroxyacyl-ACP to trans-2-enoyl-ACP, a key step in the elongation of meromycolate chains [1, 10]. These chains are precursors to mycolic acids, which are long-chain fatty acids that form the waxy, protective outer membrane of the tubercle bacillus [5, 12]. Because mycolic acids are vital for the structural integrity, antibiotic resistance, and virulence of the bacterium, the HadAB complex is a major target for anti-tuberculosis therapy [1, 4]. Drugs such as isoxyl and thiacetazone act as prodrugs that, upon activation by the monooxygenase EthA, inhibit the dehydratase activity of HadAB, leading to the cessation of cell wall synthesis and bacterial death [6, 8, 10]. However, the clinical utility of these drugs is often challenged by the emergence of resistance mutations within the HadAB complex and associated safety concerns in specific patient populations [1, 10].

Other names

Beta-hydroxyacyl-ACP dehydratase HadAB complexFAS-II dehydrataseHadA-HadB heterodimer(3R)-hydroxyacyl-acyl carrier protein dehydratase

Inhibition of the (3R)-hydroxyacyl-ACP dehydratase activity within the FAS-II pathway, which prevents the dehydration of 3-hydroxyacyl-ACP to trans-2-enoyl-ACP, thereby halting the biosynthesis of mycolic acids essential for the mycobacterial cell wall [1, 10].