Beta-hydroxyacyl-ACP dehydratase HadC (HadC)

Beta-hydroxyacyl-ACP dehydratase HadC is an essential enzyme component of the Type II Fatty Acid Synthase (FAS-II) system in Mycobacterium tuberculosis (UniProt: P9WNV3). It functions primarily as part of heterodimeric complexes, such as HadBC or HadAB, which are responsible for the dehydration of (3R)-hydroxyacyl-ACP to trans-2-enoyl-ACP (PubMed: 19502586). This enzymatic step is a critical part of the elongation cycle that produces long-chain fatty acids, which serve as the building blocks for mycolic acids. Mycolic acids are unique, essential lipids that form the protective, waxy cell wall of mycobacteria, contributing to their survival and resistance to antibiotics (PubMed: 22423237). Because HadC is vital for cell wall integrity and has no human homolog, it is considered a high-priority target for antitubercular drug development. Therapeutic agents like isoxyl (thiocarlide) and thiacetazone act as prodrugs that, once activated by the bacterial monooxygenase EthA, specifically target and inhibit the HadABC complex (PubMed: 22423237). Inhibition of this target leads to a rapid decrease in mycolic acid synthesis, resulting in bacterial growth inhibition and increased susceptibility to other drugs.

Other names

(3R)-hydroxyacyl-ACP dehydratase subunit HadCRv0637cBeta-hydroxyacyl-acyl carrier protein dehydratase HadCHadABC complex subunit HadC

Inhibition of the (3R)-hydroxyacyl-ACP dehydratase activity within the FAS-II complex, leading to the disruption of mycolic acid synthesis and cell wall instability.