3-hydroxyacyl-CoA dehydratase 2 (HACD2)

3-hydroxyacyl-CoA dehydratase 2 (HACD2) is an endoplasmic reticulum membrane-associated enzyme that catalyzes the third (dehydration) step in the fatty acid elongation cycle, essential for generating long-chain and very long-chain fatty acids vital for membrane biosynthesis and lipid signaling[1][2][3][4]. HACD2 exhibits broad substrate specificity, active toward saturated, monounsaturated, and polyunsaturated 3-hydroxyacyl-CoAs; it is considered the major 3-hydroxyacyl-CoA dehydratase in most mammalian tissues, exhibiting functional redundancy with its paralog HACD1[4]. Disruption of HACD2 leads to reduced very long-chain fatty acid biosynthesis, alters energy homeostasis, protects against diet-induced metabolic disease in mice, but can also result in fatal mitochondrial dysfunction if globally inhibited[1][4][5]. Thus, HACD2 is both an essential enzyme in lipid metabolism and a putative therapeutic target for obesity and associated metabolic disorders, though safety concerns must be carefully addressed due to its central role in cell biology[1][5].

Other names

Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 2Protein-tyrosine phosphatase-like member B (PTPLB)Very-long-chain (3R)-3-hydroxyacyl-[acyl-carrier protein] dehydratase 2PTPLBHACD2_HUMANProtein tyrosine phosphatase-like (proline instead of catalytic arginine), member b

Not directly targeted by specific drugs in current clinical or preclinical development. Mechanistically, any compounds would act as enzyme inhibitors of fatty acid elongation, reducing VLCFA synthesis.