ABHDs

ABHDs (alpha/beta hydrolase domain-containing proteins) constitute a large and diverse family of serine hydrolases characterized by the alpha/beta hydrolase fold. In humans, the family comprises ABHD1 through ABHD16 and related proteins, many of which have lipid substrates or regulate lipid signaling.

The enzymes typically contain the catalytic triad (Ser-His-Asp) and a conserved motif around the active serine, often described as the nucleophile elbow with the G-X-S-X-G sequence. This structural arrangement underpins their esterases, lipases, and amidases activities.

Substrates include various glycerolipids, lysophospholipids, cholesterol esters, and endocannabinoids; some ABHDs regulate signaling by hydrolyzing 2-arachidonoylglycerol (2-AG) and anandamide (AEA). Beyond lipid hydrolysis, some ABHDs participate in protein lipidation cycles; for example, ABHD17 family members serve as depalmitoylases, modulating palmitoylation of signaling proteins.

Physiological roles and disease relevance: ABHDs influence energy homeostasis, inflammation, synaptic transmission, and neural function. Mutations in ABHD12 cause PHARC, a hereditary neurodegenerative syndrome. Because of their enzymatic activity and substrate diversity, ABHDs are active research targets for metabolic, inflammatory, and neurodegenerative disorders, and selective inhibitors or activators are used as research tools and potential therapeutics.