Abhydrolase domain-containing protein 2 (ABHD2)

Abhydrolase domain-containing protein 2 (ABHD2) is a serine hydrolase enzyme of the alpha/beta hydrolase fold superfamily that catalyzes the hydrolysis of acylglycerols, including endocannabinoids such as 2-arachidonoylglycerol (2AG), particularly in response to progesterone[1][2][4][5][7][8]. ABHD2 is a key regulator of sperm hyperactivation by mediating 2AG breakdown, thus releasing CatSper calcium channels essential for fertilization, and functions as a non-genomic progesterone receptor in sperm[4][5][8]. The enzyme is also active in lung epithelial cells and macrophages, where it regulates lipid homeostasis and immune cell migration, with documented involvement in atherosclerosis, emphysema, and several cancers[1][8][9]. ABHD2 can be inhibited by sex steroids and specific plant triterpenoids, and is the subject of active research as a novel contraceptive target and as a potential therapeutic target in lipid metabolism disorders and inflammatory diseases[2][5][9].

Other names

Monoacylglycerol lipase ABHD22-arachidonoylglycerol hydrolaseAcetylesteraseLung alpha/beta hydrolase 2Progesterone-sensitive lipaseProtein PHPS1-2LABH2PHPS1-2Testicular tissue protein Li 6

Inhibition by steroids (testosterone, hydrocortisone) or triterpenoids results in suppressed ABHD2 activity and prevention of premature sperm hyperactivation. Small-molecule inhibition reduces sperm acrosome reaction, blocks sperm activation. Progesterone binding activates ABHD2 to catalyze acylglycerol and endocannabinoid hydrolysis, leading to Ca²⁺ influx.