- Manna JD, Wepy JA, Hsu K, Chang JW, Cravatt BF, Marnett LJ. Identification of the Major Prostaglandin Glycerol Ester Hydrolase in Human Cancer Cells. The Journal of biological chemistry. 2014 Oct 9. PMID: 25301951 [PubMed].
Prostaglandin glycerol esters (PG-Gs) are produced as a result of the oxygenation of the endocannabinoid, 2-arachidonoylglycerol (2-AG), by cyclooxygenase 2. Understanding the role that PG-Gs play in a biological setting has been difficult because of their sensitivity to enzymatic hydrolysis. By comparing PG-G hydrolysis across human cancer cell lines to serine hydrolase activities determined by activity-based protein profiling, we identified lysophospholipase A2 (LYPLA2) as a major enzyme responsible for PG-G hydrolysis. The principal role played by LYPLA2 in PGE2-G hydrolysis was confirmed by siRNA knockdown. Purified, recombinant LYPLA2 hydrolyzed PG-Gs in the following order of activity - PGE2-G > PGF2α-G > PGD2-G; LYPLA2 hydrolyzed 1-AG but not 2-AG or arachidonoylethanolamide (AEA). Chemical inhibition of LYPLA2 in the mouse macrophage-like cell line, RAW264.7, elicited an increase in PG-G production. Our data indicate that LYPLA2 serves as a major PG-G hydrolase in human cells. Perturbation of this enzyme should enable selective modulation of PG-Gs without alterations in endocannabinoids, thereby providing a means to decipher the unique functions of PG-Gs in biology and disease.