Hydrolysis of prostaglandin glycerol esters by the endocannabinoid-hydrolyzing enzymes, monoacylglycerol lipase and fatty acid amide hydrolase.
Cyclooxygenase-2 (COX-2) can oxygenate the endocannabinoids, arachidonyl ethanolamide (AEA) and 2-arachidonylglycerol (2-AG), to prostaglandin-H2-ethanolamide (PGH2-EA) and -glycerol ester (PGH2-G), respectively. Further metabolism of PGH2-EA and PGH2-G by prostaglandin synthases produces a variety of prostaglandin-EA's and prostaglandin-G's nearly as diverse as those derived from arachidonic acid. Thus, COX-2 may regulate endocannabinoid levels in neurons during retrograde signaling or produce novel endocannabinoid metabolites for receptor activation. Endocannabinoid-metabolizing enzymes are important regulators of their action, so we tested whether PG-G levels may be regulated by monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH). We found that PG-Gs are poor substrates for purified MGL and FAAH compared to 2-AG and/or AEA. Determination of substrate specificity demonstrates a 30-100- and 150-200-fold preference of MGL and FAAH for 2-AG over PG-Gs, respectively. The substrate specificity of AEA compared to those of PG-Gs was approximately 200-300 fold higher for FAAH. Thus, PG-Gs are poor substrates for the major endocannabinoid-degrading enzymes, MGL and FAAH.
Vila
Andrew
A
Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Rosengarth
Anja
A
Piomelli
Daniele
D
Cravatt
Benjamin
B
Marnett
Lawrence J
LJ
D000581:Amidohydrolases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000201:enzymology; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D004285:Dogs; D006868:Hydrolysis; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D015232:Dinoprostone; D008994:Monoacylglycerol Lipases; D000099252:Fatty Acid Amide Hydrolases; C518978:prostaglandin E2 glyceryl ester