Diacylglycérol lipase

Diacylglycerol lipase, also known as DAG lipase, DAGL, or DGL, is an enzyme that catalyzes the hydrolysis of diacylglycerol, releasing a free fatty acid and monoacylglycerol:diacylglycerol + H2O ⇌ monoacylglycerol + free fatty acidDAGL has been studied in multiple domains of life, including bacteria, fungi, plants, insects, and mammals. By searching with BLAST for the previously sequenced microorganism DAGL, Bisogno et al discovered two distinct mammalian isoforms, designated DAGLα () and DAGLβ (). Most animal DAGL enzymes cluster into the DAGLα and DAGLβ isoforms. Mammalian DAGL is a crucial enzyme in the biosynthesis of 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid in tissues. The endocannabinoid system has been identified to have considerable involvement in the regulation of homeostasis and disease. As a result, much effort has been made toward investigating the mechanisms of action and the therapeutic potential of the system's receptors, endogenous ligands, and enzymes like DAGLα and DAGLβ. While both DAGLα and DAGLβ are extensively homologous (sharing 34% of their sequence), DAGLα (1042 amino acids) is much larger than DAGLβ (672 amino acids) due to the presence of a sizeable C-terminal tail in the former. Both DAGLα and DAGLβ have a transmembrane domain at the N-terminal that starts with a conserved 19 amino acid cytoplasmic sequence followed by four transmembrane helices. These transmembrane helices are connected by three short loops, of which the two extracellular loops may be glycosylated. The catalytic domain of both isoforms is an α/β hydrolase domain which consists of 8 core β sheets that are mutually hydrogen-bonded and variously linked by α helices, β sheets, and loops. The hydrophobic active site presents a highly conserved Serine-Aspartate-Histidine catalytic triad. The serine and aspartate residues of the active site were first identified in DAGLα as Ser-472 and Asp-524, and in DAGLβ as Ser-443 and Asp-495. The histidine residue was later identified in DAGLα as His-650, which aligns with His-639 in DAGLβ.