| IED ID | IndEnz0005001030 |
| Enzyme Type ID | lipase001030 |
| Protein Name |
Diacylglycerol lipase-alpha DAGL-alpha DGL-alpha EC 3.1.1.116 Neural stem cell-derived dendrite regulator Sn1-specific diacylglycerol lipase alpha |
| Gene Name | DAGLA C11orf11 KIAA0659 NSDDR |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MPGIVVFRRRWSVGSDDLVLPAIFLFLLHTTWFVILSVVLFGLVYNPHEACSLNLVDHGRGYLGILLSCMIAEMAIIWLSMRGGILYTEPRDSMQYVLYVRLAILVIEFIYAIVGIVWLTQYYTSCNDLTAKNVTLGMVVCNWVVILSVCITVLCVFDPTGRTFVKLRATKRRQRNLRTYNLRHRLEEGQATSWSRRLKVFLCCTRTKDSQSDAYSEIAYLFAEFFRDLDIVPSDIIAGLVLLRQRQRAKRNAVLDEANNDILAFLSGMPVTRNTKYLDLKNSQEMLRYKEVCYYMLFALAAYGWPMYLMRKPACGLCQLARSCSCCLCPARPRFAPGVTIEEDNCCGCNAIAIRRHFLDENMTAVDIVYTSCHDAVYETPFYVAVDHDKKKVVISIRGTLSPKDALTDLTGDAERLPVEGHHGTWLGHKGMVLSAEYIKKKLEQEMVLSQAFGRDLGRGTKHYGLIVVGHSLGAGTAAILSFLLRPQYPTLKCFAYSPPGGLLSEDAMEYSKEFVTAVVLGKDLVPRIGLSQLEGFRRQLLDVLQRSTKPKWRIIVGATKCIPKSELPEEVEVTTLASTRLWTHPSDLTIALSASTPLYPPGRIIHVVHNHPAEQCCCCEQEEPTYFAIWGDNKAFNEVIISPAMLHEHLPYVVMEGLNKVLENYNKGKTALLSAAKVMVSPTEVDLTPELIFQQQPLPTGPPMPTGLALELPTADHRNSSVRSKSQSEMSLEGFSEGRLLSPVVAAAARQDPVELLLLSTQERLAAELQARRAPLATMESLSDTESLYSFDSRRSSGFRSIRGSPSLHAVLERDEGHLFYIDPAIPEENPSLSSRTELLAADSLSKHSQDTQPLEAALGSGGVTPERPPSAAANDEEEEVGGGGGGPASRGELALHNGRLGDSPSPQVLEFAEFIDSLFNLDSKSSSFQDLYCMVVPESPTSDYAEGPKSPSQQEILLRAQFEPNLVPKPPRLFAGSADPSSGISLSPSFPLSSSGELMDLTPTGLSSQECLAADKIRTSTPTGHGASPAKQDELVISAR |
| Enzyme Length | 1042 |
| Uniprot Accession Number | Q9Y4D2 |
| Absorption | |
| Active Site | ACT_SITE 472; /note=Charge relay system; /evidence=ECO:0000255|PROSITE-ProRule:PRU10037; ACT_SITE 524; /note=Charge relay system; /evidence=ECO:0000255|PROSITE-ProRule:PRU10037 |
| Activity Regulation | ACTIVITY REGULATION: Inhibited by 1,2,3-triazole urea covalent inhibitors KT172, DH376 and DO34 (PubMed:26668358). Inhibited by p-hydroxy-mercuri-benzoate and HgCl(2), but not to PMSF. Also inhibited by RHC80267 (PubMed:14610053). Diacylglycerol lipase activity is inhibited by the phosphorylation of Ser-782 and Ser-808 by CAMK2A (PubMed:23502535). {ECO:0000269|PubMed:14610053, ECO:0000269|PubMed:23502535, ECO:0000269|PubMed:26668358}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=a 1,2-diacyl-sn-glycerol + H2O = a 2-acylglycerol + a fatty acid + H(+); Xref=Rhea:RHEA:33275, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17389, ChEBI:CHEBI:17815, ChEBI:CHEBI:28868; EC=3.1.1.116; Evidence={ECO:0000269|PubMed:14610053};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33276; Evidence={ECO:0000305|PubMed:14610053}; CATALYTIC ACTIVITY: Reaction=1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol + H2O = 2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol + H(+) + octadecanoate; Xref=Rhea:RHEA:38507, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:25629, ChEBI:CHEBI:52392, ChEBI:CHEBI:75728; Evidence={ECO:0000269|PubMed:14610053, ECO:0000269|PubMed:23502535, ECO:0000269|PubMed:26668358};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38508; Evidence={ECO:0000305|PubMed:14610053, ECO:0000305|PubMed:23502535, ECO:0000305|PubMed:26668358}; CATALYTIC ACTIVITY: Reaction=1,2-di-(9Z-octadecenoyl)-sn-glycerol + H2O = (9Z)-octadecenoate + 2-(9Z-octadecenoyl)-glycerol + H(+); Xref=Rhea:RHEA:38511, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30823, ChEBI:CHEBI:52333, ChEBI:CHEBI:73990; Evidence={ECO:0000269|PubMed:14610053};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38512; Evidence={ECO:0000305|PubMed:14610053}; CATALYTIC ACTIVITY: Reaction=1-(9Z-octadecenoyl)-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol + H2O = (9Z)-octadecenoate + 2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol + H(+); Xref=Rhea:RHEA:38515, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30823, ChEBI:CHEBI:52392, ChEBI:CHEBI:75449; Evidence={ECO:0000269|PubMed:14610053};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38516; Evidence={ECO:0000305|PubMed:14610053}; CATALYTIC ACTIVITY: Reaction=1-(9Z-octadecenoyl)-2-octadecanoyl-sn-glycerol + H2O = (9Z)-octadecenoate + 2-octadecanoylglycerol + H(+); Xref=Rhea:RHEA:38519, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30823, ChEBI:CHEBI:75448, ChEBI:CHEBI:75456; Evidence={ECO:0000269|PubMed:14610053};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38520; Evidence={ECO:0000305|PubMed:14610053}; CATALYTIC ACTIVITY: Reaction=1-(9Z-octadecenoyl)-2-(9Z,12Z-octadecadienoyl)-sn-glycerol + H2O = (9Z)-octadecenoate + 2-(9Z,12Z-octadecadienoyl)-glycerol + H(+); Xref=Rhea:RHEA:38523, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30823, ChEBI:CHEBI:75450, ChEBI:CHEBI:75457; Evidence={ECO:0000269|PubMed:14610053};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38524; Evidence={ECO:0000305|PubMed:14610053}; CATALYTIC ACTIVITY: Reaction=1-(9Z-octadecenoyl)-2-O-(5Z,8Z,11Z,14Z-eicosatetraenyl)-sn-glycerol + H2O = (9Z)-octadecenoate + 2-O-(5Z,8Z,11Z,14Z)-eicosatetraenylglycerol + H(+); Xref=Rhea:RHEA:38527, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30823, ChEBI:CHEBI:75913, ChEBI:CHEBI:75914; Evidence={ECO:0000269|PubMed:14610053};PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38528; Evidence={ECO:0000305|PubMed:14610053}; |
| DNA Binding | |
| EC Number | 3.1.1.116 |
| Enzyme Function | FUNCTION: Serine hydrolase that hydrolyzes arachidonic acid-esterified diacylglycerols (DAGs) to produce the principal endocannabinoid, 2-arachidonoylglycerol (2-AG) (PubMed:14610053, PubMed:26668358, PubMed:23502535). Preferentially hydrolyzes sn-1 fatty acids from diacylglycerols (DAG) that contain arachidonic acid (AA) esterified at the sn-2 position to biosynthesize 2-AG (PubMed:14610053, PubMed:26668358, PubMed:23502535). Has negligible activity against other lipids including monoacylglycerols and phospholipids (PubMed:14610053). Plays a key role in regulating 2-AG signaling in the central nervous system (CNS). Regulates 2-AG involved in retrograde suppression at central synapses. Supports axonal growth during development and adult neurogenesis. Plays a role for eCB signaling in the physiological regulation of anxiety and depressive behaviors. Regulates also neuroinflammatory responses in the brain, in particular, LPS-induced microglial activation (By similarity). {ECO:0000250|UniProtKB:Q6WQJ1, ECO:0000269|PubMed:14610053, ECO:0000269|PubMed:23502535, ECO:0000269|PubMed:26668358}. |
| Temperature Dependency | |
| PH Dependency | BIOPHYSICOCHEMICAL PROPERTIES: pH dependence: Optimum pH is 7.0. {ECO:0000269|PubMed:14610053}; |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (2); Chain (1); Compositional bias (1); Erroneous initiation (1); Glycosylation (1); Modified residue (12); Mutagenesis (4); Natural variant (3); Region (2); Topological domain (5); Transmembrane (4) |
| Keywords | Calcium;Cell junction;Cell membrane;Cell projection;Endosome;Glycoprotein;Hydrolase;Lipid degradation;Lipid metabolism;Membrane;Metal-binding;Neurodegeneration;Phosphoprotein;Postsynaptic cell membrane;Reference proteome;Spinocerebellar ataxia;Synapse;Transmembrane;Transmembrane helix |
| Interact With | Q96FZ5; Q8TAF8; P21145; Q13021; Q5J8X5; P27105; A2RU14; A5PKU2; O75841; Q3ZAQ7 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:27595600}; Multi-pass membrane protein {ECO:0000255}. Cell junction, synapse, postsynaptic density membrane {ECO:0000269|PubMed:27595600}; Multi-pass membrane protein {ECO:0000255}. Early endosome membrane {ECO:0000269|PubMed:27595600}; Multi-pass membrane protein {ECO:0000255}. Cell projection, dendritic spine membrane {ECO:0000250|UniProtKB:Q6WQJ1}; Multi-pass membrane protein {ECO:0000255}. Note=Cycles between the cell surface and an intracellular endosomal compartment. Internalized by early endosomes via a clathrin-independent pathway before transport back to the postsynaptic membrane surface in a PKC-dependent manner. {ECO:0000269|PubMed:27595600}. |
| Modified Residue | MOD_RES 727; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q5YLM1; MOD_RES 729; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q6WQJ1; MOD_RES 732; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q6WQJ1; MOD_RES 743; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q6WQJ1; MOD_RES 782; /note=Phosphoserine; /evidence=ECO:0000269|PubMed:23502535; MOD_RES 784; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q6WQJ1; MOD_RES 806; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q5YLM1; MOD_RES 808; /note=Phosphoserine; /evidence=ECO:0000269|PubMed:23502535; MOD_RES 833; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q5YLM1; MOD_RES 847; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q5YLM1; MOD_RES 952; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q6WQJ1; MOD_RES 1023; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:Q6WQJ1 |
| Post Translational Modification | PTM: Phosphorylated at Ser-782 and Ser-808 by CAMK2A; phosphorylation by CAMK2A inhibits diacylglycerol lipase activity. {ECO:0000269|PubMed:23502535}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 10348910; 19126434; 22827915; 24076015; 24616451; 29145497; 29477030; 29614312; 31985073; |
| Motif | |
| Gene Encoded By | |
| Mass | 114,952 |
| Kinetics | BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=154.7 uM for diacylglycerol {ECO:0000269|PubMed:14610053}; KM=158 uM for 1-steroyl-2-arachidonoylglycerol {ECO:0000269|PubMed:23502535}; Vmax=33.3 nmol/min/mg enzyme {ECO:0000269|PubMed:14610053}; Vmax=9.8 pmol/min/mg enzyme with 1-steroyl-2-arachidonoylglycerol as substrat {ECO:0000269|PubMed:23502535}; |
| Metal Binding | |
| Rhea ID | RHEA:33275; RHEA:33276; RHEA:38507; RHEA:38508; RHEA:38511; RHEA:38512; RHEA:38515; RHEA:38516; RHEA:38519; RHEA:38520; RHEA:38523; RHEA:38524; RHEA:38527; RHEA:38528 |
| Cross Reference Brenda |