Biology:Diacylglycerol lipase

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Short description: Enzyme that breaks down diacylglycerol in many organisms.
diacylglycerol lipase α
Diacylglycerol lipase α (via AlphaFold2, ColabFold, and PyMol).png
DAGLα structure, folded with AlphaFold.[1][2][3] Transmembrane domain in marine blue. Catalytic domain in yellow. C-terminal tail in gray. See Structure for details. Click image for higher resolution.
Identifiers
SymbolDAGLA
Alt. symbolsC11orf11
NCBI gene747
HGNC1165
RefSeqNM_006133
UniProtQ9Y4D2
Other data
EC number3.1.1.116
LocusChr. 11 q12.3
diacylglycerol lipase β
Diacylglycerol lipase β (via AlphaFold2, ColabFold, and PyMol).png
DAGLβ structure, folded with AlphaFold.[1][2][3] Transmembrane domain in marine blue. Catalytic domain in yellow. Note missing C-terminal tail. See Structure for details. Click image for higher resolution.
Identifiers
SymbolDAGLB
NCBI gene221955
HGNC28923
RefSeqNM_139179
UniProtQ8NCG7
Other data
EC number3.1.1.116
LocusChr. 7 p22.1

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:[1]

diacylglycerol + H2O ⇌ monoacylglycerol + free fatty acid

DAGL has been studied in multiple domains of life, including bacteria, fungi, plants, insects, and mammals.[4] By searching with BLAST for the previously sequenced microorganism DAGL,[5] Bisogno et al discovered two distinct mammalian isoforms, designated DAGLα (DAGLA) and DAGLβ (DAGLB).[1] Most animal DAGL enzymes cluster into the DAGLα and DAGLβ isoforms.[4]

Mammalian DAGL is a crucial enzyme in the biosynthesis of 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid in tissues.[1] The endocannabinoid system has been identified to have considerable involvement in the regulation of homeostasis and disease.[6] 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.[6]

Structure

While both DAGLα and DAGLβ are extensively homologous (sharing 34% of their sequence[4]), 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.[1][7]

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.[1][7] These transmembrane helices are connected by three short loops, of which the two extracellular loops may be glycosylated.[7]

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.[7] The hydrophobic active site presents a highly conserved Serine-Aspartate-Histidine catalytic triad.[7] 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.[1] The histidine residue was later identified in DAGLα as His-650,[8] which aligns with His-639 in DAGLβ.[1]

Between β strands 7 and 8 is a 50-60 residue regulatory loop that is believed to act as a well-positioned "lid" controlling access to the catalytic site.[7] Numerous phosphorylation sites have been identified on this loop as evidence of its regulatory nature.[7]

Mechanism

Diacylglycerol lipase uses a Serine-Aspartate-Histidine catalytic triad to hydrolyze the ester bond of an acyl chain from diacylglycerol (DAG), generating a monoacylglycerol (MAG), and a free fatty acid.[9][10] This hydrolytic cleavage mechanism for DAGLα and DAGLβ is more selective for the sn-1 position of DAG over the sn-2 position.[1]

Initially, histidine deprotonates serine forming a strong nucleophilic alkoxide, which attacks the carbonyl of the acyl group at the sn-1 position of DAG.[1] A tetrahedral intermediate briefly forms before the instability of the oxyanion collapses the tetrahedral intermediate to re-form the double bond while cleaving the ester bond.[11] The monoacylglycerol product, which in this case is 2-arachidonoylglycerol, is released leaving behind an acyl-enzyme intermediate.[11]

An incoming water molecule is deprotonated, and the hydroxide ion attacks the ester linkage generating a second tetrahedral intermediate.[12] The instability of the negative charge once again collapses the tetrahedral intermediate, this time displacing the serine.[12] The second product (a fatty acid) is released from the catalytic site.

Diacylglycerol lipase mechanism.[10][9] Products are shown in blue. Intermolecular interactions are shown in cyan. Arrow-pushing is shown in red.

Biological function

DAGLα and DAGLβ have been identified as the enzymes predominantly responsible for the biosynthesis of the endogenous signaling lipid, 2-arachidonoylglycerol (2-AG).[1][13] 2-AG is the most abundant endocannabinoid found in tissues[1] and activates the CB1 and CB2 G-protein-coupled receptors.[6] Endocannabinoid signaling via these receptors is involved in core body temperature control, inflammation, appetite promotion, memory formation, mood and anxiety regulation, pain relief, addiction reward, neuron protection, and more.[10][14]

Studies utilizing DAGL α or β knockout mice show that these enzymes regulate 2-AG production in a tissue-dependent manner.[13][14] DAGLα is prevalent in central nervous tissues where it is primarily responsible for the on-demand production[15] of 2-AG, which is involved in retrograde synaptic suppression, regulation of axonal growth, adult neurogenesis, and neuroinflammation.[13][14][15]

DAGLβ has enriched activity in innate immune cells such as macrophages and microglia enabling regulation of 2-AG and downstream metabolic products (e.g. prostaglandins) important for proinflammatory signaling in neuroinflammation and pain.[16][17][18][19]

Disease relevance

Diacylglycerol lipase has been identified as a tunable target in the endocannabinoid system.[6] It has been the subject of extensive preclinical research, and many propose that disease states, including inflammatory disease, neurodegeneration, pain, and metabolic disorders may benefit from drug discovery.[6] However currently, the conversion of these preclinical findings into viable approved therapeutics for disease remains elusive.[6]

Inhibiting DAGLα in the gastrointestinal tract has been shown to reduce constipation in mice through a CB1-dependent pathway.[10]

DAGLα inhibition in mice has also been shown to reduce neuroinflammatory response due to the reduction of overall 2-AG, a precursor to the synthesis of proinflammatory prostaglandins. Therefore DAGLα inhibition has been identified as an approach to treating neurodegenerative diseases.[10] Indeed, rat models of Huntington's disease show the neuroprotective nature of DAGLα inhibition.[20]

DAGLα inhibition in mice produced weight loss through a reduction in food intake. Moreover, DAGLα knockout mice have low fasting insulin, triglycerides, and total cholesterol.[10] Thus, DAGLα inhibition may be a novel therapy for treating obesity and metabolic syndrome.[21]

However, DAGLα inhibition has also been associated reduction in neuroplasticity, increased anxiety and depression, seizures, and other neuropsychiatric side effects due to drastic alteration of brain lipids.[15][21]

In vivo experiments show that selectively inhibiting DAGLβ has the potential to be a powerful anti-inflammatory therapy by suppressing the production of the proinflammatory molecules arachidonic acid, prostaglandins, tumor necrosis factor α in macrophages and dendritic cells.[16][17][18] As a consequence, DAGLβ inhibition has been identified as a potential therapy for pathological pain that does not impair immunity.[10][17]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 "Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain". J. Cell Biol. 163 (3): 463–8. November 2003. doi:10.1083/jcb.200305129. PMID 14610053. 
  2. ↑ 2.0 2.1 Jumper, John; Evans, Richard; Pritzel, Alexander; Green, Tim; Figurnov, Michael; Ronneberger, Olaf; Tunyasuvunakool, Kathryn; Bates, Russ et al. (2021-07-15). "Highly accurate protein structure prediction with AlphaFold" (in en). Nature 596 (7873): 583–589. doi:10.1038/s41586-021-03819-2. ISSN 1476-4687. PMID 34265844. Bibcode: 2021Natur.596..583J. 
  3. ↑ 3.0 3.1 Mirdita, Milot; Schütze, Konstantin; Moriwaki, Yoshitaka; Heo, Lim; Ovchinnikov, Sergey; Steinegger, Martin (2022-05-30). "ColabFold: making protein folding accessible to all" (in en). Nature Methods 19 (6): 679–682. doi:10.1038/s41592-022-01488-1. ISSN 1548-7105. PMID 35637307. 
  4. ↑ 4.0 4.1 4.2 Yuan, Dongjuan; Wu, Zhongdao; Wang, Yonghua (2016-08-26). "Evolution of the diacylglycerol lipases". Progress in Lipid Research 64: 85–97. doi:10.1016/j.plipres.2016.08.004. ISSN 1873-2194. PMID 27568643. https://pubmed.ncbi.nlm.nih.gov/27568643/. 
  5. ↑ Yamaguchi, Shotaro; Tamio, Mase; Kazuyuki, Takeuchi (1991-07-15). "Cloning and structure of the mono- and diacylglycerol lipase-encoding gene from Penicillium camembertii U-150" (in en). Gene 103 (1): 61–67. doi:10.1016/0378-1119(91)90391-N. ISSN 0378-1119. PMID 1879699. https://dx.doi.org/10.1016/0378-1119%2891%2990391-N. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Wilkerson, Jenny L.; Bilbrey, Joshua A.; Felix, Jasmine S.; Makriyannis, Alexandros; McMahon, Lance R. (2021-04-29). "Untapped endocannabinoid pharmacological targets: Pipe dream or pipeline?". Pharmacology, Biochemistry, and Behavior 206: 173192. doi:10.1016/j.pbb.2021.173192. ISSN 1873-5177. PMID 33932409. https://pubmed.ncbi.nlm.nih.gov/33932409/. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 Reisenberg, Melina; Singh, Praveen K.; Williams, Gareth; Doherty, Patrick (2012-12-05). "The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling" (in en). Philosophical Transactions of the Royal Society B: Biological Sciences 367 (1607): 3264–3275. doi:10.1098/rstb.2011.0387. ISSN 0962-8436. PMID 23108545. 
  8. ↑ Pedicord, Donna L.; Flynn, Michael J.; Fanslau, Caroline; Miranda, Maricar; Hunihan, Lisa; Robertson, Barbara J.; Pearce, Bradley C.; Yu, Xuan-Chuan et al. (2011-08-12). "Molecular characterization and identification of surrogate substrates for diacylglycerol lipase α" (in en). Biochemical and Biophysical Research Communications 411 (4): 809–814. doi:10.1016/j.bbrc.2011.07.037. ISSN 0006-291X. PMID 21787747. https://www.sciencedirect.com/science/article/pii/S0006291X11012563. 
  9. ↑ 9.0 9.1 Baggelaar, Marc P.; Chameau, Pascal J. P.; Kantae, Vasudev; Hummel, Jessica; Hsu, Ku-Lung; Janssen, Freek; van der Wel, Tom; Soethoudt, Marjolein et al. (2015-07-15). "Highly Selective, Reversible Inhibitor Identified by Comparative Chemoproteomics Modulates Diacylglycerol Lipase Activity in Neurons". Journal of the American Chemical Society 137 (27): 8851–8857. doi:10.1021/jacs.5b04883. ISSN 1520-5126. PMID 26083464. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 Janssen, Freek J.; van der Stelt, Mario (2016-08-15). "Inhibitors of diacylglycerol lipases in neurodegenerative and metabolic disorders". Bioorganic & Medicinal Chemistry Letters 26 (16): 3831–3837. doi:10.1016/j.bmcl.2016.06.076. ISSN 1464-3405. PMID 27394666. https://pubmed.ncbi.nlm.nih.gov/27394666/. 
  11. ↑ 11.0 11.1 Cen, Yixin; Singh, Warispreet; Arkin, Mamatjan; Moody, Thomas S.; Huang, Meilan; Zhou, Jiahai; Wu, Qi; Reetz, Manfred T. (2019-07-19). "Artificial cysteine-lipases with high activity and altered catalytic mechanism created by laboratory evolution" (in en). Nature Communications 10 (1): 3198. doi:10.1038/s41467-019-11155-3. ISSN 2041-1723. PMID 31324776. Bibcode: 2019NatCo..10.3198C. 
  12. ↑ 12.0 12.1 Stryer, Lubert (1981). Biochemistry (2nd ed.). W. H. Freeman and Company. pp. 162. ISBN 0716712261. 
  13. ↑ 13.0 13.1 13.2 Gao, Ying; Vasilyev, Dmitry V.; Goncalves, Maria Beatriz; Howell, Fiona V.; Hobbs, Carl; Reisenberg, Melina; Shen, Ru; Zhang, Mei-Yi et al. (2010-02-10). "Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice". The Journal of Neuroscience 30 (6): 2017–2024. doi:10.1523/JNEUROSCI.5693-09.2010. ISSN 1529-2401. PMID 20147530. 
  14. ↑ 14.0 14.1 14.2 Tanimura, Asami; Yamazaki, Maya; Hashimotodani, Yuki; Uchigashima, Motokazu; Kawata, Shinya; Abe, Manabu; Kita, Yoshihiro; Hashimoto, Kouichi et al. (2010-02-11). "The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission". Neuron 65 (3): 320–327. doi:10.1016/j.neuron.2010.01.021. ISSN 1097-4199. PMID 20159446. 
  15. ↑ 15.0 15.1 15.2 Ogasawara, Daisuke; Deng, Hui; Viader, Andreu; Baggelaar, Marc P.; Breman, Arjen; den Dulk, Hans; van den Nieuwendijk, Adrianus M. C. H.; Soethoudt, Marjolein et al. (2016-01-05). "Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition" (in en). Proceedings of the National Academy of Sciences 113 (1): 26–33. doi:10.1073/pnas.1522364112. ISSN 0027-8424. PMID 26668358. Bibcode: 2016PNAS..113...26O. 
  16. ↑ 16.0 16.1 Hsu, Ku-Lung; Tsuboi, Katsunori; Adibekian, Alexander; Pugh, Holly; Masuda, Kim; Cravatt, Benjamin F. (2012-10-28). "DAGLβ inhibition perturbs a lipid network involved in macrophage inflammatory responses" (in en). Nature Chemical Biology 8 (12): 999–1007. doi:10.1038/nchembio.1105. ISSN 1552-4469. PMID 23103940. 
  17. ↑ 17.0 17.1 17.2 Shin, Myungsun; Snyder, Helena W.; Donvito, Giulia; Schurman, Lesley D.; Fox, Todd E.; Lichtman, Aron H.; Kester, Mark; Hsu, Ku-Lung (2018-03-05). "Liposomal Delivery of Diacylglycerol Lipase-Beta Inhibitors to Macrophages Dramatically Enhances Selectivity and Efficacy in Vivo". Molecular Pharmaceutics 15 (3): 721–728. doi:10.1021/acs.molpharmaceut.7b00657. ISSN 1543-8392. PMID 28901776. 
  18. ↑ 18.0 18.1 Shin, Myungsun; Buckner, Andrew; Prince, Jessica; Bullock, Timothy N.J.; Hsu, Ku-Lung (2019-05-16). "Diacylglycerol Lipase-β Is Required for TNF-α Response but Not CD8+ T Cell Priming Capacity of Dendritic Cells" (in en). Cell Chemical Biology 26 (7): 1036–1041.e3. doi:10.1016/j.chembiol.2019.04.002. PMID 31105063. 
  19. ↑ Viader, Andreu; Ogasawara, Daisuke; Joslyn, Christopher M; Sanchez-Alavez, Manuel; Mori, Simone; Nguyen, William; Conti, Bruno; Cravatt, Benjamin F (2016-01-18). "A chemical proteomic atlas of brain serine hydrolases identifies cell type-specific pathways regulating neuroinflammation" (in en). eLife 5: e12345. doi:10.7554/eLife.12345. ISSN 2050-084X. PMID 26779719. 
  20. ↑ Valdeolivas, S.; Pazos, M. R.; Bisogno, T.; Piscitelli, F.; Iannotti, F. A.; Allarà, M.; Sagredo, O.; Di Marzo, V. et al. (2013-10-17). "The inhibition of 2-arachidonoyl-glycerol (2-AG) biosynthesis, rather than enhancing striatal damage, protects striatal neurons from malonate-induced death: a potential role of cyclooxygenase-2-dependent metabolism of 2-AG" (in en). Cell Death & Disease 4 (10): e862. doi:10.1038/cddis.2013.387. ISSN 2041-4889. PMID 24136226. 
  21. ↑ 21.0 21.1 Powell, David R.; Gay, Jason P.; Wilganowski, Nathaniel; Doree, Deon; Savelieva, Katerina V.; Lanthorn, Thomas H.; Read, Robert; Vogel, Peter et al. (2015-06-02). "Diacylglycerol Lipase α Knockout Mice Demonstrate Metabolic and Behavioral Phenotypes Similar to Those of Cannabinoid Receptor 1 Knockout Mice". Frontiers in Endocrinology 6: 86. doi:10.3389/fendo.2015.00086. ISSN 1664-2392. PMID 26082754. 

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