Diacylglycerol lipase

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diacylglycerol lipase α
Diacylglycerol lipase a (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 gene 747
HGNC 1165
RefSeq NM_006133
UniProt Q9Y4D2
Other data
EC number 3.1.1.116
Locus Chr. 11 q12.3
Search for
Structures Swiss-model
Domains InterPro
diacylglycerol lipase β
Diacylglycerol lipase b (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 gene 221955
HGNC 28923
RefSeq NM_139179
UniProt Q8NCG7
Other data
EC number 3.1.1.116
Locus Chr. 7 p22.1
Search for
Structures Swiss-model
Domains InterPro

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]

Contents

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. Products are shown in blue. Intermolecular interactions are shown in cyan. Arrow-pushing is shown in red. Diacylglycerol lipase's hydrolysis mechanism producing 2-arachidonoylglycerol.png
Diacylglycerol lipase mechanism. 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 2 3 4 5 6 7 8 9 10 11 12 13 Bisogno T, Howell F, Williams G, et al. (November 2003). "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. doi:10.1083/jcb.200305129. PMC   2173631 . PMID   14610053.
  2. 1 2 Jumper, John; Evans, Richard; Pritzel, Alexander; Green, Tim; Figurnov, Michael; Ronneberger, Olaf; Tunyasuvunakool, Kathryn; Bates, Russ; Žídek, Augustin; Potapenko, Anna; Bridgland, Alex; Meyer, Clemens; Kohl, Simon A. A.; Ballard, Andrew J.; Cowie, Andrew (2021-07-15). "Highly accurate protein structure prediction with AlphaFold". Nature. 596 (7873): 583–589. Bibcode:2021Natur.596..583J. doi:10.1038/s41586-021-03819-2. ISSN   1476-4687. PMC   8371605 . PMID   34265844.
  3. 1 2 Mirdita, Milot; Schütze, Konstantin; Moriwaki, Yoshitaka; Heo, Lim; Ovchinnikov, Sergey; Steinegger, Martin (2022-05-30). "ColabFold: making protein folding accessible to all". Nature Methods. 19 (6): 679–682. doi:10.1038/s41592-022-01488-1. ISSN   1548-7105. PMC   9184281 . PMID   35637307.
  4. 1 2 3 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.
  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" . Gene. 103 (1): 61–67. doi:10.1016/0378-1119(91)90391-N. ISSN   0378-1119. PMID   1879699.
  6. 1 2 3 4 5 6 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. S2CID   233477096.
  7. 1 2 3 4 5 6 7 Reisenberg, Melina; Singh, Praveen K.; Williams, Gareth; Doherty, Patrick (2012-12-05). "The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling". Philosophical Transactions of the Royal Society B: Biological Sciences. 367 (1607): 3264–3275. doi:10.1098/rstb.2011.0387. ISSN   0962-8436. PMC   3481529 . PMID   23108545.
  8. ↑ Pedicord, Donna L.; Flynn, Michael J.; Fanslau, Caroline; Miranda, Maricar; Hunihan, Lisa; Robertson, Barbara J.; Pearce, Bradley C.; Yu, Xuan-Chuan; Westphal, Ryan S.; Blat, Yuval (2011-08-12). "Molecular characterization and identification of surrogate substrates for diacylglycerol lipase α" . Biochemical and Biophysical Research Communications. 411 (4): 809–814. Bibcode:2011BBRC..411..809P. doi:10.1016/j.bbrc.2011.07.037. ISSN   0006-291X. PMID   21787747.
  9. 1 2 Baggelaar, Marc P.; Chameau, Pascal J. P.; Kantae, Vasudev; Hummel, Jessica; Hsu, Ku-Lung; Janssen, Freek; van der Wel, Tom; Soethoudt, Marjolein; Deng, Hui; den Dulk, Hans; Allarà, Marco; Florea, Bogdan I.; Di Marzo, Vincenzo; Wadman, Wytse J.; Kruse, Chris G. (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. Bibcode:2015JAChS.137.8851B. doi:10.1021/jacs.5b04883. ISSN   1520-5126. PMC   4773911 . PMID   26083464.
  10. 1 2 3 4 5 6 7 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. hdl: 1887/3188875 . ISSN   1464-3405. PMID   27394666. S2CID   206269983.
  11. 1 2 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". Nature Communications. 10 (1): 3198. Bibcode:2019NatCo..10.3198C. doi:10.1038/s41467-019-11155-3. ISSN   2041-1723. PMC   6642262 . PMID   31324776.
  12. 1 2 Stryer, Lubert (1981). Biochemistry (2nd ed.). W. H. Freeman and Company. p. 162. ISBN   0716712261.
  13. 1 2 3 Gao, Ying; Vasilyev, Dmitry V.; Goncalves, Maria Beatriz; Howell, Fiona V.; Hobbs, Carl; Reisenberg, Melina; Shen, Ru; Zhang, Mei-Yi; Strassle, Brian W.; Lu, Peimin; Mark, Lilly; Piesla, Michael J.; Deng, Kangwen; Kouranova, Evguenia V.; Ring, Robert H. (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. PMC   6634037 . PMID   20147530.
  14. 1 2 3 Tanimura, Asami; Yamazaki, Maya; Hashimotodani, Yuki; Uchigashima, Motokazu; Kawata, Shinya; Abe, Manabu; Kita, Yoshihiro; Hashimoto, Kouichi; Shimizu, Takao; Watanabe, Masahiko; Sakimura, Kenji; Kano, Masanobu (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. S2CID   14879766.
  15. 1 2 3 Ogasawara, Daisuke; Deng, Hui; Viader, Andreu; Baggelaar, Marc P.; Breman, Arjen; den Dulk, Hans; van den Nieuwendijk, Adrianus M. C. H.; Soethoudt, Marjolein; van der Wel, Tom; Zhou, Juan; Overkleeft, Herman S.; Sanchez-Alavez, Manuel; Mori, Simone; Nguyen, William; Conti, Bruno (2016-01-05). "Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition". Proceedings of the National Academy of Sciences. 113 (1): 26–33. Bibcode:2016PNAS..113...26O. doi: 10.1073/pnas.1522364112 . ISSN   0027-8424. PMC   4711871 . PMID   26668358.
  16. 1 2 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". Nature Chemical Biology. 8 (12): 999–1007. doi:10.1038/nchembio.1105. ISSN   1552-4469. PMC   3513945 . PMID   23103940.
  17. 1 2 3 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. PMC   5837917 . PMID   28901776.
  18. 1 2 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". Cell Chemical Biology. 26 (7): 1036–1041.e3. doi:10.1016/j.chembiol.2019.04.002. PMC   6641989 . 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". eLife. 5: e12345. doi: 10.7554/eLife.12345 . ISSN   2050-084X. PMC   4737654 . PMID   26779719.
  20. ↑ Valdeolivas, S.; Pazos, M. R.; Bisogno, T.; Piscitelli, F.; Iannotti, F. A.; Allarà, M.; Sagredo, O.; Di Marzo, V.; Fernández-Ruiz, J. (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". Cell Death & Disease. 4 (10): e862. doi:10.1038/cddis.2013.387. ISSN   2041-4889. PMC   3920947 . PMID   24136226.
  21. 1 2 Powell, David R.; Gay, Jason P.; Wilganowski, Nathaniel; Doree, Deon; Savelieva, Katerina V.; Lanthorn, Thomas H.; Read, Robert; Vogel, Peter; Hansen, Gwenn M.; Brommage, Robert; Ding, Zhi-Ming; Desai, Urvi; Zambrowicz, Brian (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. PMC   4451644 . PMID   26082754.
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