Enzyme that breaks down diacylglycerol in many organisms.
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 + H2 O ⇌
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
^
a
b
c
d
e
f
g
h
i
j
k
l
m 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 .
^
a
b 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 .
^
a
b 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 .
^
a
b
c 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 .
^ 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 .
^
a
b
c
d
e
f 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 .
^
a
b
c
d
e
f
g 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 .
^ 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.
doi :
10.1016/j.bbrc.2011.07.037 .
ISSN
0006-291X .
PMID
21787747 .
^
a
b 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.
doi :
10.1021/jacs.5b04883 .
ISSN
1520-5126 .
PMC
4773911 .
PMID
26083464 .
^
a
b
c
d
e
f
g 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 .
^
a
b 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 .
^
a
b Stryer, Lubert (1981). Biochemistry (2nd ed.). W. H. Freeman and Company. p. 162.
ISBN
0716712261 .
^
a
b
c 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 .
^
a
b
c 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 .
^
a
b
c 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 .
^
a
b 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 .
^
a
b
c 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 .
^
a
b 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 .
^ 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 .
^ 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 .
^
a
b 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 .
External links
Activity Regulation Classification Kinetics Types
Receptor (
ligands )
DP (D2 ) Tooltip Prostaglandin D2 receptor
DP1 Tooltip Prostaglandin D2 receptor 1
DP2 Tooltip Prostaglandin D2 receptor 2
EP (E2 ) Tooltip Prostaglandin E2 receptor
EP1 Tooltip Prostaglandin EP1 receptor
EP2 Tooltip Prostaglandin EP2 receptor
EP3 Tooltip Prostaglandin EP3 receptor
EP4 Tooltip Prostaglandin EP4 receptor Unsorted
FP (F2α ) Tooltip Prostaglandin F receptor
IP (I2 ) Tooltip Prostacyclin receptor
TP (TXA2 ) Tooltip Thromboxane receptor Unsorted
Enzyme (
inhibitors )
COX (
PTGS )
PGD2 S Tooltip Prostaglandin D synthase
PGES Tooltip Prostaglandin E synthase
PGFS Tooltip Prostaglandin F synthase
PGI2 S Tooltip Prostacyclin synthase
TXAS Tooltip Thromboxane A synthase
Others
Receptor (
ligands )
BLT Tooltip Leukotriene B4 receptor
BLT1 Tooltip Leukotriene B4 receptor 1
BLT2 Tooltip Leukotriene B4 receptor 2
CysLT Tooltip Cysteinyl leukotriene receptor
CysLT1 Tooltip Cysteinyl leukotriene receptor 1
CysLT2 Tooltip Cysteinyl leukotriene receptor 2
CysLTE Tooltip Cysteinyl leukotriene receptor E
Enzyme (
inhibitors )
5-LOX Tooltip Arachidonate 5-lipoxygenase
12-LOX Tooltip Arachidonate 12-lipoxygenase
15-LOX Tooltip Arachidonate 15-lipoxygenase
LTA4 H Tooltip Leukotriene A4 hydrolase
LTB4 H Tooltip Leukotriene B4 ω-hydroxylase
LTC4 S Tooltip Leukotriene C4 synthase
LTC4 H Tooltip Leukotriene C4 hydrolase
LTD4 Tooltip Leukotriene D4 hydrolase
Others