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]

Related Research Articles

<span class="mw-page-title-main">Lingual lipase</span> Mammalian protein found in Homo sapiens

Lingual lipase is a member of a family of digestive enzymes called triacylglycerol lipases, EC 3.1.1.3, that use the catalytic triad of aspartate, histidine, and serine to hydrolyze medium and long-chain triglycerides into partial glycerides and free fatty acids. The enzyme, released into the mouth along with the saliva, catalyzes the first reaction in the digestion of dietary lipid, with diglycerides being the primary reaction product. However, due to the unique characteristics of lingual lipase, including a pH optimum 4.5–5.4 and its ability to catalyze reactions without bile salts, the lipolytic activity continues through to the stomach. Enzyme release is signaled by autonomic nervous system after ingestion, at which time the serous glands under the circumvallate and foliate lingual papillae on the surface of the tongue secrete lingual lipase to the grooves of the circumvallate and foliate papillae, co-localized with fat taste receptors. The hydrolysis of the dietary fats is essential for fat absorption by the small intestine, as long chain triacylglycerides cannot be absorbed, and as much as 30% of fat is hydrolyzed within 1 to 20 minutes of ingestion by lingual lipase alone.

<span class="mw-page-title-main">Catalytic triad</span> Set of three coordinated amino acids

A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes. An acid-base-nucleophile triad is a common motif for generating a nucleophilic residue for covalent catalysis. The residues form a charge-relay network to polarise and activate the nucleophile, which attacks the substrate, forming a covalent intermediate which is then hydrolysed to release the product and regenerate free enzyme. The nucleophile is most commonly a serine or cysteine amino acid, but occasionally threonine or even selenocysteine. The 3D structure of the enzyme brings together the triad residues in a precise orientation, even though they may be far apart in the sequence.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

<span class="mw-page-title-main">Diacylglycerol kinase</span> Class of enzymes

Diacylglycerol kinase is a family of enzymes that catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA), utilizing ATP as a source of the phosphate. In non-stimulated cells, DGK activity is low, allowing DAG to be used for glycerophospholipid biosynthesis, but on receptor activation of the phosphoinositide pathway, DGK activity increases, driving the conversion of DAG to PA. As both lipids are thought to function as bioactive lipid signaling molecules with distinct cellular targets, DGK therefore occupies an important position, effectively serving as a switch by terminating the signalling of one lipid while simultaneously activating signalling by another.

<span class="mw-page-title-main">Monoacylglycerol lipase</span> Class of enzymes

Monoacylglycerol lipase is an enzyme that, in humans, is encoded by the MGLL gene. MAGL is a 33-kDa, membrane-associated member of the serine hydrolase superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases. The catalytic triad has been identified as Ser122, His269, and Asp239.

<span class="mw-page-title-main">Fatty-acid amide hydrolase 1</span>

Fatty-acid amide hydrolase 1 or FAAH-1(EC 3.5.1.99, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an N-acylethanolamine (NAE) in 1993. In humans, it is encoded by the gene FAAH. FAAH also regulate the contents of NAE's in Dictyostelium discoideum, as they modulate their NAE levels in vivo through the use of a semispecific FAAH inhibitor.

<span class="mw-page-title-main">2-Arachidonoylglycerol</span> Chemical compound

2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994–1995, although it had been discovered some time before that. The activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).

Serine hydrolases are one of the largest known enzyme classes comprising approximately ~200 enzymes or 1% of the genes in the human proteome. A defining characteristic of these enzymes is the presence of a particular serine at the active site, which is used for the hydrolysis of substrates. The hydrolysis of the ester or peptide bond proceeds in two steps. First, the acyl part of the substrate is transferred to the serine, making a new ester or amide bond and releasing the other part of the substrate is released. Later, in a slower step, the bond between the serine and the acyl group is hydrolyzed by water or hydroxide ion, regenerating free enzyme. Unlike other, non-catalytic, serines, the reactive serine of these hydrolases is typically activated by a proton relay involving a catalytic triad consisting of the serine, an acidic residue and a basic residue, although variations on this mechanism exist.

<span class="mw-page-title-main">Gastric lipase</span> Class of enzymes

Gastric lipase, also known as LIPF, is an enzymatic protein that, in humans, is encoded by the LIPF gene.

<span class="mw-page-title-main">Cutinase</span>

The enzyme cutinase is a member of the hydrolase family. It catalyzes the following reaction:

<span class="mw-page-title-main">JZL184</span> Chemical compound

JZL184 is an irreversible inhibitor for monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG). It displays high selectivity for MAGL over other brain serine hydrolases, including the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), thereby making it a useful tool for studying the effects of endogenous 2-AG signaling, in vivo. Administration of JZL184 to mice was reported to cause dramatic elevation of brain 2-AG leading to several cannabinoid-related behavioral effects.

<span class="mw-page-title-main">Lipase</span> Class of enzymes

Lipase is a family of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually treated separately from "conventional" lipases. Unlike esterases, which function in water, lipases "are activated only when adsorbed to an oil–water interface". Lipases perform essential roles in digestion, transport and processing of dietary lipids in most, if not all, organisms.

<span class="mw-page-title-main">URB602</span> Chemical compound

URB602 is a compound that has been found to inhibit hydrolysis of monoacyl glycerol compounds, such as 2-arachidonoylglycerol (2-AG) and 2-oleoylglycerol (2-OG). It was first described in 2003. A study performed in 2005 found that the compound had specificity for metabolizing 2-AG over anandamide in rat brain presumably by inhibiting the enzyme monoacylglycerol lipase (MAGL), which is the primary metabolic enzyme of 2-AG. However, subsequent studies have shown that URB602 lacks specificity for MAGL inhibition in vitro.

<span class="mw-page-title-main">2-Oleoylglycerol</span> Chemical compound

2-Oleoylglycerol (2OG) is a monoacylglycerol that is found in biologic tissues. Its synthesis is derived from diacylglycerol precursors. It is metabolized to oleic acid and glycerol primarily by the enzyme monoacylglycerol lipase (MAGL). In 2011, 2OG was found to be an endogenous ligand to GPR119. 2OG has been shown to increase glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels following administration to the small intestine.

<span class="mw-page-title-main">JZL195</span> Chemical compound

JZL195 is a potent inhibitor of both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the primary enzymes responsible for degrading the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively.

<span class="mw-page-title-main">Diglyceride</span> Type of fat derived from glycerol and two fatty acids

A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as surfactants and are commonly used as emulsifiers in processed foods. DAG-enriched oil has been investigated extensively as a fat substitute due to its ability to suppress the accumulation of body fat; with total annual sales of approximately USD 200 million in Japan since its introduction in the late 1990s till 2009.

IDFP is an organophosphorus compound related to the nerve agent sarin.

<span class="mw-page-title-main">ABHD6</span> Protein-coding gene in the species Homo sapiens

alpha/beta-Hydrolase domain containing 6 (ABHD6), also known as monoacylglycerol lipase ABHD6 or 2-arachidonoylglycerol hydrolase is an enzyme that in humans is encoded by the ABHD6 gene.

<span class="mw-page-title-main">ABHD12</span> Protein-coding gene in the species Homo sapiens

alpha/beta-Hydrolase domain containing 12 (ABHD12) is a serine hydrolase encoded by the ABHD12 gene that participates in the breakdown of the endocannabinoid neurotransmitter 2-arachidonylglycerol (2-AG) in the central nervous system. It is responsible for about 9% of brain 2-AG hydrolysis. Together, ABHD12 along with two other enzymes, monoacylglycerol lipase (MAGL) and ABHD6, control 99% of 2-AG hydrolysis in the brain. ABHD12 also serves as a lysophospholipase and metabolizes lysophosphatidylserine (LPS).

<span class="mw-page-title-main">Discovery and development of gastrointestinal lipase inhibitors</span>

Lipase inhibitors belong to a drug class that is used as an antiobesity agent. Their mode of action is to inhibit gastric and pancreatic lipases, enzymes that play an important role in the digestion of dietary fat. Lipase inhibitors are classified in the ATC-classification system as A08AB . Numerous compounds have been either isolated from nature, semi-synthesized, or fully synthesized and then screened for their lipase inhibitory activity but the only lipase inhibitor on the market is orlistat . Lipase inhibitors have also shown anticancer activity, by inhibiting fatty acid synthase.

References

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  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.
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