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Regulation of the Arachidonic Acid Cascade and PAF Metabolism in Reproductive Tissues
Published in Murray D. Mitchell, Eicosanoids in Reproduction, 2020
John M. Johnston, Noriei Maki, Marlane J. Angle, Dennis R. Hoffman
In support of the view that diacylglycerol was produced physiologically by phospholipase C, we demonstrated that diacylglycerol was produced in increased amounts in amnion tissue obtained from women in labor and that the diacylglycerol had a fatty acid composition almost identical to that of the parent phosphatidylinositol.49 This experiment provided further support for the presence of a phosphatidylinositol-specific phospholipase C in amnion tissue. The diacylglycerol produced in this tissue can be metabolized by at least two pathways: (1) diacylglycerol lipase or (2) phosphorylation by a diacylglycerol kinase. The activity of diacylglycerol lipase in amnion tissue was shown to be highest in the microsomal fraction and specific for the ester bond at the sn-1 position, producing fatty acid and 2-monoacylglycerol.50 This diacylglycerol lipase also preferentially cleaved diacylglycerol containing arachidonoyl in the sn-2 position. Monoacylglycerol lipase activity was also demonstrated in the cytosolic fraction of amnion tissue.50 The specific activity of monoacylglycerol lipase was significantly greater than that of diacylglycerol lipase and preferentially catalyzed the hydrolysis of 2-monoacylglycerol containing an arachidonoyl group. Based on the subcellular distribution and the effects of various inhibitors, it was concluded that monoacylglycerol lipase and diacylglycerol lipase in fetal membranes and decidua tissue were two distinct enzyme activities.
Endocannabinoid System & Cannabinoid Receptors
Published in Betty Wedman-St Louis, Cannabis as Medicine, 2019
Monoacylglycerol lipase (MAGL) is a key enzyme that converts monoacylglycerol to the free fatty acid and glycerol which results in the degradation of lipoprotein triglycerides. This may be a possible therapeutic target to regulate the homeostatic action of endocannabinoids for pain, anxiety, and inflammatory bowel disease [17]. MAGL inhibition has also been shown to reduce cancer cell growth and brain inflammation [18]. Blocking MAGL, which controls levels of a pain-reducing metabolite in the brain and regulates neuroinflammation, could provide a therapeutic benefit in neurodegenerative disorders like Parkinson’s disease and Alzheimer’s disease.
Phosphatidate Phosphohydrolase Activity in Adipose Tissue
Published in David N. Brindley, John R. Sabine, Phosphatidate Phosphohydrolase, 2017
The rate of this process in white adipose tissue is dependent on the interplay between a number of factors both in the short and long term. Much of the work in this area has been reviewed elsewhere154-160 from various standpoints. The central feature of lipolysis is the hormone-sensitive lipase which is ratelimiting for the process and catalyzes hydrolysis of triacylglycerol to diacylglycerol and diacylglycerol to monoacylglycerol (Figure 3). The hydrolysis of the resulting monoacylglycerol is mainly catalyzed by a separate monoacylglycerol lipase. Hormone-sensitive lipase is activated by cAMP-dependent protein kinase161-171and it is now established that this is due to the phosphorylation of the enzyme172-175 at a single serine residue.176,177 Dephosphorylation and deactivation of the lipase can be achieved by cellular protein phosphatases of types 1A, 2A, and 2C.160
Advances in luminescence-based technologies for drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Bolormaa Baljinnyam, Michael Ronzetti, Anton Simeonov
Other bioluminescence-based enzyme assays exploit the unique structure of luciferin and how it cannot be metabolized by many mammalian and prokaryotic enzymes. For such assays, a pro-luciferin molecule which cannot enable luminescence directly is used. It must first be converted into luciferin by another enzyme before it can be used as a substrate for a luciferase. For example, DEVD-6′-aminoluciferin is a specific substrate for protease cleavage by caspase-3 or caspase-7. The cleavage by caspase-3 and −7 liberates aminoluciferin which becomes available for the luciferase, generating a luminescence signal that is directly proportional to the caspase enzyme activity. Since the substrate is specific for caspase-3 and −7, this assay can be used in both biochemical and cell-based assays and has seen widespread adoption as a method with which to measure the population of apoptotic cells [27]. Based on the same principle, a new ultra-sensitive assay to monitor monoacylglycerol lipase activity, a promising therapeutic target involved in endocannabinoid system modulation, was recently reported [28].
Monoacylglycerol lipase deficiency in the tumor microenvironment slows tumor growth in non-small cell lung cancer
Published in OncoImmunology, 2021
Melanie Kienzl, Carina Hasenoehrl, Kathrin Maitz, Arailym Sarsembayeva, Ulrike Taschler, Paulina Valadez-Cosmes, Oliver Kindler, Dusica Ristic, Sofia Raftopoulou, Ana Santiso, Thomas Bärnthaler, Luka Brcic, Lisa Hahnefeld, Robert Gurke, Dominique Thomas, Gerd Geisslinger, Julia Kargl, Rudolf Schicho
Monoacylglycerol lipase (MGL) was characterized several decades ago as the major enzyme that hydrolyzes monoglycerides into glycerol and fatty acids (rev. in1). One of these monoglycerides is 2-arachidonoyl glycerol (2-AG),2 which has been also identified as an endocannabinoid (rev. in3). 2-AG is a full agonist at cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors, thereby causing cannabimimetic effects.4 MGL contributes to many (patho)physiological conditions, such as pain, food intake, stress, metabolic disorders, addiction, inflammation, and cancer (rev. in1). Cannabinoid receptor signaling is terminated through degradation of 2-AG by MGL, which therefore plays, aside from its lipolytic function, a major role in endocannabinoid metabolism.3 It accounts for around 85% of brain 2-AG hydrolase activity while the remaining part is degraded by enzymes like α/β-hydrolase domain containing (ABHD) 6 and 12.5 2-AG, CB1/CB2 and MGL are a chain of key regulators that operate cooperatively within the endocannabinoid system (ECS). Notably, pharmacological inhibition or genetic deletion of MGL results in the accumulation of endogenous 2-AG, but not of arachidonoyl ethanolamide (anandamide; AEA), another well-described endocannabinoid.6–9 In addition, MGL provides a large pool of arachidonic acid (AA), from which pro-inflammatory prostaglandins may be generated.10 This indicates that besides 2-AG, MGL regulates the availability of AA.8,11
Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Alessandro Deplano, Jessica Karlsson, Mona Svensson, Federica Moraca, Bruno Catalanotti, Christopher J. Fowler, Valentina Onnis
In a key study from 2009, Naidu, Lichtman and colleagues2 reported that the ulcerogenic potency of the NSAID diclofenac was lower in mice lacking the enzyme fatty acid amide hydrolase (FAAH) than in the corresponding wild-type mice. A similar result was found in wild-type mice pre-treated with the irreversible FAAH inhibitor URB597 ((3′-(aminocarbonyl)[1,1′-biphenyl] − 3-yl)-cyclohexylcarbamate). Further, URB597 and diclofenac acted synergistically in reducing acetic acid-induced visceral nociception2. FAAH catalyses the hydrolysis of the endogenous cannabinoid (endocannabinoid) ligand anandamide (AEA, arachidonoylethanolamide)3 and the effects of FAAH inhibition upon diclofenac-induced ulceration were not seen in mice lacking cannabinoid-1 receptors2. The ability of FAAH inhibition to reduce the ulcerogenic potency of NSAIDs has also been seen with a peripherally-restricted FAAH inhibitor, URB937 (N-cyclohexyl-carbamic acid, 3′-(aminocarbonyl)−6-hydroxy[1,1′-biphenyl] − 3-yl ester) and with indomethacin as NSAID4. A second endocannabinoid, 2-arachidonoylglycerol (2-AG) is primarily hydrolysed by monoacylglycerol lipase, and inhibition of that enzyme also reduces the ulcerogenic potency of diclofenac5,6.