Lipases diacylglycerol

Eicosanoids, so named because they are all derived from 20-carbon fatty acids, are ubiquitous breakdown products of phospholipids. In response to appropriate stimuli, cells activate the breakdown of selected phospholipids (Figure 25.27). Phospholipase Ag (Chapter 8) selectively cleaves fatty acids from the C-2 position of phospholipids. Often these are unsaturated fatty acids, among which is arachidonic acid. Arachidonic acid may also be released from phospholipids by the combined actions of phospholipase C (which yields diacyl-glycerols) and diacylglycerol lipase (which releases fatty acids). 

Two possible pathways for the biosynthesis of 2-AG have been proposed (1) a phospholipase C (PLC) hydrolysis of membrane phospholipids followed by a second hydrolysis of the resulting 1,2-diacylglycerol by diacylglycerol lipase or (2) a phospholipase Ai (PLA,) activity that generates a lysophospholipid, which in turn is hydrolyzed to 2-AG by lysophospholipase C (Fig. 5) (Piomelli, 1998). Alternative pathways may also exist from either triacylglycerols by a neutral lipase activity or lysophosphatidic acid by a dephosphorylase. The fact that PLC and diacylglycerol lipase inhibitors inhibit 2-AG formation in cortical neurons supports the contention that 2-AG is, at least predominantly, biosynthesized by the PLC pathway (Stella, 1997). However, a mixed pathway may also be plausible. 

Figure 6.17. Leukotriene formation in neutrophils. Arachidonic acid, which is released from membrane phospholipids by the action of either phospholipase A2 or diacylglycerol lipase (see Fig. 6.13), is oxygenated by 5-lipoxygenase to yield 5 hydroperoxy-6,8,11,14 eicosa-tetraenoic acid (5-HPETE). This is then converted into 5 hydroxy-6,8,11,14 eicosatetra-enoic acid (5-HETE) and leukotriene (LT) A4. LTA4 may then be enzymically converted into LTC4 and LTB4. LTB4 is the major product in activated neutrophils.

Synthesizing Enzymes Phospholipase D Phospholipase C Diacylglycerol lipase... 

Anandamide is believed to be synthesized from a phospholipid precursor, /V-arachidonoyl-phosphatidylethanolamine, catalysed by phospholipase D (Di Marzo et al. 1998). The other proposed route of synthesis is from condensation of arachidonic acid and ethanolamine, although this has yet to be demonstrated in living cells. 2-AG is formed in a calcium-dependent manner, and mediated by the enzymes phospholipase C and diacylglycerol lipase (Kondo et al. 1998 Stella et al. 1997). 

This enzyme [EC 3.1.1.34] (also called clearing factor lipase, diglyceride lipase, and diacylglycerol lipase) catalyzes the hydrolysis of a triacylglycerol to produce a diacylglycerol and a fatty acid anion. This enzyme hydrolyzes triacylglycerols in chylomicrons and in low-density lipoproteins and also acts on diacylglycerols. See also Lipases... 

Fig. 5.4 Effects of glutamate on diacylglycerol lipase and monoacylglycerol lipase activities of neuron-enriched cultures from fetal mouse spinal cord. Diacylglycerol lipase (clear bars) and monoacylglycerol glycerol lipase (hatched bars). Data modified from Farooqui et al., 1993...

Enzymic activities were determined by procedures described earlier (Faiooqui et al., 1993). Specific activity was expressed as nmol/min/mg protein. Results are the means SEM for three different cultures. Glu, glutamate. RHC 80267 is a potent inhibitor of diacylglycerol lipase. 

Fig. 5.9 Temporal changes in the diacylglycerol lipase activity after ibotenate injection. Sodium chloride injected (clear bars) and ibotenate injected (hatched bar). Brains were removed after 1 day (1), 3 days (2), 10 days (3), and 6 months (4) after ibotenate injections. Diacylglycerol lipase activity was determined in 10,000 rpm supernatant (having PM and SPM) fraction from hippocampal region. Data modified from Farooqui et at., 1991...

Farooqui A. A., Wallace L. J., and Horrocks L. A. (1991). Stimulation of mono- and diacylglycerol lipase activities in ibotenate-induced lesions of nucleus basalis magnocellularis. Neurosci. Lett. 131 97-99. 

Chau L. Y. and Tai H. H. (1981). Release of arachidonate from diglyceride in human platelet requires the sequential action of a diacylglycerol lipase and a monoglyceride lipase. Biochem. Biophys. Res. Commun. 100 1688-1695. 

Diacylglycerol Lipase (2-AG Tetrahydroiip-statin (THL) Inhibitor 2-6 nM (IC50)... 

CW Hendrickse, S Radley, IA Donovan, MR Keighley, JP Neoptolemos. Activities of phospholipase A2 and diacylglycerol lipase are increased in human colorectal cancer. Br J Surg 82 475-478, 1995. 

Fig. 2. Targeted lipidomics of 2-AG metabolism. Postulated pathways for 2-AG metabolism. Abbreviations PLC, phospholipase C DAG, diacylglycerol DGL, diacylglycerol lipase MGL, monoacylglycerol lipase PLA, phospholipase A AT, acyltransferase TAGL, triacylglycerol lipase PIP2, phosphatidylinositol bisphosphate ABHD-6/12 hydrolase lyso-PL, lysophospholipid lyso-PA, lysophosphatidic acid PA, phosphatidic add P, phosphatase COX, cydooxygen-ase LOX, lipoxygenase CYP450, cytochrome P450 CDP, cytidine diphosphate.

Jung, K. M., Astarita, G., Zhu, C., Wallace, M., Mackie, K., and Piomelli, D. (2007). A key role for diacylglycerol lipase-alpha in metabotropic glutamate receptor-dependent endocannabinoid mobilization. Mol Pharmacol 72, 612-621. 

Hashimotodani, Y., Ohno-Shosaku, T., Maejima, T., Fukami, K., and Kano, M. (2008). Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization-induced endocana-binoid release. Neuropharmacology 54, 58-67. 

During hormonal stimulation of Ptdlns 4,5-P2 hydrolysis there appears to be a preferential degradation of molecules, such as diacylglycerol and phosphatidic acid, which contain arachidonate in the 2-position. Two separate pathways have been proposed for the release of arachidonic acid from these two products of the phosphoinositide response. The first proposes that diacylglycerol is the source of the liberated arachidonate and that diacylglycerol lipase acts on the DG released by hydrolysis of phosphoinositides. The second suggests that a phosphatidic acid-specific phospholipase A2 is responsible for cleaving the arachidonic acid from phosphati-date. 

Hormone-sensitive lipase hydrolyses fatty acids from carbon atoms 1 or 3 of triacylglycerols. The resulting diacylglycerols are substrates for either hormone-sensitive lipase or the noninducible enzyme diacylglycerol lipase. Finally, monoacylglycerols are snbstrates for monoa-cylglycerol lipase. 

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