- Phospholipase A2
Phospholipases A2 (PLA2s) EC number|126.96.36.199 are upstream regulators of many inflammatory processes. This particular
phospholipasespecifically recognizes the sn-2 acylbond of phospholipidsand catalytically hydrolyzesthe bond releasing arachidonic acidand lysophospholipids. Upon downstream modification by cyclooxygenases, arachidonic acidis modified into active compounds called eicosanoids. Eicosanoids include prostaglandinsand leukotrieneswhich are categorized as inflammatory mediators. [Dennis, et al. "Diversity of Group Types, Regulation, and Function of Phospholipase A2." The Journal of Biological Chemistry. VOl. 269. No 18. 13057-13060.]
PLA2 are commonly found in mammalian tissues as well as insect and snake venom. [ Nicholas, et al. "Localization of Structural Elements of Bee Venom Phospholipase A2 Involved in N-type Receptor Binding and Neurotoxicity." Journal of Biological Chemistry. Vol. 227. No. 11. 7173-7181.] Venom from both snakes and insects is largely composed of
melittinwhich is a stimulant of PLA2. Due to the increased presence and activity of PLA2 resulting from a snake or insect bite, arachidonic acidis released from the phospholipid membranedisproportionately. As a result, inflammation and pain occur at the site. [Argiolas, Pianso. "Facilitation of Phospholipase A2 Activity by Mastoparans, a New Class of Mast Cell Degranulating Peptides from Wasp Venom." Journal of Biological Chemistry. Vol. 285. Issue 122. 13697-13702] There are also prokaryotic A2 phospholipases.
Additional types of
phospholipasesinclude phospholipase A1, phospholipase B, phospholipase C, and phospholipase D. [Lehninger. "Principles of Biochemistry". 2004. W H Freeman and Company. Fourth Edition.]
Phospholipases A2 include several unrelated protein families with common enzymatic activity. Two most notable families are secreted and cytosolic phospholipases A2. Other families include Ca2+ independent PLA2 (iPLA2) and lipoprotein-associated PLA2s (lp-PLA2), also known as platelet activating factor acetylhydrolase (PAF-AH).
ecreted phospholipases A2 (sPLA2)
extracellularforms of phospholipases A2 have been isolated from different venoms (snake, bee, and wasp), from virtually every studied mammalian tissue (including pancreasand kidney) as well as from bacteria. They require Ca2+ for activity.
Pancreatic PLA2 serve for the initial
digestionof phospholipid compounds in dietary fat. Venom phospholipases help to immobilize prey by promoting cell lysis.
Cytosolic phospholipases A2 (cPLA2)
intracellularPLA2 are also Ca-dependent, but they have completely different 3D structure and significantly larger than secreted PLA2 (more than 700 residues). They include C2 domainand large catalytic domain.
These phospholipases are involved in
cell signalingprocesses, such as inflammatory response. The produced Arachidonic acidis both a signaling moleculeand the precursor for other signalling molecules termed eicosanoids. These include leukotrienes and prostaglandins. Some eicosanoids are synthesized from diacylglycerol, released from the lipid bilayerby phospholipase C (see below).
Phospholipases A2 can be classified based on sequence homology.cite journal |author=Six DA, Dennis EA |title=The expanding superfamily of phospholipase A(2) enzymes: classification and characterization |journal=Biochim. Biophys. Acta |volume=1488 |issue=1-2 |pages=1–19 |year=2000 |pmid=11080672]
Lipoprotein-associated PLA2s (lp-PLA2)
Increased levels of lp-PLA2 are associated with cardiac disease, and may contribute to
. The role of calcium can also be duplicated by other relatively small cations like colbalt and nickel. [Berg et al. “Interfacial Enzymology: The Secreted Phospholipase A2-Paradigm” Chemical Review, 2001. Vol. 101. No. 9 2638-2640.]
PLA2 can also be characterized as having a channel featuring a
hydrophobicwall in which hydrophobic amino acid residues such as Phe, Leu, and Tyrserve to bind the substrate. Another component of PLA2 is the seven disulfide bridgeswhich are influential in regulation and stable protein folding. [Berg et al. “Interfacial Enzymology: The Secreted Phospholipase A2-Paradigm” Chemical Review, 2001. Vol. 101. No. 9 2638-2640.]
Symbol = Phospholip_A2_1
Name = Phospholipase A2
SCOP = 1bbc
OPM family= 90
OPM protein= 1g4i
PDB=PDB3|1vkqA:23-145 PDB3|1mks :23-145 PDB3|1gh4A:23-145PDB3|4bp2 :23-145 PDB3|1kvw :23-145 PDB3|1irb :23-145PDB3|1kvx :23-145 PDB3|1o2eA:23-145 PDB3|2bpp :23-145PDB3|1une :23-145 PDB3|1vl9A:23-145 PDB3|1g4iA:23-145PDB3|1bvmA:23-145 PDB3|1o3wA:23-145 PDB3|2bp2 :23-145PDB3|1mkv :23-145 PDB3|1ceh :23-145 PDB3|1bpq :23-145PDB3|1mku :23-145 PDB3|1bp2 :23-145 PDB3|1c74A:23-145PDB3|3bp2 :24-145 PDB3|1kvy :23-145 PDB3|1fdk :23-145PDB3|1mkt :23-145 PDB3|2baxA:23-145 PDB3|1y6oA:23-146PDB3|2phiA:23-146 PDB3|1hn4A:23-146 PDB3|1y6pA:23-146PDB3|1fxfB:23-146 PDB3|1fx9B:23-146 PDB3|1l8sB:23-146PDB3|1pis :23-146 PDB3|1sfw :23-146 PDB3|1sfv :23-146PDB3|1pir :23-146 PDB3|3p2pB:23-146 PDB3|5p2pB:23-146PDB3|4p2p :23-146 PDB3|1p2p :23-146 PDB3|1m8tD:28-146PDB3|1gp7B:28-151 PDB3|1pobA:28-145 PDB3|1poa :28-145PDB3|1pshA:1-118 PDB3|1owsB:4-118 PDB3|1a3fC:1-118PDB3|1a3d :1-118 PDB3|1sz8A:8-125 PDB3|1ln8A:8-125PDB3|1yxlA:8-125 PDB3|1t37A:8-125 PDB3|1mf4A:8-125PDB3|1zm6A:8-125 PDB3|1oxrA:8-125 PDB3|1td7A:9-125PDB3|1mh2B:8-125 PDB3|1xxwB:8-125 PDB3|1s6bB:8-125PDB3|1yxhA:8-125 PDB3|1y75A:8-124 PDB3|1mh8A:8-125PDB3|1mh7A:8-125 PDB3|1oo1A:1-117 PDB3|1g2xA:28-141PDB3|1fe5A:28-144 PDB3|1dpyA:28-144 PDB3|1po8A:34-132PDB3|1u4jA:20-136 PDB3|1tc8A:20-136 PDB3|1ae7N:1-118PDB3|2notA:1-118 PDB3|1lx1A:1-118 PDB3|1bunA:28-146PDB3|1vipP:1-121 PDB3|1oz6A:17-136 PDB3|1q5tB:1-122PDB3|1aokA:1-122 PDB3|1jltA:1-122 PDB3|1vpi :1-122PDB3|1oqsA:17-138 PDB3|1rgbA:1-122 PDB3|1pp2L:17-138PDB3|1ijlA:1-123 PDB3|1m8rA:1-124 PDB3|1bk9 :1-124PDB3|1psj :1-124 PDB3|1m8sA:1-124 PDB3|1vapA:1-123PDB3|1u73B:17-138 PDB3|1umvX:17-138 PDB3|1pa0B:1-119PDB3|1pc9B:1-119 PDB3|1qllA:1-121 PDB3|1xxsB:1-122PDB3|1clpB:1-121 PDB3|1y4lA:1-121 PDB3|1godA:1-121PDB3|1s8iA:17-137 PDB3|1s8hA:17-137 PDB3|1s8gA:17-137PDB3|1ppa :1-121 PDB3|1mc2A:17-138 PDB3|1mg6A:17-138PDB3|1gmzB:1-106 PDB3|1bjjF:1-122 PDB3|1a2aF:1-122PDB3|1c1jC:1-122 PDB3|1jiaB:18-138 PDB3|1b4wC:18-138PDB3|1y38A:1-121 PDB3|1cl5B:1-121 PDB3|1jq9A:1-121PDB3|2fnxA:1-121 PDB3|1tg1A:1-121 PDB3|1fv0A:1-121PDB3|1tj9A:1-121 PDB3|1tjqA:1-121 PDB3|1sxkA:1-121PDB3|1tp2B:1-121 PDB3|1zyxA:1-121 PDB3|1tdvA:1-121PDB3|1jq8B:1-121 PDB3|1tgmA:1-121 PDB3|2b17A:1-121PDB3|1oxlB:1-121 PDB3|1sv3A:1-121 PDB3|1oyfA:1-121PDB3|1tk4A:1-121 PDB3|1th6A:1-121 PDB3|1kpmA:1-121PDB3|2armA:1-121 PDB3|1sqzA:1-121 PDB3|1fb2B:1-121PDB3|1ti0A:1-121 PDB3|1q7aA:1-121 PDB3|1tg4A:1-121PDB3|1sv9A:1-121 PDB3|1q6vA:1-121 PDB3|1zr8A:1-121PDB3|1tjkA:1-121 PDB3|1kvoA:21-144 PDB3|1aypD:21-144PDB3|1n28A:22-144 PDB3|1dcyA:21-144 PDB3|1n29A:22-144PDB3|1db4A:21-144 PDB3|1j1aB:21-144 PDB3|1bbc :21-144PDB3|1pod :21-144 PDB3|1poeB:21-144 PDB3|1kquA:21-144PDB3|1db5A:21-144 PDB3|1le7A:33-154 PDB3|1le6B:33-154
Due to the importance of PLA2 in
inflammatory responses, regulation of the enzyme is essential. PLA2 is regulated by phosphorylationand calcium concentrations. PLA2 is phosphorylated by a MAPKat Serine-505. When phosphorylation is coupled with an influx of calcium ions, PLA2 becomes stimulated and can translocate to the membrane to begin catalysis. [Leslie et al. “Properties and Regulation of Cytosolic Phospholipase A2”. 1997. The Journal of Biochemistry. Vol. 272. No. 27. 16709-16712.]
Relevance in Neurological Disorders
In normal brain cells, PLA2 regulation accounts for a balance between
arachidonic acidconversion into proinflammatory mediators and arachidonic acidreincorporation into the membrane. In the absence of strict regulation of PLA2 activity, a disproportionate amount of proinflammatory mediators are produced. The resulting induced oxidative stressand neuroinflammation is analogous to neurological diseases such as Alzheimer’s disease, epilepsy, multiple sclerosis, ischemia. Lysophospholipids are another class of molecules released from the membrane that are upstream predecessors of platelet activating factors (PAF). Abnormal levels of potent PAF are also associated with neurological damage. An optimal enzyme inhibitorwould specifically target PLA2 activity on neural cell membranes already under oxidative stressand potent inflammation. Thus, specific inhibitors of brain PLA2 could be a pharmaceutical approach to treatment of several disorders associated with neural trauma. [Farooqui et al. “Inhibitors of Brain Phospholipase A2 Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders” 2006. Pharmacological Reviews. Vol. 58. 591-620.]
Increased phospholipase A2 has also been associated with neuropsychiatric disorders such as
schizophreniaand pervasive developmental disorders(such as autism), though the mechanisms involved are not known. [Bell, JG et al.. Essential fatty acids and phospholipase A2 in autistic spectrum disorders. 2004. Prostaglandins, Leukotrienes and Essential Fatty Acids. Vol. 71. 201-204]
Human proteins containing phospholipase A2 domain
OC90; PLA2G10; PLA2G1B; PLA2G2A; PLA2G2D; PLA2G2E; PLA2G2F; PLA2G3; PLA2G5;
* Group I: Gene|PLA2G1B
* Group II: Gene|PLA2G2A, Gene|PLA2G2C, Gene|PLA2G2D, Gene|PLA2G2E, Gene|PLA2G2F
* Group III: Gene|PLA2G3
* Group IV: Gene|PLA2G4A, Gene|PLA2G4B, Gene|PLA2G4C, Gene|PLA2G4D, Gene|PLA2G4E, Gene|PLA2G4F
* Group V: Gene|PLA2G5
* Group VI: Gene|PLA2G6
* Group VII: Gene|PLA2G7
* Group X: Gene|PLA2G10
* Group XII: Gene|PLA2G12A, Gene|PLA2G12B
* [http://www.expasy.org/cgi-bin/nicedoc.pl?PDOC00109 Phospholipase A2 active sites] in
* - Secreted phospholipases A2 in the lipid bilayer
* - Cytosolic phospholipase A2 and patatin
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