Phospholipase A2

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phospholipase A2 Phospholipase Cleavage Sites. Note that an enzyme that displays both PLA1 and PLA2 activities is called a Phospholipase B Identifiers EC number 3.1.1.4 CAS number 9001-84-7 IntEnz IntEnz view BRENDA BRENDA entry ExPASy NiceZyme view KEGG KEGG entry MetaCyc metabolic pathway PRIAM profile PDB structures Gene Ontology AmiGO / EGO Search PMC articles PubMed articles

Phospholipase A2 ee venom phospholipase A2 sPLA2. Middle plane of the lipid bilayer - black dots. Boundary of the hydrocarbon core region - red dots (extracellular side). Layer of lipid phosphates - yellow dots. Identifiers Symbol Phospholip_A2_1 Pfam PF00068 InterPro IPR001211 PROSITE PDOC00109 SCOP 1bbc OPM family 90 OPM protein 1g4i Available PDB structures: 1vkqA:23-145 1mks :23-145 1gh4A:23-145 4bp2 :23-145 1kvw :23-145 1irb :23-145 1kvx :23-145 1o2eA:23-145 2bpp :23-145 1une :23-145 1vl9A:23-145 1g4iA:23-145 1bvmA:23-145 1o3wA:23-145 2bp2 :23-145 1mkv :23-145 1ceh :23-145 1bpq :23-145 1mku :23-145 1bp2 :23-145 1c74A:23-145 3bp2 :24-145 1kvy :23-145 1fdk :23-145 1mkt :23-145 2baxA:23-145 1y6oA:23-146 2phiA:23-146 1hn4A:23-146 1y6pA:23-146 1fxfB:23-146 1fx9B:23-146 1l8sB:23-146 1pis :23-146 1sfw :23-146 1sfv :23-146 1pir :23-146 3p2pB:23-146 5p2pB:23-146 4p2p :23-146 1p2p :23-146 1m8tD:28-146 1gp7B:28-151 1pobA:28-145 1poa :28-145 1pshA:1-118 1owsB:4-118 1a3fC:1-118 1a3d :1-118 1sz8A:8-125 1ln8A:8-125 1yxlA:8-125 1t37A:8-125 1mf4A:8-125 1zm6A:8-125 1oxrA:8-125 1td7A:9-125 1mh2B:8-125 1xxwB:8-125 1s6bB:8-125 1yxhA:8-125 1y75A:8-124 1mh8A:8-125 1mh7A:8-125 1oo1A:1-117 1g2xA:28-141 1fe5A:28-144 1dpyA:28-144 1po8A:34-132 1u4jA:20-136 1tc8A:20-136 1ae7N:1-118 2notA:1-118 1lx1A:1-118 1bunA:28-146 1vipP:1-121 1oz6A:17-136 1q5tB:1-122 1aokA:1-122 1jltA:1-122 1vpi :1-122 1oqsA:17-138 1rgbA:1-122 1pp2L:17-138 1ijlA:1-123 1m8rA:1-124 1bk9 :1-124 1psj :1-124 1m8sA:1-124 1vapA:1-123 1u73B:17-138 1umvX:17-138 1pa0B:1-119 1pc9B:1-119 1qllA:1-121 1xxsB:1-122 1clpB:1-121 1y4lA:1-121 1godA:1-121 1s8iA:17-137 1s8hA:17-137 1s8gA:17-137 1ppa :1-121 1mc2A:17-138 1mg6A:17-138 1gmzB:1-106 1bjjF:1-122 1a2aF:1-122 1c1jC:1-122 1jiaB:18-138 1b4wC:18-138 1y38A:1-121 1cl5B:1-121 1jq9A:1-121 2fnxA:1-121 1tg1A:1-121 1fv0A:1-121 1tj9A:1-121 1tjqA:1-121 1sxkA:1-121 1tp2B:1-121 1zyxA:1-121 1tdvA:1-121 1jq8B:1-121 1tgmA:1-121 2b17A:1-121 1oxlB:1-121 1sv3A:1-121 1oyfA:1-121 1tk4A:1-121 1th6A:1-121 1kpmA:1-121 2armA:1-121 1sqzA:1-121 1fb2B:1-121 1ti0A:1-121 1q7aA:1-121 1tg4A:1-121 1sv9A:1-121 1q6vA:1-121 1zr8A:1-121 1tjkA:1-121 1kvoA:21-144 1aypD:21-144 1n28A:22-144 1dcyA:21-144 1n29A:22-144 1db4A:21-144 1j1aB:21-144 1bbc :21-144 1pod :21-144 1poeB:21-144 1kquA:21-144 1db5A:21-144 1le7A:33-154 1le6B:33-154

Phospholipases A2 (PLA2s) EC 3.1.1.4 are enzymes that release fatty acids from the second carbon group of glycerol. This particular phospholipase specifically recognizes the sn-2 acyl bond of phospholipids and catalytically hydrolyzes the bond releasing arachidonic acid and lysophospholipids. Upon downstream modification by cyclooxygenases, arachidonic acid is modified into active compounds called eicosanoids. Eicosanoids include prostaglandins and leukotrienes which are categorized as inflammatory mediators.^[1]

PLA2 are commonly found in mammalian tissues as well as insect and snake venom.^[2] Venom from both snakes and insects is largely composed of melittin which is a stimulant of PLA2. Due to the increased presence and activity of PLA2 resulting from a snake or insect bite, arachidonic acid is released from the phospholipid membrane disproportionately. As a result, inflammation and pain occur at the site.^[3] There are also prokaryotic A2 phospholipases.

Additional types of phospholipases include phospholipase A1, phospholipase B, phospholipase C, and phospholipase D.^[4]

Families

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).

Secreted phospholipases A2 (sPLA2)

The extracellular forms of phospholipases A2 have been isolated from different venoms (snake, bee, and wasp), from virtually every studied mammalian tissue (including pancreas and kidney) as well as from bacteria. They require Ca²⁺ for activity.

Pancreatic PLA2 serve for the initial digestion of phospholipid compounds in dietary fat. Venom phospholipases help to immobilize prey by promoting cell lysis.

Cytosolic phospholipases A2 (cPLA2)

The intracellular PLA2 are also Ca-dependent, but they have completely different 3D structure and significantly larger than secreted PLA2 (more than 700 residues). They include C2 domain and large catalytic domain.

These phospholipases are involved in cell signaling processes, such as inflammatory response. The produced Arachidonic acid is both a signaling molecule and the precursor for other signalling molecules termed eicosanoids. These include leukotrienes and prostaglandins. Some eicosanoids are synthesized from diacylglycerol, released from the lipid bilayer by phospholipase C (see below).

Phospholipases A2 can be classified based on sequence homology.^[5]

Lipoprotein-associated PLA2s (lp-PLA2)

Increased levels of lp-PLA2 are associated with cardiac disease, and may contribute to atherosclerosis^[6].

Mechanism

The suggested catalytic mechanism of pancreatic sPLA2 is initiated by a His-48/Asp-99/calcium complex within the active site. The calcium ion polarizes the sn-2 carbonyl oxygen while also coordinating with a catalytic water molecule, w5. His-48 improves the nucleophilicity of the catalytic water via a bridging second water molecule, w6. It has been suggested that two water molecules are necessary to traverse the distance between the catalytic histidine and the ester. The basicity of His-48 is thought to be enhanced through hydrogen bonding with Asp-99. An asparagine substitution for His-48 maintains wild-type activity, as the amide functional group on asparagine can also function to lower the pKa, or acid dissociation constant, of the bridging water molecule. The rate limiting state is characterized as the degradation of the tetrahedral intermediate composed of a calcium coordinated oxyanion. The role of calcium can also be duplicated by other relatively small cations like cobalt and nickel. ^[7]

Close-up rendering of PLA2 active site with phosphate enzyme inhibitor. Calcium ion (pink) coordinates with phosphate (light blue). Phosphate mimics tetrahedral intermediate blocking substrate access to active site. His-48, Asp-99, and 2 water molecules are also shown.[8]

Mechanism of hydrolysis catalyzed by PLA2

PLA2 can also be characterized as having a channel featuring a hydrophobic wall in which hydrophobic amino acid residues such as Phe, Leu, and Tyr serve to bind the substrate. Another component of PLA2 is the seven disulfide bridges which are influential in regulation and stable protein folding.^[7]

Regulation

Due to the importance of PLA2 in inflammatory responses, regulation of the enzyme is essential. PLA2 is regulated by phosphorylation and calcium concentrations. PLA2 is phosphorylated by a MAPK at Serine-505. When phosphorylation is coupled with an influx of calcium ions, PLA2 becomes stimulated and can translocate to the membrane to begin catalysis. ^[9]

Phosphorylation of PLA2 may be a result of ligand binding to receptors, including:

• 5-HT2 receptors ^[10]
• mGLUR1^[10]
• bFGF receptor^[10]
• IFN-α receptor^[10]
• IFN-γ receptor^[10]

Relevance in Neurological Disorders

In normal brain cells, PLA2 regulation accounts for a balance between arachidonic acid conversion into proinflammatory mediators and arachidonic acid reincorporation into the membrane. In the absence of strict regulation of PLA2 activity, a disproportionate amount of proinflammatory mediators are produced. The resulting induced oxidative stress and 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 inhibitor would specifically target PLA2 activity on neural cell membranes already under oxidative stress and potent inflammation. Thus, specific inhibitors of brain PLA2 could be a pharmaceutical approach to treatment of several disorders associated with neural trauma.^[11]

Increase in phospholipase A2 activity is an acute phase reaction that rises during inflammation, which is also seen to be exponentially higher in low back disc herniations compared to rheumatoid arthritis.^{[citation needed]} It is a mixture of inflammation and substance P that are responsible for pain.^{[citation needed]}

Increased phospholipase A2 has also been associated with neuropsychiatric disorders such as schizophrenia and pervasive developmental disorders (such as autism), though the mechanisms involved are not known.^[12]

Isozymes

Human phospholipase A2 isozymes include:

• Group I: PLA2G1B
• Group II: PLA2G2A, PLA2G2C, PLA2G2D, PLA2G2E, PLA2G2F
• Group III: PLA2G3
• Group IV: PLA2G4A, PLA2G4B, PLA2G4C, PLA2G4D, PLA2G4E, PLA2G4F
• Group V: PLA2G5
• Group VI: PLA2G6
• Group VII: PLA2G7
• Group X: PLA2G10
• Group XII: PLA2G12A, PLA2G12B

In addition, the following human proteins contain the phospholipase A2 domain:

• OC90

References

External links

• MeSH Phospholipase+A2