Disease relevance of Pla2

• However, when these venoms were serially diluted (removing their overt toxicity), they, too, mitigated hypoxic cell death (LDH release with PLA2, 33 +/- 2%; without PLA2, 60 +/- 1% LDH release; P < 0.001) [1].
• Bee and snake venom PLA2 (0.4 unit/ml) were directly toxic to tubules under oxygenated conditions, and this injury was additive with that induced by hypoxia [1].
• Because these changes can compromise cellular integrity, PLA2 activity has been widely proposed as a critical mediator of hypoxic renal tubular injury and, hence, of ischemic acute renal failure [1].
• We have now studied the effects of these two lipolytic modifications on the aggregation and fusion of LDL particles by hydrolyzing the particles with Bacillus cereus SMase or bee venom PLA2 [2].
• Several lines of evidence suggest that extracellular PLA2 is pathophysiologically related to some disorders, including inflammation and hypersensitivity [3].

High impact information on Pla2

• Docking phospholipase A2 on membranes using electrostatic potential-modulated spin relaxation magnetic resonance [4].
• The 2.0 angstroms crystal structure of a complex containing bee-venom phospholipase A2 (PLA2) and a phosphonate transition-state analogue was solved by multiple isomorphous replacement [5].
• Bee venom and phospholipase A2 extracted from bee venom enhanced guanylate cyclase (E.C. 4.6.1.2) activity two- to threefold in rat liver, lung, heart, kidney, ileum, and cerebellum [6].
• In bee venom (BV)-SIT the specific proliferative and cytokine responses against the main allergen, the phospholipase A2 (PLA), and T cell epitope-containing PLA peptides were significantly suppressed after 7 d of treatment [7].
• The addition of IL-10 to soluble CD40 ligand IL-4-stimulated PBMC or purified B cells inhibited the PLA-specific and total IgE and enhanced the IgG4 formation [7].

Chemical compound and disease context of Pla2

• Previously, we reported AA release and prostaglandin F(2alpha) (PGF(2alpha)) formation via activation of cytosolic PLA2 by orthovanadate (Na3VO4), an inhibitor of tyrosine phosphatases, in rat pheochromocytoma PC12 cells [8].
• Phospholipase A2 (1 microM) alone caused less than 2% hemolysis, despite high levels (54%) of phosphatidylcholine hydrolysis [9].
• The major products of phospholipase A2 activity, arachidonic acid and lysophosphatidylcholine, when exogenously added, also greatly increased hemolysis induced by halothane, with arachidonic acid most closely resembling the synergism observed with phospholipase A2 [9].
• In addition, we examined the effects of the same PLA2 inhibitors on contractures induced by halothane in combination with suxamethonium [10].
• Dantrolene and mepacrine antagonize the hemolysis of human red blood cells by halothane and bee venom phospholipase A2 [9].

Biological context of Pla2

• Analysis of the cDNA for phospholipase A2 from honeybee venom glands. The deduced amino acid sequence reveals homology to the corresponding vertebrate enzymes [11].
• Finally, an increase in cell recognition as determined by monocyte phagocytosis and adherence in vitro, as well as decreased phosphatidylcholine accessibility to bee venom phospholipase A2, was found in H2O2-treated erythrocytes compared with controls [12].
• These results indicate that PLA2 activity can exert both beneficial and deleterious effects on O2-deprived renal tubules, the net result of which can be a salvaging of cells from hypoxic cell death [1].
• PLA2-mediated cytoprotection was Ca2+ dependent (negated by Ca2+ chelation), and it was expressed despite worsening hypoxia-associated membrane deacylation/fatty acid accumulation (12 times) and ATP depletion [1].
• An essential role for lysophosphatidylcholine in the inhibition of platelet aggregation by secretory phospholipase A2 [13].

Anatomical context of Pla2

• Interfacial binding of bee venom secreted phospholipase A2 to membranes occurs predominantly by a nonelectrostatic mechanism [14].
• After successful immunotherapy, PLA and T cell epitope peptide-specific T cell proliferation was suppressed [15].
• Low concentrations of indomethacin inhibit phospholipase A2 of rabbit polymorphonuclear leukocytes [16].
• Upon crosslinking of CD3, the hybridoma produced GIF having affinity for PLA2 [17].
• Four other phospholipases A2--from venoms of Russell viper, Crotalus adamanteus, and bee, and from pig pancreas--are unaffected by 50 micrometer indomethacin, which inhibits leukocyte phospholipase A2 by 70% [16].

Associations of Pla2 with chemical compounds

• Dose-response relationships revealed that bee venom at concentrations as low as 1 microgram per milliliter and phospholipase A2 at 1 microunit per milliliter caused a maximal enhancement of guanylate cyclase [6].
• A method involving electron paramagnetic resonance spectroscopy of a site-selectively spin-labeled peripheral membrane protein in the presence and absence of membranes and of a water-soluble spin relaxant (chromium oxalate) has been developed to determine how bee venom phospholipase A2 sits on the membrane [4].
• Bee venom phospholipase A2 (PLA) is the major allergen in bee sting allergy [15].
• Activatable cellular phospholipase A2 (PLase; phosphatide 2-acyl-hydrolase, EC 3.1.1.4) has been proposed to constitute the first and rate-limiting step in prostaglandin synthesis and to regulate membrane function by altering the levels in the membrane of the detergent lipids lysolecithin and free fatty acids [18].
• Similar results were obtained for PE membrane distribution using either chemical (TNBS) or enzymatic (PLA2 plus SMC) methods, although changes in PS distribution were observed only with TNBS [19].

Regulatory relationships of Pla2

• These studies do not support the suggestion that snake venom cardiotoxins and melittin selectively activate endogenous phospholipase A2 activity [20].

Other interactions of Pla2

• Twenty micrograms of bee venom melittin, which activates endogenous phospholipase A2, administered intracisternally into rabbits also produced signs of level 3 (our grading system) coma for several hours [21].
• METHODS: By genetic engineering, we produced a fusion protein composed of the 2 major bee venom allergens: phospholipase A 2 (Api m 1) and hyaluronidase (Api m 2) [22].
• 1. The m. triangularis sterni of the mouse was used to investigate the actions of dendrotoxin, beta-bungarotoxin, crotoxin, taipoxin, bee venom phospholipase A2, aprotinin and apamin on presynaptic currents which flow inside the perineural sheath of nerve bundles upon nerve stimulation [23].
• Melittin is a polypeptide component of bee venom which stimulates phospholipase A2 activity, thereby increasing arachidonic acid release and prostaglandin (PG) synthesis, and which inhibits protein kinase C activity [24].

Analytical, diagnostic and therapeutic context of Pla2

• Epitope mapping of Pla2-specific MoAbs identified three independent binding regions [25].
• Northern blot analysis indicated that the PLA2 mRNA is specifically expressed in the guts of transgenic mosquitoes with peak expression at approximately 4 h after blood ingestion [26].
• Western blot and immunofluorescence analyses detected PLA2 protein in the midgut epithelia of transgenic mosquitoes from 8 to 24 h after a blood meal [26].
• Epitope mapping on phospholipase A2 was done with the PEPSCAN method and ELISA techniques [27].
• RESULTS: Phospholipase A2-specific IgG1 and IgG2a production turned out to be 2 times higher using cationic microspheres compared with anionic microspheres, but was not influenced by the presence of DNA [28].

References