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PLA2G6  -  phospholipase A2, group VI (cytosolic,...

Homo sapiens

Synonyms: 85/88 kDa calcium-independent phospholipase A2, CaI-PLA2, GVI, GVI PLA2, Group VI phospholipase A2, ...
 
 
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Disease relevance of PLA2G6

 

High impact information on PLA2G6

  • We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome [3].
  • Since inhibition of iPLA2, but not cPLA2, attenuated IgM binding to apoptotic cells, these results strongly suggest that the endogenous calcium independent PLA(2), iPLA(2), is involved in the hydrolysis of plasma membrane phospholipids and exposure of the epitope(s) recognized by IgM [6].
  • The lacking H+ efflux could be restored (1) by adding lysophosphatidylcholine (LPC), a product of PLA2 activity, to vacuoles in situ and (2) by exposing intact cells to isotonic, near-neutral HEPES buffers [7].
  • The disease gene was mapped to a 1.17-Mb locus on chromosome 22q13.1 (LOD score 4.7 at recombination fraction 0 for SNP rs139897), and an underlying mutation common to both affected families was identified in PLA2G6, the gene encoding phospholipase A2 group VI (cytosolic, calcium-independent) [4].
  • Down-regulation of endogenous iPLA2 by STS may result in the loss of mitochondrial membrane repair functions and lead to mitochondrial failure and apoptosis [8].
 

Chemical compound and disease context of PLA2G6

  • It is speculated that LTB4 and PAF, both produced with type II PLA2, interact with each other and are involved in the deterioration of pathologic features associated with sepsis [9].
  • We measured serum concentrations of nitrite/nitrate (NOX), type II phospholipase A2 (PLA2), leukotriene B4 (LTB4), and platelet-activating factor (PAF) in patients with sepsis [9].
 

Biological context of PLA2G6

 

Anatomical context of PLA2G6

 

Associations of PLA2G6 with chemical compounds

  • Finally, iPLA2-derived AA was not metabolized to prostaglandin E2 [18].
  • The positive correlation of spatial descriptor Pmiz with inhibitory activity shows that proper orientation of the substitution at R position towards Z-axis is necessary to facilitate the possible interactions of the indole core with active site residues of the PLA2 enzyme [19].
  • We demonstrate that iPLA2 selectively hydrolyzes the sn-2 over sn-1 fatty acid by 5-fold for 1,2-dipalmitoyl phosphatidylcholine in a mixed micelle [20].
  • Unexpectedly, however, abrogation of U937 cell iPLA2 activity by either methyl arachidonyl fluorophosphonate or an antisense oligonucleotide did not delay or decrease the extent of apoptosis induced by hydrogen peroxide [14].
  • However, iPLA2 does have a marked preference for 1,2-dipalmitoyl phosphatidic acid presented in a vesicle, generating the lipid second messenger lysophosphatidic acid [20].
 

Regulatory relationships of PLA2G6

 

Other interactions of PLA2G6

  • Fcgamma RI-triggered generation of arachidonic acid and eicosanoids requires iPLA2 but not cPLA2 in human monocytic cells [22].
  • The putative promotor for the iPLA2 gene lacks a TATA-box and contains a CpG island as well as several potential Sp-1-binding sites [15].
  • RESULTS: Thrombin and tryptase stimulation resulted in a 2 to 3-fold increase in membrane associated iPLA2 that was accompanied by comparative increases in arachidonic acid and prostaglandin E2 release [23].
  • Serum concentrations of NOX, type II PLA2, LTB4, and PAF acetylhydrolase (PAF-AH) were significantly higher in the group with septic shock (P < 0.0001; P = 0.0060; P = 0.0052; P = 0.0052), indicating the severity of the disease [9].
  • These results suggest that the increases in plasma type II PLA2 and PAFAH are related to vascular endothelial disorders in patients with infected burns [24].
 

Analytical, diagnostic and therapeutic context of PLA2G6

References

  1. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. Jenkins, C.M., Mancuso, D.J., Yan, W., Sims, H.F., Gibson, B., Gross, R.W. J. Biol. Chem. (2004) [Pubmed]
  2. Human pancreatic islets express mRNA species encoding two distinct catalytically active isoforms of group VI phospholipase A2 (iPLA2) that arise from an exon-skipping mechanism of alternative splicing of the transcript from the iPLA2 gene on chromosome 22q13.1. Ma, Z., Wang, X., Nowatzke, W., Ramanadham, S., Turk, J. J. Biol. Chem. (1999) [Pubmed]
  3. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Morgan, N.V., Westaway, S.K., Morton, J.E., Gregory, A., Gissen, P., Sonek, S., Cangul, H., Coryell, J., Canham, N., Nardocci, N., Zorzi, G., Pasha, S., Rodriguez, D., Desguerre, I., Mubaidin, A., Bertini, E., Trembath, R.C., Simonati, A., Schanen, C., Johnson, C.A., Levinson, B., Woods, C.G., Wilmot, B., Kramer, P., Gitschier, J., Maher, E.R., Hayflick, S.J. Nat. Genet. (2006) [Pubmed]
  4. PLA2G6 Mutation Underlies Infantile Neuroaxonal Dystrophy. Khateeb, S., Flusser, H., Ofir, R., Shelef, I., Narkis, G., Vardi, G., Shorer, Z., Levy, R., Galil, A., Elbedour, K., Birk, O.S. Am. J. Hum. Genet. (2006) [Pubmed]
  5. Identification and distribution of endoplasmic reticulum iPLA2. Kinsey, G.R., Cummings, B.S., Beckett, C.S., Saavedra, G., Zhang, W., McHowat, J., Schnellmann, R.G. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  6. I-PLA(2) activation during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural immunoglobulin M antibodies and complement activation. Kim, S.J., Gershov, D., Ma, X., Brot, N., Elkon, K.B. J. Exp. Med. (2002) [Pubmed]
  7. The Galpha protein controls a pH-dependent signal path to the induction of phytoalexin biosynthesis in Eschscholzia californica. Viehweger, K., Schwartze, W., Schumann, B., Lein, W., Roos, W. Plant Cell (2006) [Pubmed]
  8. Calcium-independent phospholipase A2 localizes in and protects mitochondria during apoptotic induction by staurosporine. Seleznev, K., Zhao, C., Zhang, X.H., Song, K., Ma, Z.A. J. Biol. Chem. (2006) [Pubmed]
  9. Nitrite/nitrate (NOX) and type II phospholipase A2, leukotriene B4, and platelet-activating factor levels in patients with septic shock. Nakae, H., Endo, S., Inada, K., Yaegashi, Y., Takakuwa, T., Yamada, Y., Arakawa, N., Suzuki, T., Taniguchi, S., Shimamura, T., Ogawa, M., Teraoka, H. Res. Commun. Mol. Pathol. Pharmacol. (1996) [Pubmed]
  10. A genetic study of two calcium-independent cytosolic PLA2 genes in schizophrenia. Yu, Y., Tao, R., Shi, J., Zhang, X., Kou, C., Guo, Y., Zhang, X., Lin, X., Liu, S., Ju, G., Xu, Q., Shang, H., Shen, Y., Wei, J. Prostaglandins Leukot. Essent. Fatty Acids (2005) [Pubmed]
  11. Cytosolic phospholipase A2 participates with TNF-alpha in the induction of apoptosis of human macrophages infected with Mycobacterium tuberculosis H37Ra. Duan, L., Gan, H., Arm, J., Remold, H.G. J. Immunol. (2001) [Pubmed]
  12. Fas-induced arachidonic acid release is mediated by Ca2+-independent phospholipase A2 but not cytosolic phospholipase A2, which undergoes proteolytic inactivation. Atsumi, G., Tajima, M., Hadano, A., Nakatani, Y., Murakami, M., Kudo, I. J. Biol. Chem. (1998) [Pubmed]
  13. Multiple splice variants of the human calcium-independent phospholipase A2 and their effect on enzyme activity. Larsson, P.K., Claesson, H.E., Kennedy, B.P. J. Biol. Chem. (1998) [Pubmed]
  14. Role of group VIA calcium-independent phospholipase A2 in arachidonic acid release, phospholipid fatty acid incorporation, and apoptosis in U937 cells responding to hydrogen peroxide. Pérez, R., Melero, R., Balboa, M.A., Balsinde, J. J. Biol. Chem. (2004) [Pubmed]
  15. The human calcium-independent phospholipase A2 gene multiple enzymes with distinct properties from a single gene. Larsson Forsell, P.K., Kennedy, B.P., Claesson, H.E. Eur. J. Biochem. (1999) [Pubmed]
  16. Ca(2+)-independent phospholipase A2 is required for alpha2-adrenergic-induced preadipocyte spreading. Pagès, C., Rey, A., Lafontan, M., Valet, P., Saulnier-Blache, J.S. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  17. Catalytic features, regulation and function of myocardial phospholipase A2. McHowat, J., Creer, M.H. Current medicinal chemistry. Cardiovascular and hematological agents. (2004) [Pubmed]
  18. The functions of five distinct mammalian phospholipase A2S in regulating arachidonic acid release. Type IIa and type V secretory phospholipase A2S are functionally redundant and act in concert with cytosolic phospholipase A2. Murakami, M., Shimbara, S., Kambe, T., Kuwata, H., Winstead, M.V., Tischfield, J.A., Kudo, I. J. Biol. Chem. (1998) [Pubmed]
  19. Quantitative structure-activity relationship (QSAR) analysis of a series of indole analogues as inhibitor for human group V secretory phospholipase A2. OmPraba, G., Velmurugan, D. Indian J. Biochem. Biophys. (2006) [Pubmed]
  20. A novel cytosolic calcium-independent phospholipase A2 contains eight ankyrin motifs. Tang, J., Kriz, R.W., Wolfman, N., Shaffer, M., Seehra, J., Jones, S.S. J. Biol. Chem. (1997) [Pubmed]
  21. Potential role for mast cell tryptase in recruitment of inflammatory cells to endothelium. Meyer, M.C., Creer, M.H., McHowat, J. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  22. Fcgamma RI-triggered generation of arachidonic acid and eicosanoids requires iPLA2 but not cPLA2 in human monocytic cells. Tay, H.K., Melendez, A.J. J. Biol. Chem. (2004) [Pubmed]
  23. Stimulation of protease activated receptors on RT4 cells mediates arachidonic acid release via Ca2+ independent phospholipase A2. McHowat, J., Creer, M.H., Rickard, A. J. Urol. (2001) [Pubmed]
  24. Relationship between plasma levels of type II phospholipase A2, PAF acetylhydrolase, endothelin-1, and thrombomodulin in patients with infected burns. Takakuwa, T., Endo, S., Nakae, H., Yamada, Y., Inada, K., Yoshida, M., Ogawa, M., Uchida, K. Res. Commun. Mol. Pathol. Pharmacol. (1994) [Pubmed]
  25. Increased calcium-independent phospholipase A2 activity in first but not in multiepisode chronic schizophrenia. Smesny, S., Kinder, D., Willhardt, I., Rosburg, T., Lasch, J., Berger, G., Sauer, H. Biol. Psychiatry (2005) [Pubmed]
  26. Polycyclic aromatic hydrocarbons present in cigarette smoke cause endothelial cell apoptosis by a phospholipase A2-dependent mechanism. Tithof, P.K., Elgayyar, M., Cho, Y., Guan, W., Fisher, A.B., Peters-Golden, M. FASEB J. (2002) [Pubmed]
 
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