Cardiovascular Drugs and Therapy

, Volume 23, Issue 1, pp 49–59 | Cite as

Phospholipase A2 Biochemistry

  • John E. Burke
  • Edward A. DennisEmail author


The phospholipase A2 (PLA2) superfamily consists of many different groups of enzymes that catalyze the hydrolysis of the sn-2 ester bond in a variety of different phospholipids. The products of this reaction, a free fatty acid, and lysophospholipid have many different important physiological roles. There are five main types of PLA2: the secreted sPLA2’s, the cytosolic cPLA2’s, the Ca2+independent iPLA2’s, the PAF acetylhydrolases, and the lysosomal PLA2’s. This review focuses on the superfamily of PLA2 enzymes, and then uses three specific examples of these enzymes to examine the differing biochemistry of the three main types of these enzymes. These three examples are the GIA cobra venom PLA2, the GIVA cytosolic cPLA2, and the GVIA Ca2+-independent iPLA2.

Key words

Phospholipase A2 Lipid enzymology Eicosanoids PAF Hydrolase 



This work was supported by NIH grants GM064611 and GM020501.


  1. 1.
    Schaloske RH, Dennis EA. The phospholipase A2 superfamily and its group numbering system. Biochim Biophys Acta. 2006;1761:1246–59.PubMedGoogle Scholar
  2. 2.
    Six DA, Dennis EA. The expanding superfamily of phospholipase A(2) enzymes: classification and characterization. Biochim Biophys Acta. 2000;1488:1–19.PubMedGoogle Scholar
  3. 3.
    Dennis EA. Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem. 1994;269:13057–60.PubMedGoogle Scholar
  4. 4.
    Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001;294:1871–5.PubMedGoogle Scholar
  5. 5.
    Moolenaar WH, van Meeteren LA, Giepmans BN. The ins and outs of lysophosphatidic acid signaling. Bioessays. 2004;26:870–81.PubMedGoogle Scholar
  6. 6.
    Prescott SM, Zimmerman GA, Stafforini DM, McIntyre TM. Platelet-activating factor and related lipid mediators. Annu Rev Biochem. 2000;69:419–45.PubMedGoogle Scholar
  7. 7.
    Fairbairn D. The phospholipase of the venom of the cottonmouth moccasin (Agkistrodon piscivorus L). J Biol Chem. 1945;157:633–44.Google Scholar
  8. 8.
    Stephens WW, Walker JL, Myers W. The action of cobra poison on the blood: a contribution to the study of passive immunity. J Pathol Bacteriol. 1898;5:279–301.Google Scholar
  9. 9.
    Heinrikson RL, Krueger ET, Keim PS. Amino acid sequence of phospholipase A2-alpha from the venom of Crotalus adamanteus. A new classification of phospholipases A2 based upon structural determinants. J Biol Chem. 1977;252:4913–21.PubMedGoogle Scholar
  10. 10.
    Puijk WC, Verheij HM, De Haas GH. The primary structure of phospholipase A2 from porcine pancreas. A reinvestigation. Biochim Biophys Acta. 1977;492:254–9.PubMedGoogle Scholar
  11. 11.
    Eerola LI, Surrel F, Nevalainen TJ, Gelb MH, Lambeau G, Laine VJ. Analysis of expression of secreted phospholipases A2 in mouse tissues at protein and mRNA levels. Biochim Biophys Acta 2006;1761:745–56.PubMedGoogle Scholar
  12. 12.
    Richmond BL, Boileau AC, Zheng S, Huggins KW, Granholm NA, Tso P, et al. Compensatory phospholipid digestion is required for cholesterol absorption in pancreatic phospholipase A(2)-deficient mice. Gastroenterology. 2001;120:1193–202.PubMedGoogle Scholar
  13. 13.
    Seilhamer JJ, Pruzanski W, Vadas P, Plant S, Miller JA, Kloss J, et al. Cloning and recombinant expression of phospholipase A2 present in rheumatoid arthritic synovial fluid. J Biol Chem. 1989;264:5335–8.PubMedGoogle Scholar
  14. 14.
    Lin G, Noel J, Loffredo W, Stable HZ, Tsai MD. Use of short-chain cyclopentano-phosphatidylcholines to probe the mode of activation of phospholipase A2 from bovine pancreas and bee venom. J Biol Chem. 1988;263:13208–14.PubMedGoogle Scholar
  15. 15.
    Verheij HM, Slotboom AJ, de Haas GH. Structure and function of phospholipase A2. Rev Physiol Biochem Pharmacol. 1981;91:91–203.PubMedGoogle Scholar
  16. 16.
    Buckland AG, Heeley EL, Wilton DC. Bacterial cell membrane hydrolysis by secreted phospholipases A(2): a major physiological role of human group IIa sPLA(2) involving both bacterial cell wall penetration and interfacial catalysis. Biochim Biophys Acta. 2000;1484:195–206.PubMedGoogle Scholar
  17. 17.
    Buckland AG, Wilton DC. The antibacterial properties of secreted phospholipases A(2). Biochim Biophys Acta. 2000;1488:71–82.PubMedGoogle Scholar
  18. 18.
    Lambeau G, Gelb MH. Biochemistry and physiology of mammalian secreted phospholipases A(2). Annu Rev Biochem 2008;77:495–520.PubMedGoogle Scholar
  19. 19.
    Boyanovsky B, Webb N. Biology of secretory phospholipase A2. Cardiovasc Drugs Ther. 2008. doi: 10.1007/s10557-008-6134-7.
  20. 20.
    Underwood KW, Song C, Kriz RW, Chang XJ, Knopf JL, Lin LL. A novel calcium-independent phospholipase A2, cPLA2-gamma, that is prenylated and contains homology to cPLA2. J Biol Chem. 1998;273:21926–32.PubMedGoogle Scholar
  21. 21.
    Ohto T, Uozumi N, Hirabayashi T, Shimizu T. Identification of novel cytosolic phospholipase A(2)s, murine cPLA(2){delta}, {epsilon}, and {zeta}, which form a gene cluster with cPLA(2){beta}. J Biol Chem. 2005;280:24576–83.PubMedGoogle Scholar
  22. 22.
    Pickard RT, Strifler BA, Kramer RM, Sharp JD. Molecular cloning of two new human paralogs of 85-kDa cytosolic phospholipase A2. J Biol Chem. 1999;274:8823–31.PubMedGoogle Scholar
  23. 23.
    Song C, Chang XJ, Bean KM, Proia MS, Knopf JL, Kriz RW. Molecular characterization of cytosolic phospholipase A2-beta. J Biol Chem. 1999;274:17063–7.PubMedGoogle Scholar
  24. 24.
    Chiba H, Michibata H, Wakimoto K, Seishima M, Kawasaki S, Okubo K, et al. Cloning of a gene for a novel epithelium-specific cytosolic phospholipase A2, cPLA2delta, induced in psoriatic skin. J Biol Chem. 2004;279:12890–7.PubMedGoogle Scholar
  25. 25.
    Clark JD, Lin LL, Kriz RW, Ramesha CS, Sultzman LA, Lin AY, et al. A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with homology to PKC and GAP. Cell. 1991;65:1043–51.PubMedGoogle Scholar
  26. 26.
    Ghosh M, Tucker DE, Burchett SA, Leslie CC. Properties of the Group IV phospholipase A2 family. Prog Lipid Res. 2006;45:487–510.PubMedGoogle Scholar
  27. 27.
    Jenkins CM, Han X, Mancuso DJ, Gross RW. Identification of calcium-independent phospholipase A2 (iPLA2) beta, and not iPLA2gamma, as the mediator of arginine vasopressin-induced arachidonic acid release in A-10 smooth muscle cells. Enantioselective mechanism-based discrimination of mammalian iPLA2s. J Biol Chem. 2002;277:32807–14.PubMedGoogle Scholar
  28. 28.
    Saavedra G, Zhang W, Peterson B, Cummings BS. Differential roles for cytosolic and microsomal Ca2+-independent phospholipase A2 in cell growth and maintenance of phospholipids. J Pharmacol Exp Ther. 2006;318:1211–9.PubMedGoogle Scholar
  29. 29.
    Tjoelker LW, Eberhardt C, Unger J, Trong HL, Zimmerman GA, McIntyre TM, et al. Plasma platelet-activating factor acetylhydrolase is a secreted phospholipase A2 with a catalytic triad. J Biol Chem. 1995;270:25481–7.PubMedGoogle Scholar
  30. 30.
    Tjoelker LW, Wilder C, Eberhardt C, Stafforini DM, Dietsch G, Schimpf B, et al. Anti-inflammatory properties of a platelet-activating factor acetylhydrolase. Nature. 1995;374:549–53.PubMedGoogle Scholar
  31. 31.
    Min JH, Jain MK, Wilder C, Paul L, Apitz-Castro R, Aspleaf DC, et al. Membrane-bound plasma platelet activating factor acetylhydrolase acts on substrate in the aqueous phase. Biochemistry. 1999;38:12935–42.PubMedGoogle Scholar
  32. 32.
    Gardner AA, Reichert EC, Topham MK, Stafforini DM. Identification of a domain that mediates association of platelet-activating factor acetylhydrolase with high density lipoprotein. J Biol Chem. 2008;283:17099–106.PubMedGoogle Scholar
  33. 33.
    Manya H, Aoki J, Kato H, Ishii J, Hino S, Arai H, et al. Biochemical characterization of various catalytic complexes of the brain platelet-activating factor acetylhydrolase. J Biol Chem. 1999;274:31827–32.PubMedGoogle Scholar
  34. 34.
    Stafforini D. Biology of platelet-activating factor acetylhydrolase (PAF-AH, lipoprotein associated phospholipase A2). Cardiovasc Drugs Ther. 2008. doi: 10.1007/s10557-008-6133-8.
  35. 35.
    Koenig W, Khuseyinova N. Lipoprotein-associated and secretory phospholipase A2 in cardiovascular disease: the epidemiological evidence. Cardiovasc Drugs Ther. 2008. doi: 10.1007/s10557-008-6135-6.
  36. 36.
    Abe A, Shayman JA. Purification and characterization of 1-O-acylceramide synthase, a novel phospholipase A2 with transacylase activity. J Biol Chem. 1998;273:8467–74.PubMedGoogle Scholar
  37. 37.
    Hiraoka M, Abe A, Shayman JA. Cloning and characterization of a lysosomal phospholipase A2, 1-O-acylceramide synthase. J Biol Chem. 2002;277:10090–9.PubMedGoogle Scholar
  38. 38.
    Hiraoka M, Abe A, Shayman JA. Structure and function of lysosomal phospholipase A2: identification of the catalytic triad and the role of cysteine residues. J Lipid Res. 2005;46:2441–7.PubMedGoogle Scholar
  39. 39.
    Fremont DH, Anderson D, Wilson IA, Dennis EA, Xuong NH. The crystal structure of phospholipase A2 from Indian cobra reveals a novel trimeric association. Proc Natl Acad Sci U S A. 1993;90:342–6.PubMedGoogle Scholar
  40. 40.
    Scott DL, White SP, Otwinowski Z, Yuan W, Gelb MH, Sigler PB. Interfacial catalysis: the mechanism of phospholipase A2. Science. 1990;250:1541–6.PubMedGoogle Scholar
  41. 41.
    Segelke BW, Nguyen D, Chee R, Xuong NH, Dennis EA. Structures of two novel crystal forms of Naja naja naja phospholipase A2 lacking Ca2+reveal trimeric packing. J Mol Biol. 1998;279:223–32.PubMedGoogle Scholar
  42. 42.
    White SP, Scott DL, Otwinowski Z, Gelb MH, Sigler PB. Crystal structure of cobra-venom phospholipase A2 in a complex with a transition-state analogue. Science. 1990;250:1560–3.PubMedGoogle Scholar
  43. 43.
    Verheij HM, Volwerk JJ, Jansen EH, Puyk WC, Dijkstra BW, Drenth J, et al. Methylation of histidine-48 in pancreatic phospholipase A2. Role of histidine and calcium ion in the catalytic mechanism. Biochemistry. 1980;19:743–50.PubMedGoogle Scholar
  44. 44.
    Dijkstra BW, Drenth J, Kalk KH. Active site and catalytic mechanism of phospholipase A2. Nature. 1981;289:604–6.PubMedGoogle Scholar
  45. 45.
    Dijkstra BW, Kalk KH, Hol WG, Drenth J. Structure of bovine pancreatic phospholipase A2 at 1.7A resolution. J Mol Biol. 1981;147:97–123.PubMedGoogle Scholar
  46. 46.
    Lombardo D, Fanni T, Pluckthun A, Dennis EA. Rate-determining step in phospholipase A2 mechanism. 18O isotope exchange determined by 13C NMR. J Biol Chem. 1986;261:11663–6.PubMedGoogle Scholar
  47. 47.
    Yu L, Dennis EA. Critical role of a hydrogen bond in the interaction of phospholipase A2 with transition-state and substrate analogues. Proc Natl Acad Sci U S A. 1991;88:9325–9.PubMedGoogle Scholar
  48. 48.
    Linderoth L, Andresen TL, Jorgensen K, Madsen R, Peters GH. Molecular basis of phospholipase A2 activity toward phospholipids with sn-1 substitutions. Biophys J. 2008;94:14–26.PubMedGoogle Scholar
  49. 49.
    Peters GH, Moller MS, Jorgensen K, Ronnholm P, Mikkelsen M, Andresen TL. Secretory phospholipase A2 hydrolysis of phospholipid analogues is dependent on water accessibility to the active site. J Am Chem Soc. 2007;129:5451–61.PubMedGoogle Scholar
  50. 50.
    Fleer EA, Verheij HM, de Haas GH. Modification of carboxylate groups in bovine pancreatic phospholipase A2. Identification of aspartate-49 as Ca2+-binding ligand. Eur J Biochem. 1981;113:283–8.PubMedGoogle Scholar
  51. 51.
    van den Bergh CJ, Slotboom AJ, Verheij HM, de Haas GH. The role of Asp-49 and other conserved amino acids in phospholipases A2 and their importance for enzymatic activity. J Cell Biochem. 1989;39:379–90.PubMedGoogle Scholar
  52. 52.
    Plesniak LA, Yu L, Dennis EA. Conformation of micellar phospholipid bound to the active site of phospholipase A2. Biochemistry. 1995;34:4943–51.PubMedGoogle Scholar
  53. 53.
    Yu L, Deems RA, Hajdu J, Dennis EA. The interaction of phospholipase A2 with phospholipid analogues and inhibitors. J Biol Chem. 1990;265:2657–64.PubMedGoogle Scholar
  54. 54.
    Roberts MF, Otnaess AB, Kensil CA, Dennis EA. The specificity of phospholipase A2 and phospholipase C in a mixed micellar system. J Biol Chem. 1978;253:1252–7.PubMedGoogle Scholar
  55. 55.
    Pluckthun A, Rohlfs R, Davidson FF, Dennis EA. Short-chain phosphatidylethanolamines: physical properties and susceptibility of the monomers to phospholipase A2 action. Biochemistry. 1985;24:4201–8.PubMedGoogle Scholar
  56. 56.
    Adamich M, Roberts MF, Dennis EA. Phospholipid activation of cobra venom phospholipase A2. 2. Characterization of the phospholipid–enzyme interaction. Biochemistry. 1979;18:3308–14.PubMedGoogle Scholar
  57. 57.
    Ortiz AR, Pisabarro MT, Gallego J, Gago F. Implications of a consensus recognition site for phosphatidylcholine separate from the active site in cobra venom phospholipases A2. Biochemistry. 1992;31:2887–96.PubMedGoogle Scholar
  58. 58.
    Boegeman SC, Deems RA, Dennis EA. Phospholipid binding and the activation of group IA secreted phospholipase A2. Biochemistry. 2004;43:3907–16.PubMedGoogle Scholar
  59. 59.
    Lefkowitz LJ, Deems RA, Dennis EA. Expression of group IA phospholipase A2 in Pichia pastoris: identification of a phosphatidylcholine activator site using site-directed mutagenesis. Biochemistry. 1999;38:14174–84.PubMedGoogle Scholar
  60. 60.
    Singer AG, Ghomashchi F, Le Calvez C, Bollinger J, Bezzine S, Rouault M, et al. Interfacial kinetic and binding properties of the complete set of human and mouse groups I, II, V, X, and XII secreted phospholipases A2. J Biol Chem. 2002;277:48535–49.PubMedGoogle Scholar
  61. 61.
    Sumandea M, Das S, Sumandea C, Cho W. Roles of aromatic residues in high interfacial activity of Naja naja atra phospholipase A2. Biochemistry. 1999;38:16290–7.PubMedGoogle Scholar
  62. 62.
    Scott DL, White SP, Browning JL, Rosa JJ, Gelb MH, Sigler PB. Structures of free and inhibited human secretory phospholipase A2 from inflammatory exudate. Science 1991;254:1007–10.PubMedGoogle Scholar
  63. 63.
    Kuipers OP, Thunnissen MM, de Geus P, Dijkstra BW, Drenth J, Verheij HM, et al. Enhanced activity and altered specificity of phospholipase A2 by deletion of a surface loop. Science. 1989;244:82–5.PubMedGoogle Scholar
  64. 64.
    Beers SA, Buckland AG, Giles N, Gelb MH, Wilton DC. Effect of tryptophan insertions on the properties of the human group IIA phospholipase A2: mutagenesis produces an enzyme with characteristics similar to those of the human group V phospholipase A2. Biochemistry. 2003;42:7326–38.PubMedGoogle Scholar
  65. 65.
    Nemec KN, Pande AH, Qin S, Bieber Urbauer RJ, Tan S, Moe D, et al. Structural and functional effects of tryptophans inserted into the membrane-binding and substrate-binding sites of human group IIA phospholipase A2. Biochemistry. 2006;45:12448–60.PubMedGoogle Scholar
  66. 66.
    Pande AH, Qin S, Nemec KN, He X, Tatulian SA. Isoform-specific membrane insertion of secretory phospholipase A2 and functional implications. Biochemistry. 2006;45:12436–47.PubMedGoogle Scholar
  67. 67.
    Han SK, Kim KP, Koduri R, Bittova L, Munoz NM, Leff AR, et al. Roles of Trp31 in high membrane binding and proinflammatory activity of human group V phospholipase A2. J Biol Chem. 1999;274:11881–8.PubMedGoogle Scholar
  68. 68.
    Pan YH, Yu BZ, Singer AG, Ghomashchi F, Lambeau G, Gelb MH, et al. Crystal structure of human group X secreted phospholipase A2. Electrostatically neutral interfacial surface targets zwitterionic membranes. J Biol Chem. 2002;277:29086–93.PubMedGoogle Scholar
  69. 69.
    Bezzine S, Bollinger JG, Singer AG, Veatch SL, Keller SL, Gelb MH. On the binding preference of human groups IIA and X phospholipases A2 for membranes with anionic phospholipids. J Biol Chem. 2002;277:48523–34.PubMedGoogle Scholar
  70. 70.
    Alonso F, Henson PM, Leslie CC. A cytosolic phospholipase in human neutrophils that hydrolyzes arachidonoyl-containing phosphatidylcholine. Biochim Biophys Acta. 1986;878:273–80.PubMedGoogle Scholar
  71. 71.
    Kramer RM, Checani GC, Deykin A, Pritzker CR, Deykin D. Solubilization and properties of Ca2+-dependent human platelet phospholipase A2. Biochim Biophys Acta. 1986;878:394–403.PubMedGoogle Scholar
  72. 72.
    Clark JD, Lin LL, Kriz RW, Ramesha CS, Sultzman LA, Lin AY, et al. A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with homology to PKC and GAP. Cell. 1991;65:1043–51.PubMedGoogle Scholar
  73. 73.
    Perisic O, Fong S, Lynch DE, Bycroft M, Williams RL. Crystal structure of a calcium-phospholipid binding domain from cytosolic phospholipase A2. J Biol Chem. 1998;273:1596–604.PubMedGoogle Scholar
  74. 74.
    Dessen A, Tang J, Schmidt H, Stahl M, Clark JD, Seehra J, et al. Crystal structure of human cytosolic phospholipase A2 reveals a novel topology and catalytic mechanism. Cell. 1999;97:349–60.PubMedGoogle Scholar
  75. 75.
    Nalefski EA, Sultzman LA, Martin DM, Kriz RW, Towler PS, Knopf JL, et al. Delineation of two functionally distinct domains of cytosolic phospholipase A2, a regulatory Ca(2+)-dependent lipid-binding domain and a Ca(2+)-independent catalytic domain. J Biol Chem. 1994;269:18239–49.PubMedGoogle Scholar
  76. 76.
    Hanel AM, Gelb MH. Multiple enzymatic activities of the human cytosolic 85-kDa phospholipase A2: hydrolytic reactions and acyl transfer to glycerol. Biochemistry. 1995;34:7807–18.PubMedGoogle Scholar
  77. 77.
    Trimble LA, Street IP, Perrier H, Tremblay NM, Weech PK, Bernstein MA. NMR structural studies of the tight complex between a trifluoromethyl ketone inhibitor and the 85-kDa human phospholipase A2. Biochemistry. 1993;32:12560–5.PubMedGoogle Scholar
  78. 78.
    Pickard RT, Chiou XG, Strifler BA, DeFelippis MR, Hyslop PA, Tebbe AL, et al. Identification of essential residues for the catalytic function of 85-kDa cytosolic phospholipase A2 Probing the role of histidine, aspartic acid, cysteine, and arginine. J Biol Chem. 1996;271:19225–31.PubMedGoogle Scholar
  79. 79.
    Leslie CC. Kinetic properties of a high molecular mass arachidonoyl-hydrolyzing phospholipase A2 that exhibits lysophospholipase activity. J Biol Chem. 1991;266:11366–71.PubMedGoogle Scholar
  80. 80.
    Reynolds L, Hughes L, Louis AI, Kramer RA, Dennis EA. Metal ion and salt effects on the phospholipase A2, lysophospholipase, and transacylase activities of human cytosolic phospholipase A2. Biochim Biophys Acta. 1993;1167:272–80.PubMedGoogle Scholar
  81. 81.
    Evans JH, Leslie CC. The cytosolic phospholipase A2 catalytic domain modulates association and residence time at Golgi membranes. J Biol Chem. 2004;279:6005–16.PubMedGoogle Scholar
  82. 82.
    Evans JH, Spencer DM, Zweifach A, Leslie CC. Intracellular calcium signals regulating cytosolic phospholipase A2 translocation to internal membranes. J Biol Chem. 2001;276:30150–60.PubMedGoogle Scholar
  83. 83.
    Glover S, de Carvalho MS, Bayburt T, Jonas M, Chi E, Leslie CC, et al. Translocation of the 85-kDa phospholipase A2 from cytosol to the nuclear envelope in rat basophilic leukemia cells stimulated with calcium ionophore or IgE/antigen. J Biol Chem. 1995;270:15359–67.PubMedGoogle Scholar
  84. 84.
    Hirabayashi T, Kume K, Hirose K, Yokomizo T, Iino M, Itoh H, et al. Critical duration of intracellular Ca2+response required for continuous translocation and activation of cytosolic phospholipase A2. J Biol Chem. 1999;274:5163–9.PubMedGoogle Scholar
  85. 85.
    Peters-Golden M, Song K, Marshall T, Brock T. Translocation of cytosolic phospholipase A2 to the nuclear envelope elicits topographically localized phospholipid hydrolysis. Biochem J. 1996;318(Pt 3):797–803.PubMedGoogle Scholar
  86. 86.
    Shirai Y, Balsinde J, Dennis EA. Localization and functional interrelationships among cytosolic group IV, secreted group V, and Ca2+-independent Group VI phospholipase A2s in P388D1 macrophages using GFP/RFP constructs. Biochim Biophys Acta 2005;1735:119–29.PubMedGoogle Scholar
  87. 87.
    Lemmon MA. Membrane recognition by phospholipid-binding domains. Nat Rev Mol Cell Biol. 2008;9:99–111.PubMedGoogle Scholar
  88. 88.
    Ball A, Nielsen R, Gelb MH, Robinson BH. Interfacial membrane docking of cytosolic phospholipase A2 C2 domain using electrostatic potential-modulated spin relaxation magnetic resonance. Proc Natl Acad Sci U S A. 1999;96:6637–42.PubMedGoogle Scholar
  89. 89.
    Bittova L, Sumandea M, Cho W. A structure-function study of the C2 domain of cytosolic phospholipase A2. Identification of essential calcium ligands and hydrophobic membrane binding residues. J Biol Chem. 1999;274:9665–72.PubMedGoogle Scholar
  90. 90.
    Malkova S, Long F, Stahelin RV, Pingali SV, Murray D, Cho W, et al. X-ray reflectivity studies of cPLA2{alpha}-C2 domains adsorbed onto Langmuir monolayers of SOPC. Biophys J. 2005;89:1861–73.PubMedGoogle Scholar
  91. 91.
    Malmberg NJ, Van Buskirk DR, Falke JJ. Membrane-docking loops of the cPLA2 C2 domain: detailed structural analysis of the protein–membrane interface via site-directed spin-labeling. Biochemistry. 2003;42:13227–40.PubMedGoogle Scholar
  92. 92.
    Nalefski EA, McDonagh T, Somers W, Seehra J, Falke JJ, Clark JD. Independent folding and ligand specificity of the C2 calcium-dependent lipid binding domain of cytosolic phospholipase A2. J Biol Chem. 1998;273:1365–72.PubMedGoogle Scholar
  93. 93.
    Stahelin RV, Rafter JD, Das S, Cho W. The molecular basis of differential subcellular localization of C2 domains of protein kinase C-alpha and group IVa cytosolic phospholipase A2. J Biol Chem. 2003;278:12452–60.PubMedGoogle Scholar
  94. 94.
    Jaud S, Tobias DJ, Falke JJ, White SH. Self-induced docking site of a deeply embedded peripheral membrane protein. Biophys J. 2007;92:517–24.PubMedGoogle Scholar
  95. 95.
    Corbin JA, Evans JH, Landgraf KE, Falke JJ. Mechanism of specific membrane targeting by C2 domains: localized pools of target lipids enhance Ca2+affinity. Biochemistry. 2007;46:4322–36.PubMedGoogle Scholar
  96. 96.
    Mosior M, Six DA, Dennis EA. Group IV cytosolic phospholipase A2 binds with high affinity and specificity to phosphatidylinositol 4,5-bisphosphate resulting in dramatic increases in activity. J Biol Chem. 1998;273:2184–91.PubMedGoogle Scholar
  97. 97.
    Six DA, Dennis EA. Essential Ca(2+)-independent role of the group IVA cytosolic phospholipase A(2) C2 domain for interfacial activity. J Biol Chem. 2003;278:23842–50.PubMedGoogle Scholar
  98. 98.
    Das S, Cho W. Roles of catalytic domain residues in interfacial binding and activation of group IV cytosolic phospholipase A2. J Biol Chem. 2002;277:23838–46.PubMedGoogle Scholar
  99. 99.
    Lamour NF, Chalfant CE. Ceramide-1-phosphate: the “missing” link in eicosanoid biosynthesis and inflammation. Mol Interv. 2005;5:358–67.PubMedGoogle Scholar
  100. 100.
    Pettus BJ, Bielawska A, Subramanian P, Wijesinghe DS, Maceyka M, Leslie CC, et al. Ceramide 1-phosphate is a direct activator of cytosolic phospholipase A2. J Biol Chem. 2004;279:11320–6.PubMedGoogle Scholar
  101. 101.
    Subramanian P, Stahelin RV, Szulc Z, Bielawska A, Cho W, Chalfant CE. Ceramide 1-phosphate acts as a positive allosteric activator of group IVA cytosolic phospholipase A2 alpha and enhances the interaction of the enzyme with phosphatidylcholine. J Biol Chem. 2005;280:17601–7.PubMedGoogle Scholar
  102. 102.
    Stahelin RV, Subramanian P, Vora M, Cho W, Chalfant CE. Ceramide-1-phosphate binds group IVA cytosolic phospholipase a2 via a novel site in the C2 domain. J Biol Chem. 2007;282:20467–74.PubMedGoogle Scholar
  103. 103.
    Subramanian P, Vora M, Gentile LB, Stahelin RV, Chalfant CE. Anionic lipids activate group IVA cytosolic phospholipase A2 via distinct and separate mechanisms. J Lipid Res. 2007;48:2701–8.PubMedGoogle Scholar
  104. 104.
    Borsch-Haubold AG, Bartoli F, Asselin J, Dudler T, Kramer RM, Apitz-Castro R, et al. Identification of the phosphorylation sites of cytosolic phospholipase A2 in agonist-stimulated human platelets and HeLa cells. J Biol Chem. 1998;273:4449–58.PubMedGoogle Scholar
  105. 105.
    Hefner Y, Borsch-Haubold AG, Murakami M, Wilde JI, Pasquet S, Schieltz D, et al. Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases. J Biol Chem. 2000;275:37542–51.PubMedGoogle Scholar
  106. 106.
    Muthalif MM, Hefner Y, Canaan S, Harper J, Zhou H, Parmentier JH, et al. Functional interaction of calcium-/calmodulin-dependent protein kinase II and cytosolic phospholipase A(2). J Biol Chem. 2001;276:39653–60.PubMedGoogle Scholar
  107. 107.
    Lin LL, Wartmann M, Lin AY, Knopf JL, Seth A, Davis RJ. cPLA2 is phosphorylated and activated by MAP kinase. Cell. 1993;72:269–78.PubMedGoogle Scholar
  108. 108.
    de Carvalho MG, McCormack AL, Olson E, Ghomashchi F, Gelb MH, Yates JR 3rd, et al. Identification of phosphorylation sites of human 85-kDa cytosolic phospholipase A2 expressed in insect cells and present in human monocytes. J Biol Chem. 1996;271:6987–97.PubMedGoogle Scholar
  109. 109.
    Pavicevic Z, Leslie CC, Malik KU. cPLA2 phosphorylation at serine-515 and serine-505 is required for arachidonic acid release in vascular smooth muscle cells. J Lipid Res. 2008;49:724–37.PubMedGoogle Scholar
  110. 110.
    Bayburt T, Gelb MH. Interfacial catalysis by human 85 kDa cytosolic phospholipase A2 on anionic vesicles in the scooting mode. Biochemistry. 1997;36:3216–31.PubMedGoogle Scholar
  111. 111.
    de Carvalho MG, Garritano J, Leslie CC. Regulation of lysophospholipase activity of the 85-kDa phospholipase A2 and activation in mouse peritoneal macrophages. J Biol Chem. 1995;270:20439–46.PubMedGoogle Scholar
  112. 112.
    Das S, Rafter JD, Kim KP, Gygi SP, Cho W. Mechanism of group IVA cytosolic phospholipase A(2) activation by phosphorylation. J Biol Chem. 2003;278:41431–42.PubMedGoogle Scholar
  113. 113.
    Tian W, Wijewickrama GT, Kim JH, Das S, Tun MP, Gokhale N, et al. Mechanism of regulation of group IVA phospholipase A2 activity by Ser727 phosphorylation. J Biol Chem. 2008;283:3960–71.PubMedGoogle Scholar
  114. 114.
    Bonventre JV, Huang Z, Taheri MR, O’Leary E, Li E, Moskowitz MA, et al. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature. 1997;390:622–5.PubMedGoogle Scholar
  115. 115.
    Nagase T, Uozumi N, Ishii S, Kume K, Izumi T, Ouchi Y, et al. Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A2. Nat Immunol. 2000;1:42–6.PubMedGoogle Scholar
  116. 116.
    Uozumi N, Kume K, Nagase T, Nakatani N, Ishii S, Tashiro F, et al. Role of cytosolic phospholipase A2 in allergic response and parturition. Nature. 1997;390:618–22.PubMedGoogle Scholar
  117. 117.
    Uozumi N, Shimizu T. Roles for cytosolic phospholipase A2alpha as revealed by gene-targeted mice. Prostaglandins Other Lipid Mediat. 2002;68–69:59–69.PubMedGoogle Scholar
  118. 118.
    Larsson Forsell PK, Kennedy BP, Claesson HE. The human calcium-independent phospholipase A2 gene multiple enzymes with distinct properties from a single gene. Eur J Biochem. 1999;262:575–85.PubMedGoogle Scholar
  119. 119.
    Larsson PK, Claesson HE, Kennedy BP. Multiple splice variants of the human calcium-independent phospholipase A2 and their effect on enzyme activity. J Biol Chem. 1998;273:207–14.PubMedGoogle Scholar
  120. 120.
    Ackermann EJ, Kempner ES, Dennis EA. Ca(2+)-independent cytosolic phospholipase A2 from macrophage-like P388D1 cells. Isolation and characterization. J Biol Chem. 1994;269:9227–33.PubMedGoogle Scholar
  121. 121.
    Balboa MA, Balsinde J, Jones SS, Dennis EA. Identity between the Ca2+-independent phospholipase A2 enzymes from P388D1 macrophages and Chinese hamster ovary cells. J Biol Chem. 1997;272:8576–80.PubMedGoogle Scholar
  122. 122.
    Lio YC, Dennis EA. Interfacial activation, lysophospholipase and transacylase activity of group VI Ca2+-independent phospholipase A2. Biochim Biophys Acta. 1998;1392:320–32.PubMedGoogle Scholar
  123. 123.
    Tang J, Kriz RW, Wolfman N, Shaffer M, Seehra J, Jones SS. A novel cytosolic calcium-independent phospholipase A2 contains eight ankyrin motifs. J Biol Chem. 1997;272:8567–75.PubMedGoogle Scholar
  124. 124.
    Atsumi G, Murakami M, Kojima K, Hadano A, Tajima M, Kudo I. Distinct roles of two intracellular phospholipase A2s in fatty acid release in the cell death pathway. Proteolytic fragment of type IVA cytosolic phospholipase A2alpha inhibits stimulus-induced arachidonate release, whereas that of type VI Ca2+-independent phospholipase A2 augments spontaneous fatty acid release. J Biol Chem. 2000;275:18248–58.PubMedGoogle Scholar
  125. 125.
    Peterson B, Knotts T, Cummings BS. Involvement of Ca2+-independent phospholipase A2 isoforms in oxidant-induced neural cell death. Neurotoxicology. 2007;28:150–60.PubMedGoogle Scholar
  126. 126.
    Seleznev K, Zhao C, Zhang XH, Song K, Ma ZA. Calcium-independent phospholipase A2 localizes in and protects mitochondria during apoptotic induction by staurosporine. J Biol Chem. 2006;281:22275–88.PubMedGoogle Scholar
  127. 127.
    Zhao X, Wang D, Zhao Z, Xiao Y, Sengupta S, Zhang R, et al. Caspase-3-dependent activation of calcium-independent phospholipase A2 enhances cell migration in non-apoptotic ovarian cancer cells. J Biol Chem. 2006;281:29357–68.PubMedGoogle Scholar
  128. 128.
    Jenkins CM, Yan W, Mancuso DJ, Gross RW. Highly selective hydrolysis of fatty acyl-CoAs by calcium-independent phospholipase A2beta. Enzyme autoacylation and acyl-CoA-mediated reversal of calmodulin inhibition of phospholipase A2 activity. J Biol Chem. 2006;281:15615–24.PubMedGoogle Scholar
  129. 129.
    Jenkins CM, Wolf MJ, Mancuso DJ, Gross RW. Identification of the calmodulin-binding domain of recombinant calcium-independent phospholipase A2beta. implications for structure and function. J Biol Chem. 2001;276:7129–35.PubMedGoogle Scholar
  130. 130.
    Wang Z, Ramanadham S, Ma ZA, Bao S, Mancuso DJ, Gross RW, et al. Group VIA phospholipase A2 forms a signaling complex with the calcium/calmodulin-dependent protein kinase IIbeta expressed in pancreatic islet beta-cells. J Biol Chem. 2005;280:6840–9.PubMedGoogle Scholar
  131. 131.
    Ma Z, Wang X, Nowatzke W, Ramanadham S, Turk J. 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. J Biol Chem. 1999;274:9607–16.PubMedGoogle Scholar
  132. 132.
    Balsinde J, Bianco ID, Ackermann EJ, Conde-Frieboes K, Dennis EA. Inhibition of calcium-independent phospholipase A2 prevents arachidonic acid incorporation and phospholipid remodeling in P388D1 macrophages. Proc Natl Acad Sci U S A. 1995;92:8527–31.PubMedGoogle Scholar
  133. 133.
    Herbert SP, Walker JH. Group VIA calcium-independent phospholipase A2 mediates endothelial cell S phase progression. J Biol Chem. 2006;281:35709–16.PubMedGoogle Scholar
  134. 134.
    Roshak AK, Capper EA, Stevenson C, Eichman C, Marshall LA. Human calcium-independent phospholipase A2 mediates lymphocyte proliferation. J Biol Chem. 2000;275:35692–8.PubMedGoogle Scholar
  135. 135.
    Song Y, Wilkins P, Hu W, Murthy KS, Chen J, Lee Z, et al. Inhibition of calcium-independent phospholipase A2 suppresses proliferation and tumorigenicity of ovarian carcinoma cells. Biochem J. 2007;406:427–36.PubMedGoogle Scholar
  136. 136.
    Zhang XH, Zhao C, Seleznev K, Song K, Manfredi JJ, Ma ZA. Disruption of G1-phase phospholipid turnover by inhibition of Ca2+-independent phospholipase A2 induces a p53-dependent cell-cycle arrest in G1 phase. J Cell Sci. 2006;119:1005–15.PubMedGoogle Scholar
  137. 137.
    Balsinde J, Perez R, Balboa MA. Calcium-independent phospholipase A2 and apoptosis. Biochim Biophys Acta 2006;1761:1344–50.PubMedGoogle Scholar
  138. 138.
    Bao S, Li Y, Lei X, Wohltmann M, Jin W, Bohrer A, et al. Attenuated free cholesterol loading-induced apoptosis but preserved phospholipid composition of peritoneal macrophages from mice that do not express group VIA phospholipase A2. J Biol Chem. 2007;282:27100–14.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of Chemistry and Biochemistry, School of MedicineUniversity of CaliforniaSan DiegoUSA
  2. 2.Department of Pharmacology, School of MedicineUniversity of CaliforniaSan DiegoUSA

Personalised recommendations