Review
Structure, Function and Regulation of Group IV Phospholipase A2 Family
Aljo{a Bavec
Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
* Corresponding author: E-mail: aljosa.bavec@mf.uni-lj.si Tel.: 386 1 543 76 59; Fax: 386 1 543 76 41
Received: 13-12-2010
Abstract
The Group IV phospholipase A2 family is consisted of six intracellular enzymes. They catalyze hydrolysis of the sn-2 ester bond of glycerophospholipids, releasing fatty acid metabolites and lysophospholipids. Agonist-induced release of arachidonic acid for the production of eicosanoids by PLA2IValpha enzyme is important in regulating normal and pathological processes in a variety of target tissues. Here, we compare PLA2IValpha, and its paralogs P, y, 8, £ and Z in term of of their structure, function and regulation.
Keywords: Group IV phospholipase A2; cytosolic phospholipase A2; arahidonic acid; C2 domain
1. Introduction
PLA2s form a superfamily that currently contains 15 separate groups and numerous subgroups of PLA2 as shown in table 1.1'2'3 Enzymes are assigned to these groups based on sequence, number of disulfide bonds, molecular weight, calcium requirement, specific substrate and cell localization3. The superfamily of PLA2 comprises a number of vary different proteins that can be divided into five principal kinds of enzymes, the small secreted PLA2s (sPLA2s), the cytosolic PLA2s (cPLA2s), the Ca2+-independent PLA2s (iPLA2s), the Platelet-Activating Factor acetylhydrolases (PAF-AHs) and the lysosomal PLA2s (LPLA2s)1. These enzymes are characterized by their ability to specifically hydrolyse the sn-2 ester bond of phospholipid substrate, to produce free fatty acids and lysophospholipids, as shown in Fig. 1. Both products represents procursors for signaling molecules that can exert a variety of biological functions.4
This review aims to introduce the group IV of PLA2 enzymes, their structure, biological function, regulation and role in pathophysiological processes, as well as focusing on one well defined mammalian enzyme called group IVA PLA2 or PLA2IValpha or cPLA2a. With the completion of the mouse and human genomes it became clear that these mammals also contain other proteins homologous to cPLA2a, namely the P, y, 8, £ and Z isoforms (groups IVB-F PLA2s).5,6
0
Phospholipids (phosphatidylcholine, phosphatidylethanolamine...)
k
Fatty acids (arahidonic acid, eicosapentaenoic acid, docosahexaenoic acid...)
Fig 1: Chemical reaction catalyzed by the PLAj enzymes. Phospholipid is hydrolyzed at the sn-2 position to yield free fatty acids and lysophospholipids.
Tabele 1: Phospholipases A2
Group	Source	Molecular Mass (kDa)		Type of enzyme
IA	Cobras and kraits		13-15	spla2
IB	Human/murine		13-15	spla2
IIA	Rattlesnakes		13-15	spla2
IIB	Gaboon viper		13-15	spla2
IIC	Rat/murine		15	spla2
IID	Human/murine		14-15	spla2
IIE	Human/murine		14-15	spla2
IIF	Human/murine		16-17	spla2
III	Human/murine		55	spla2
IVA	Human/murine		85	cPLA2
IVB	Human		114	cPLA2
IVC	Human		61	cPLA2*
IVD	Human/murine		92-93	cPLA2
IVE	Murine		100	cPLA2
IVF	Murine		96	cPLA2
V	Human/murine heart/lung/macrophage		14	spla2
VIA-1	Human/murine		84-85	iPLA2
VIA-2	Human/murine		88-90	iPLA2
VIB	Human/murine		88-91	iPLA2
VIC	Human/murine		146	iPLA2
VID	Human		53	iPLA2
VIE	Human		57	iPLA2
VIF	Human		28	iPLA2
VIIA	Human, murine, porcine, bovine		45	PAF-AH
VIIB	Human, bovine		40	PAF-AH
VIIIA	Human		26	PAF-AH
VIIIB	Human		26	PAF-AH
IX	Snail venom (conodipine-M)		14	sPLA2
X	Human spleen/thymus/leukocyte		14	spla2
XIA	Green rice shoots (PLA2-I)		12.4	spla2
XIB	Green rice shoots (PLA2-II)		12.9	spla2
XII	Human/murine		19	spla2
XIII	Parvovirus		<10	spla2
XIV	Symbiotic fungus/ bacteria		13-19	spla2
XV	Human, murine, bovine	45 (deglycosylated)		lpla2
* On the basis of sequence similarities, membrane bound group IVC PLA2 is part of the cytosolic PLAjS enzymes
hout evolution with human and mouse homologues sharing over 95% amino acid identity10. The homologues found in chickens, zebra fish and xenopus have over 80% amino acid identity with human PLA2IValpha, consistent with an important conserved functional role. On the contrary, the mammalian Group IV paralogs PLA2s p, y, 5, e and Z genes are less conserved and share approximately 30-37% amino acid identity with PLA2IValpha, suggesting different role in the cell.5
The PLA2IValpha cDNA encodes a protein with a molecular weight of 85 kDa.10 Primary structure of this enzyme starts with N-terminal calcium-dependent lipid binding domain (C2 or CaLB) followed by a catalytic domain (Fig. 2, Fig. 3).10,12 The group IV PLA2 family does not contain a classical lipase catalytic domain composed of a serine/acid/histidine triad. Instead, catalytic center is utilizing a conserved serine/aspartatic acid dyad.12 Recent
2. Properties of Group IVA PLA2 (PLA2IValpha)
PLA2IValpha plays a very important role in the release of arachidonic acid, a regulator of diverse cellular functions and a precursor for biosynthesis of potent inflammatory lipids such as eisosanoids, including prosta-glandins, thromboxanes, leukotrienes and lipoxins7. PLA2IValpha shows almost no homology with other PLA2s. Among all PLA2s, receptor-mediated arachidonic release is primarily attributed to PLA2IValpha. It preferentially hydrolyses arachidonic acid from the sn-2 position of membrane phospholipids in enzyme reaction that occurs in many cell types in response to varieties of extracellular stimuli8,9,10. PLA2IValpha is on human chromosome 1 (mouse chromosome 1)11. It is highly conserved throug-
kinetic study of PLA2IValpha revealed that enzyme displays a PLAj/PLA2 specific activity ratio of 0.1 showing that it is PLA2 enzyme. PLA2IValpha displays relatively high lysophospholipase activity as well.13 With the exception of PLA2IVgamma all members of the group IV contain a C2 domain (Fig. 2). This hydrophobic C2 domain function to promote interaction of proteins with membra-nes.14 It is composed approximately 120 amino acids that fold in an eight-stranded anti-paralel P-sheet. C2 domain binds 2-3 ions of calcium through aspartatic acid residues. Calcium binding neutralizes the anionic residues and favours PLA2IValpha interaction with the membranes.15
Fig 2: Shematical representation of primary structures of murine group IV of PLAj enzymes. Length of lines represents the polypeptide lengths, and boxes represent conserved domains with similarity within group IV of PLA^. C2 domain: calcium binding domain; catalytic domain A: the lipase consensus sequence, GXSGS, is located in its N-terminal; catalytic domain B: the lipase consensus sequence, DxG (except DTA in PLA^Vepsilon).
Fig 3: Structural features of human PLA^Valpha. The cartoon diagram of human PLA2IValpha shows a-helices (purple) and P-sheets (yellow). C2 domain binds two calcium ions (green) and promotes an enzyme to translocate from the cytosol to the membranes. In the catalytic domain, residues essential for catalytic activity including the Ser228/Asp549 dyad are shown in active site.
PLA2IValpha is a widely distributed enzyme which is constitutively expressed in most cells and tissues.816 Expression of PLA2IValpha is increased by certain cytokines or inhibited by glucocorticoides.8 Regulation of PLA2IValpha by activators or signal transducers can in-
volve effects on mRNA stability and transcription.1718 PLA2IValpha is regulated by physiological levels of intra-cellular calcium concentration and phosphorylation by mitogen-activated protein kinase (MAPK)1019,20. PLA2IV-alpha is activated at submicromolar rather than millimolar calcium concentration21,22. Calcium binds to C2 domain and induces translocation of PLA2IValpha from cytosol to the membranes of Golgi, endoplasmatic reticulum, nuclear envelope23'24'25'26 and less frequently to the plasma membranes27 or inside of the nucleus28. This is an important step in regulation of enzyme to access its substrate. However, translocation of PLA2IValpha can occur without increase in calcium, indicating alternative regulatory mec-hanisms23. The MAPK family includes several subgroups including extracellular signal-regulated kinases, ERK1 (p44) and ERK2 (p42); c-Jun N-terminal kinases (JNKs) and p38. Agonist-induced phosphorylation of PLA2IValp-ha at serine 505 by ERKs increases its catalytic activity and results in characteristic gel shift192629. Although the PLA2IValpha phosphorylation by ERKs19,26,29 and p3830,31,32 is well documented in the literature, only few reports indicate possible involvement of JNKs in PLA2IV-alpha phosphorylation32,33. Beside PLA2IValpha regulation by protein kinases and calcium, there is also evidence for direct association C2 domain with other binding proteins such as vimetin, which augments arahidonic acid re-lease34. Activated receptors mediate signal via heterotri-meric GTP-binding (G) proteins to their effector enzymes, which include several phospholipases1935. In particular, the Go/Gj and Gq protein families have been shown to couple signaling to PLA2IValpha36,37. Studies on dominant negative Gi2 mutant demonstrated that inhibition of thrombin and ATP stimulated PLA2IValpha mediated arachidonic release is MAPK and calcium independent, indicating possible direct coupling G-proteins with PLA2IValpha3638. We demonstrated that in CHO cells, the G12/G13 family is also able to activate PLA2IValpha, through the activation of RhoA and, subsequently, ERK1/239.
3. Properties of Group IVB PLA2 (PLA2IVbeta)
Human PLA2IVbeta was cloned several years ago40,41, but little is known about its structure, function and regulation. PLA2IVbeta gene is located on chromosome 15. PLA2IVbeta mRNA is expressed ubiquitously in human but more highly in cerebellum, heart, and pan-creas41. More specifically, in rat cerebellum PLA2IVbeta is localized in granule cells42. The form of PLA2IVbeta c-DNA encodes a protein with a predicted molecular weight of 114 kDa40. Catalytic and C2 domains of PLA2IValpha and PLA2IVbeta share about 30% amino acid identity. Human PLA2IVbeta contains a unique N-terminal 242 amino acid extension upstream of the C2 domain that con-
tains a partial JmjC domain, but mouse PLA2IVbeta does not. JmjC domains are predicted to be metalloenzymes that are often found in nuclear proteins and contain DNA and/or chromatin binding motifs, and regulate chromatin stability43. The truncated JmjC in PLA2IVbeta would not be predicted to have a similar function since its structure is not complete. However, the truncated JmjC domain of PLA2IVbeta may affect its membrane binding and/or catalytic properties although this remains to be determined. It is obvious that PLA2IVbeta mRNA undergoes complex transcriptional and splicing regulation resulting in the production of functionally diverse protein products. PLA2IV-beta was found to be expressed as a 100 kDa protein in human tissues and in a human lung epithelial cell line (BEAS-2B), not the 114 kDa protein originally predicted44. BEAS-2B cells contain three PLA2IVbeta splice variants (PLA2IVP1, P2 and P3). All three transcripts contain the truncated JmjC domain and the C2 domain, but have differences in the catalytic domain. PLA2IVP1 is identical to the originally cloned form, whereas PLA2IVP2 and PLA2IVP3 contain internal deletions in the catalytic domain resulting in smaller proteins of 100 kDa. However, only PLA2IVP3 is translated into protein in BEAS-2B cells44. Alth2ough PLA2IVP3 exhibits calcium-dependent PLA2 activity, it was found to be consti-tutively associated with membrane in BEAS-2B cells, and localizes to mitochondria and early endosomes44. PLA2IVP3 is widely expressed in tissues suggesting that it plays a generalized role at these organelles. A recent kinetic study of PLA2IVbeta revealed that enzyme displays a PLA1/PLA2 specific activity ratio of 1.3 showing that it is a dual PLA1/PLA2 enzyme. PLA2IVbeta displays relatively high lysophospholipase activity as well13. PLA2IV-beta is an important metabolic enzyme not only in mammals but also in plants, where regulates light-induced sto-matal opening in Arabidopsis45.
4. Properties of Group IVC PLA2 (PLA2IVgamma)
Like PLA2IVbeta, human PLA2IVgamma was cloned several years ago40,46 but little is known about its structure and function. PLA2IVgamma gene is located on chromosome 19. Unlike PLA2IValpha, human PLA2IV-gamma mRNA is not ubiquitous. PLA2IVgamma mRNA is expressed most strongly in skeletal muscle and heart. The form of PLA2IVgamma cDNA encodes a protein with a molecular weight of 61 kDa40. Human PLA2IV-gamma is 30% homologous to PLA2IValpha and the residues necessary for PLA2IValpha catalytic activity are conserved in PLA2IVgamma40. PLA2IVgamma lacks both the regulatory phosphorylation sites present in PLA2IValpha and a C2 domain, but contains a prenyl group-binding site motif46. Farnesylation of C-terminal of the PLA2IVgamma, together with palmitoylation47 en-
hance protein hydrophobicity and most likely facilitate its localization to the endoplasmatic reticulum, Golgi apparatus48 and mitohondria47. This calcium independent enzyme displays a PLA1/PLA2 specific activity ratio of 0.2 showing that it is mainly PLA2 enzyme. PLA2y also displays lysophospholipase activity on 14C-P-LPC comparable to that of PLA2IVbeta and PLA2IValpha13. In some cases, PLA2IVgamma may also function as a tran-sacylase and consequently may play a role in phospholipid remodeling49. Furthermore, H2O2 and other hydroperoxides induce arachidonic acid release in PLA2IVgam-ma, suggesting that it may be involved in metabolism of oxidative stress to repair oxidized phospholipids50. The arachidonic acid released by PLA2IVgamma upon agonist stimulation is metabolized further to prostaglandin E2 via cyclo-oxygenase-1 (COX-1) in the immediate response, and via COX-2 in the delayed response48. In bovine endometrial epithelial cells PLA2IVgamma regulates prostaglandin E2 and F2alpha production upon oxytocin stimulation51. PLA2IVgamma is also present in human retina, but its function remains unknown52. Epithelial PLA2IVgamma accounts for the increased lysophospho-lipase activity observed during intestinal nematodiasis and it plays a major role in the inflammatory response to nematodes53. Interestingly, expression of mouse PLA2IV-gamma is restricted to the oocyte and early embryo, suggesting a unique role for mouse PLA2IVgamma in early embryonic development54.
5. Properties of Group IVD (PLA2IVdelta)
Like PLA2IVgamma, human PLA2IVdelta was cloned several years ago55. PLA2IVdelta gene is located on chromosome 15, near PLA2IVbeta gene. PLA2IVdelta m-RNA is uniquely expressed in stratified squamous epithelium of cervix, fetal skin and prostate. cDNA of PLA2IV-delta encodes a protein of approximately 90 kD and has greatest homology with PLA2IVbeta, PLA2IValpha and PLA2IVgamma in the C2 and catalytic domain. Human PLA2IVdelta has calcium-dependent release of arachido-nic acid from 1-palmitoyl-2[14C]arachidonoyl-phospha-tidylcholine55. It displays a PLA1/PLA2 specific activity ratio of 5.3 showing that it is predominantly PLA1 enzyme. PLA2IVdelta also displays lysophospholipase activity on 14C-P2-LPC comparable to that of PLA2IValpha, PLA2IVbeta and PLA2IVgamma13. In humans, PLA2IV-delta may play a critical role in inflammation in psoriatic lesions55. Murine PLA2IVdelta gene is located on chromosome 2, forms gene cluster with PLA2IVbeta, PLA2IV-epsilon and PLA2IVzeta gene. PLA2IVdelta mRNA is in majority expressed in placenta, unlike the human homologue. The deduced amino acid sequence of PLA2IVdelta revealed a C2 domain and catalytic domain. Murine PLA2IVdelta is more homologous to PLA2IVbeta
(41-50% amino acid identity in the catalytic domain and 33-43% identity in the C2 domain) than to PLA2IValpha or PLA2IVgamma (30-37% identity in the catalytic domain and 25-28% identity in the C2 domain). Recombinant protein demonstrated molecular weight of about 100 kDa and exhibited calcium dependent PLA2 activity. Protein is enzymatically active but do not exhibit specificity for sn-2 arachidonic acid. PLA2IVdelta translocates from cytosol to perinuclear sites in response to calcium ionop-
hore5.
6. Properties of Group IVE (PLA2IVepsilon)
Human PLA2IVepsilon has not been cloned yet. But like murine PLA2IVdelta, murine PLA2IVepsilon was cloned several years ago5. Murine PLA2IVepsilon gene is located on chromosome 2, forms gene cluster with PLA2IV-beta, PLA2IVdelta and PLA2IVzeta gene. PLA2IVepsilon mRNA is predominantly expressed in thyroid, heart, testis and skeletal muscle. From the deduced amino acid sequence of PLA2IVepsilon, C2 domain and catalytic domain has been determined. Both domains are more homologous to PLA2IVbeta than to PLA2IValpha or PLA2IV-gamma, similarly as seen in murine PLA2IVdelta. Recombinant protein demonstrated molecular weight of about 100 kDa. It requires calcium for its activity. Protein is enzymatically active but do not exhibit specificity for sn-2 arachidonic acid. PLA2IVepsilon appears to be partly associated with lysosomes, but not with ER/Golgi or mitoc-hondoria. Stimulation with ionomycin did not cause redistribution of PLA2IVepsilon in cytosol5. Recently same synthetic genes coding for human PLA2IVepsilon were prepared and kinetic studies on recombinant protein were determined. Enyzme displays only a PLA1 specific activity, which is relativily low compared to other cPLA2s. This human PLA2IVepsilon has extremely low specific activity as a lysophospholipase on 14C-P-LPC and as a PLA2 on 14C-PAPC vesicles13.
7. Properties of Group IVF (PLA2IVzeta)
Human PLA2IVzeta has not been cloned yet. Like murine PLA2IVdelta and PLA2IVepsilon, murine PLA2IVzeta was cloned several years ago5. Murine PLA2IVzeta gene is located on chromosome 2 and it is part of a gene cluster containing PLA2IVbeta, PLA2IV-delta and PLA2IVepsilon. PLA2IVzeta mRNA is expressed in thyroid and stomach. Both, C2 domain and catalytic domain are more homologous to PLA2IVbeta than to PLA2IValpha or PLA2IVgamma, similarly as seen in mu-rine PLA2IVdelta and PLA2IVepsilon. Recombinant protein with a molecular weight of about 100 kDa requires
calcium for its activity. Enzyme does not exhibit specificity for sn-2 arachidonic acid. It displays a PLA1/PLA2 specific activity ratio of 0.6 showing that it is predominantly PLA2 enzyme. PLA2IVzeta displays very high lysophospholipase activity on 14C-P-LPC comparable to that of PLA2IValpha, and PLA2IVbeta13. PLA2IVzeta is cytosolic in resting cells and does not translocate to membranes after addition of ionomycin in CHO-K1 cells5. PLA2IVzeta exhibits specific activity, inhibitor sensitivity, and low micromolar calcium dependence similar to PLA2IValpha but different sublocalization in mouse lung fibroblasts. In response to ionomycin, EGFP-PLA2IVzeta translocated to ruffles and dynamic vesicular structures56.
8. Physiological and Pathological Roles of cPLA2
The PLA2IValpha knockout mouse model has provided important information about its role in physiological processes and disease.80 The normal phenotype of PLA2IValpha-null mice suggested that this enzyme is not crucial for development and normal physiology59. However, when the mice were tested for various diseases, especially those involving inflammation, the symptoms were much milder than wild type mice. PLA2IValp-ha-null mice showed a great reduction in lipid mediator production which led to resistance to ischemia-reperfu-sion injury60, anaphylactic responses61 acute respiratory distress syndrome caused by acid or endotoxin62,63, bleomycin-induced pulmonary fibrosis64, collagen-induced autoimmune arthritis65, experimental allergic encep-halomyelitis66. In tumorigenesis of small intestine, PLA2IValpha may have a role in the expansion of polyps rather than the initiation process67. Concerning normal physiology, the loss of PLA2IValpha causes some defects on the renal concentrating function, have ulcerative lesions in the small intestine, enlarged hearts and defects in female reproduction implicating PLA2IValpha and its metabolites in regulating normal physiological proces-
ses68,69,70,71,72,73 Activation of PLA2IValpha is essential
for thrombin induced smooth muscle cell proliferation, which might lead to pathological thickening of vascular walls in atherosclerosis74. There is very little published evidence on the role of PLA2IValpha in animal models of atherosclerosis. But Wyeth suggests that apoE-/-, PLA2IValpha ko mice showed a reduced atherosclerotic plaque burden75. There are also some reports on PLA2IValpha which might play a role in severe asthma pathogenesis76. Recognition of the importance of the PLA2IValpha in inflammatory diseases has made it a very attractive drug target. Two of the most promising drug candidates include the indole derivative inhibitors developed by Wyeth77,78, which display anti-arthritic and anti-bone destructive action79, and prevent experimental
autoimmune encephalomyelitis80, and the 2-oxoamide inhibitors developed by Six81 and McKew82, which show potency in reducing inflammatory effects82. There is also a report on a series of ketone-containing compounds that are also potent inhibitors of PLA2IValpha83,84. The Wyeth are developing a new PLA2IValpha inhibitor, gi-rapladib, for osteoarthritis but data are limited75.
Among many PLA2s, PLA2IValpha plays a central role in the lipid mediator production in pathological conditions, and therefore, we propose that PLA2IValpha can be a potential target for the development of a novel class of non-steroidal anti-inflammatory drugs. Different biochemical approaches in vivo59 and in vitro85,86,87 must be carefully used to elucidate the role of the group IV PLA2 in normal and pathological physiology.
9. References
1.	R. H. Schaloske, E. A. Dennis, Biochim. Biophys. Acta 2006, 1761, 1246-1259.
2.	D. A. Six, E. A. Dennis, Biochim Biophys Acta 2000, 1488, 1-19.
3.	E. A. Dennis, J. Biol. Chem. 1994, 269, 13057-13060.
4.	C. D. Funk, Science 2001, 294, 1871-1875.
5.	T. Ohto, N. Uozumi, T. Hirabayashi, T. Shimizu, J. Biol. Chem. 2005, 280, 24576-24583.
6.	M. Ghosh, D. E. Tucker, S. A. Burchett, C. C. Leslie, Prog. Lipid Res. 2006, 45, 487-510.
7.	B. Samuelsson, S. E. Dahlen, J.A. Lindgren, C. A. Rouzer, C. N. Serhan, Science 1987, 257, 1171-1176.
8.	J. D. Clark, A. R. Schievella, E. A. Nalefski, L.-L. Lin, J. Lipid Mediat. Cell Signal. 1995, 12, 83-117.
9.	J. D. Sharp, D. L. White, X. G. Chiou, T. Goodson, G. C. Gamboa, D. McClure, S. Burgett, J. Hoskins, P. L. Skatrud, J. R. Sportsman, G. W. Becker, L. H. Kang, E. F. Roberts, R. M. Kramer, J. Biol. Chem. 1991, 266, 14850-14853.
10.	J. D. Clark, L.-L. Lin, R. W. Kriz, C. S. Ramesha, L. A. Sultzman, A. Y. Lin, N. Milona, J. L. Knopf, Cell 1991, 65, 1043-1051.
11.	A. Tay, J. S. Simon, J. Squire, K. Hamel, H. J. Jacob, K. Sko-recki, Genomics 1995, 26 138-141.
12.	A. Dessen, J. Tang, H. Schmidt, M. Stahl, J. D. Clark, J. See-hra, W. S. Somers, Cell 1999, 97, 349-360.
13.	F. Ghomashchi, G.S. Naika, J. G. Bollinger, A. Aloulou, M. Lehr, C. C. Leslie, M. H. Gelb, J Biol Chem 2010, 285, 36100-36111.
14.	E. A. Nalefski, J. J. Falke, Protein Sci. 1996, 5, 2375-2390.
15.	D. Murray, B. Honig, Mol. Cell 2002, 9, 145-154.
16.	J. D. Sharp, D. L. White, J. Lipid Mediators 1993, 8, 183189.
17.	M. Dolan-O'Keefe, V. Chow, J. Monnier, G. A. Visner, H. S. Nick, Am. J. Physiol. Lung Cell Mol. Physiol. 2000, 278, L649-L657.
18.	A. Tay, P. Maxwell, Z.-G. Li, H. Goldberg, K. Skorecki, Biochem J. 1994, 304, 417-422.
19.	L. -L. Lin, M. Wartmann, A. Y. Lin, J. L. Knopf, A. Seth, R. J. Davis, Cell 1993, 72, 269-278.
20.	Z. H. Qiu, M. A. Gijon, M. S. de Carvalho, D. M. Spencer, C. C. Leslie, J. Biol. Chem. 1998, 275, 8203-8211.
21.	E. A. Dennis Trends Biochem. Sci. 1997, 22, 1-2.
22.	J. A. A. Tischfield, J. Biol. Chem. 1997, 272, 17247-17250.
23.	J. H. Evans, D. M. Spencer, A. Zweifach, C. C. Leslie, J. Biol. Chem. 2001, 276, 30150-30160.
24.	M. A. Gijon, D. M. Spencer, A. L. Kaiser, C. C. Leslie, J. Cell Biol. 1999, 145, 1219-1232.
25.	E. A. Nalefski, L. A. Sultzman, D. M. Martin, R. W. Kriz, P. S. Towler, J. L. Knopf, J. D. Clark, J. Biol. Chem. 1994, 269, 18239-18249.
26.	A. R. Schievella, M. K. Regier, W. L. Smith, L.-L. Lin, J. Biol. Chem 1995, 270, 30749-30754.
27.	Z. Shmelzer, N. Haddad, E. Admon, I. Pessach, T. L. Leto, Z. Eitan-Hazan, M. Hershfinkel, R. Levy, J Cell Biol 2003, 162, 683-692.
28.	M. R. Sierra-Honigmann, J. R. Bradley, J. S. Pober, Lab Invest 1996, 74, 684-695.
29.	R. A. Nemenoff, S. Winitz, N.-X. Qian, V. Van Putten, G. L. Johnson, L. E. Heasley, J. Biol. Chem. 1993, 268, 1960-1964.
30.	R. M. Kramer, E. F. Roberts, S. L. Um, A. G. Börsch-Hau-bold, S. P. Watson, M. J. Fisher, J. A. Jakubowski, J. Biol. Chem. 1996, 271, 27723-27729.
31.	A. G. Börsch-Haubold, R. M. Kramer, S. P. Watson, Eur. J. Biochem. 1997, 245, 751-759.
32.	M. A. Gijon, D. M. Spencer, A. R. Siddiqi, J. V. Bonventre, C. C. Leslie, J. Biol. Chem. 2000, 275, 20146-20156.
33.	M. Hernandez, Y. Bayon, M. Sanchez Crespo, M. L. Nieto, J. Neurochem. 1999, 73, 1641-1649.
34.	Y. Nakatani, T. Tanioka, S. Sunaga, M. Murakami, I. Kudo, J Biol Chem 2000, 275, 1161-1168.
35.	L. L. Lin, A. Y. Lin, J. L. Knopf, Proc. Natl. Acad. Sci. U S A. 1992, 89, 6147-6151.
36.	S. Winitz, S. K. Gupta, N. X. Qian, L. E. Heasley, R.A. Ne-menoff, G. L. Johnson, J. Biol. Chem. 1994, 269, 1889-1895.
37.	J. M. Dickenson, S. J. Hill, Eur. J. Pharmacol. 1997, 321, 77-86.
38.	R. Murray-Whelan, J. D. Reid, I. Piuz, M. Hezareh, W. Schlegel, Eur. J. Biochem. 1995, 230, 64-69.
39.	S. Mariggio, A. Bavec, E. Natale, P. Zizza, M. Salmona, D. Corda, M. Di Girolamo, Cell Signal. 2006, 18, 2200-2208.
40.	R. T. Pickard, B. A. Strifler, R. M. Kramer, J. D. Sharp, J. Biol. Chem. 1999, 274, 8823-8831.
41.	C. Song, X. J. Chang, K. M. Bean, M. S. Proia, J. L. Knopf, R. W. Kriz, J. Biol. Chem. 1999, 274, 17063-17067.
42.	Y. Shirai, M. Ito, J. Neurocytol. 2004, 33, 297-307.
43.	S. C. Trewick, P. J. McLaughlin, R. C. Allshire, EMBO Reports 2005, 6, 315-320.
44.	M. Ghosh, R. Loper, M. H. Gelb, C.C. Leslie, J Biol Chem 2006, 281, 16615-16624.
45.	J. Seo, H. Y. Lee, H. Choi, Y. Choi, Y. Lee, Y. W. Kim, S. B. Ryu, Y. Lee, J. Exp. Bot. 2008, 59, 3587-3594.
46.	K. W. Underwood, C. Song, R. W. Kriz, X. J. Chang, J. L. Knopf, L.-L. Lin, J Biol Chem 1998, 273, 21926-21932.
47.	D. E. Tucker, A. Stewart, L. Nallan, P. Bendale, F. Gho-mashchi, M. H. Gelb, C. C. Leslie J Lipid Res 2005, 46, 2122-2133.
48.	M. Murakami, S. Masuda, I. Kudo, Biochem. J. 2003, 372, 695-702.
49.	A. Yamashita, R. Kamata, N. Kawagishi, H. Nakanishi, H. Suzuki, T. Sugiura, K. Waku, J. Biochem. 2005, 137, 557567.
50.	K. Asai, T. Hirabayashi, T. Houjou, N. Uozumi, R. Taguchi and T. Shimizu, J Biol Chem 2003, 278, 8809-8814.
51.	P. K. Tithof, M. P. Roberts, W. Guan, M. Elgayyar, J. D. Godkin, Reprod. Biol. Endocrinol. 2007, 5, 16.
52.	M. Kolko, J. Wang, C. Zhan, K. A. Poulsen, J. U. Prause, M. H. Nissen, S. Heegaard, N. G. Bazan, Invest. Ophthalmol. Vis. Sci. 2007, 48, 1401-1409.
53.	J. K. Brown, P. A. Knight, E. M. Thornton, J. A. Pate, S. Coonrod, H. R. Miller, A. D. Pemberton, Int. J. Parasitol. 2008, 38, 143-147.
54.	A. Vitale, J. Perlin, L. Leonelli, J. Herr, P. Wright, L. Digilio, S. Coonrod, Dev. Biol. 2005, 282, 374-384.
55.	H. Chiba, H. Michibata, K. Wakimoto, M. Seishima, S. Kawasaki, K. Okubo, H. Mitsui, H. Torii, Y. Imai, J. Biol. Chem. 2004, 279, 12890-12897.
56.	M. Ghosh, R. Loper, F. Ghomashchi, D. E. Tucker, J. V. Bon-ventre, M. H. Gelb, C. C. Leslie, J. Biol. Chem. 2007, 282, 11676-11686.
57.	N. Uozumi, T. Shimizu, Prostaglandin Other Lipid Mediat.
2002,	68-69, 59-69.
58.	J. V. Bonventre, A. Sapirstein, Adv. Exp. Med. Biol. 2002, 507, 25-31.
59.	N. Uozumi, K. Kume, T. Nagase, N. Nakatani, S. Ishii, F. Tashiro, Y. Komagata, K. Maki, K. Ikuta, Y. Ouchi, J. Miyazaki, T. Shimizu, Nature 1997, 390, 618-622.
60.	J. V. Bonventre, Z. Huang, M. R. Taheri, E. O'Leary, E. Li, M. A. Moskowitz, A. Sapirstein, Nature 1997, 390, 622-625.
61 H. Fujishima, R. O. Sanchez Mejia, C. O. Bingham III, B. K. Lam, A. Sapirstein, J. V. Bonventre, K. F. Austen, J. P. Arm, Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 4803-4807.
62.	T. Nagase, N. Uozumi, S. Ishii, K. Kume, T. Izumi, Y. Ouchi, T. Shimizu, Nat. Immunol. 2000, 1, 42-46.
63.	T. Nagase, N. Uozumi, T. Aoki-Nagase, K. Terawaki, S. Ishii, T. Tomita, H. Yamamoto, K. Hashizume, Y. Ouchi, T. Shimizu, Am. J. Physiol. Lung Cell Mol. Physiol. 2003, 284, L720-L726.
64.	T. Nagase, N. Uozumi, S. Ishii, Y. Kita, H. Yamamoto, E. Ohga, Y. Ouchi, T. Shimizu, Nat. Med. 2002, 8, 480-484.
65.	M. Hegen, L. Sun, N. Uozumi, K. Kume, M. E. Goad, C. L. Nickerson-Nutter, T. Shimizu, J. D. Clark, J. Exp. Med.
2003,	197, 1297-1302.
66.	S. Marusic, M. W. Leach, J. W. Pelker, M. L. Azoitei, N. Uo-zumi, J. Cui, M. W. Shen, C. M. DeClercq, J. S. Miyashiro, B. A. Carito, P. Thakker, D. L. Simmons, J. P. Leonard, T. Shimizu, J. D. Clark, J. Exp. Med. 2005, 202, 841-851.
67.	K. Takaku, M. Sonoshita, N. Sasaki, N. Uozumi, Y. Doi, T. Shimizu, M. M. Taketo, J. Biol. Chem. 2000, 275, 3401334016.
68.	J. V. Bonventre, Z. Huang, M. R. Taheri, E. O'Leary, E. Li, M. A. Moskowitz, A. Sapirstein, Nature 1997, 390, 622625.
69.	N. Uozumi, K. Kume, T. Nagase, N. Nakatani, S. Ishii, F. Tashiro, Y. Komagata, K. Maki, K. Ikuta, Y. Ouchi, J. Miyazaki, T. Shimizu, Nature 1997, 390, 618-622.
70.	P. Downey, A. Sapirstein, E. O'Leary, T. Sun, D. Brown, J. V. Bonventre, Am. J. Physiol. Renal. Physiol. 2001, 280, F607-F619.
71.	S. Haq, H. Kilter, A. Michael, J. Tao, E. O'Leary, X. M. Sun, B. Walters, K. Bhattacharya, X. Chen, L. Cui, M. Andreucci, A. Rosenzweig, J. L. Guerrero, R. Patten, R. Liao, J. Molkentin, M. Picard, J. V. Bonventre, T. Force, Nat. Med. 2003, 9, 944-951.
72.	H. Song, H. Lim, B. C. Paria, H. Matsumoto, L. L. Swift, J. Morrow, J. V. Bonventre, S. K. Dey, Development, 2002, 129, 2879-2889.
73.	K. Takaku, M. Sonoshita, N. Sasaki, N. Uozumi, Y. Doi, T. Shimizu, Taketo MM. J. Biol. Chem. 2000, 275, 3401334016.
74.	N. Gluck, O. Schwob, M. Krimsky, S. Yedgar, Am. J. Physiol. Cell Physiol. 2008, 294, 1597-1603.
75.	K. Suckling, Atherosclerosis 2010, 212, 357-366.
76.	M. Sokolowska, M. Borowiec, A. Ptasinska, M. Cieslak, J. H. Shelhamer, M. L. Kowalski, R. Pawliczak, Clin. Exp. Immunol. 2007, 150, 124-131.
77.	K. Seno, T. Okuno, K. Nishi, Y. Murakami, F. Watanabe, T. Matsuura, M. Wada, Y. Fujii, M. Yamada, T. Ogawa, T. Oka-da, H. Hashizume, M. Kii, S. Hara, S. Hagishita, S. Nakamo-to, K. Yamada, Y. Chikazawa, M. Ueno, I. Teshirogi, T. Ono, M. Ohtani, J. Med. Chem. 2000, 43, 1041-1044.
78.	K. L. Lee, M. A. Foley, L. Chen, M. L. Behnke, F. E. Love-ring, S. J. Kirincich, W. Wang, J. Shim, S. Tam, M. W. H. Shen, S. P. Khor, X. Xu, D. G. Goodwin, M. K. Ramarao, C. Nickerson-Nutter, F. Donahue, M. S. Ku, J. D. Clark, J. C. McKew, J. Med. Chem. 2007, 50, 1380-1400.
79.	N. Tai, K. Kuwabara, M. Kobayashi, K. yamada, T. Ono, K. Seno, Y. Gahara, J. Ishizaki, Y. Hori, Inflamm. Res. 2009, 59, 53-62.
80.	S. Marusic, P. Thakker, J. W. Pelker, N. L. Stedman, K. L. Lee, J. C. McKew, L. Han, X. Xu, S. F. Wolf, A. J. Borey, J. Cui, M. W. Shen, F. Donahue, M. hassan-Zahraee, M. W. Leach, T. Shimizu, J. D. Clark, J. Neuroimmunol. 2008, 204, 29-37.
81.	D. A. Six, E. Barbayianni, V. Loukas, V. Constantinou-Koko-tou, D. Hadjipavlou-Litina, D. Stephens, A. C. Wong, V. Ma-grioti, P. Moutevelis-Minakakis, S. F. Baker, et al., J. Med. Chem. 2007, 50, 4222-4235.
82.	J. C. McKew, K. L. Lee, M. W. Shen, P. Thakker, M. A. Foley, M. L. Behnke, B. Hu, F. W. Sum, S. Tam, Y. Hu, et al., J. Med. Chem. 2008, 51, 3388-3413.
83.	J. Ludwig, S. Bovens, C. Brauch, A.S. Elfringhoff, M. Lehr, J. Med. Chem. 2006, 49, 2611-2620.
84.	G. Kokotos, S. Kotsovolou, D. A. Six, V. Constantinou-Ko-kotou, C. C. Beltzner, E. A. Dennis, J. Med. Chem. 2002, 45, 2891-2893.
85. T. Mars, M. P. King, A. F. Miranda, W. F. Walker, K. Mis, Z. 87. N. Debeljak, A. J. Sytkowski, Curr. Pharma. Des. 2008, 14, Grubic. Neuroscience 2003, 118, 87-97.	1302-1310.
86. M. Golicnik, D. Fournier, J. Stojan. Biochemistry 2001, 40, 1214-1219.
Povzetek
Skupina IV fosfolipaz A2 trenutno obsega šest encimov. Encimi katalizirajo hidrolizo sn-2 estrske vezi glicerofosfolpi-dov, pri čemer nastane maščobna kislina in lizofosfolipid. Največkrat je produkt hidrolize arahidonska kislina, ki se pretvarja v aktivne eikozanoide, ki imajo pomembno vlogo pri regulaciji celičnih procesov v različnih tarčnih tkivih. V tem prispevku si bomo pogledali strukturo, funkcijo in regulacijo encima PLA2IValpha in jo primerjali z ostalimi predstavniki skupine IV fosfolipaz A2, in sicer z P, y, 8, £ and Z.