Phospholipase A2 (E.C. 3.1.1.4)
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PROVIDER: S-EPMC2884554 | biostudies-literature | 2009 Nov
REPOSITORIES: biostudies-literature
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| S-EPMC2884596 | biostudies-literature
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| S-EPMC2884610 | biostudies-literature
Project description:As saprophytes or disease causing microorganisms, fungi acquire nutrients from dead organic material or living host organisms. Lipids as structural components of cell membranes and storage compartments play an important role as energy-rich food source. In recent years, it also has become clear that lipids have a wide range of bioactive properties including signal transduction and cell to cell communication. Thus, it is not surprising that fungi possess a broad range of hydrolytic enzymes that attack neutral lipids and phospholipids. Especially during infection of a mammalian host, phospholipase A(2) (PLA(2)) enzymes released by fungi could play important roles not only for nutrient acquisition and tissue invasion, but for intricate modulation of the host's immune response. Sequencing of fungal genomes has revealed a wide range of genes encoding PLA(2) activities in fungi. We are just beginning to become aware of the significance these enzymes could have for the fungal cells and their interaction with the host.
| S-EPMC2077850 | biostudies-literature
Project description:A lysosomal phospholipase A2, LPLA2, was recently characterized and shown to have substrate specificity for phosphatidylcholine and phosphatidylethanolamine. LPLA2 is ubiquitously expressed but is most highly expressed in alveolar macrophages. Double conditional gene targeting was employed to elucidate the function of LPLA2. LPLA2-deficient mice (Lpla2-/-) were generated by the systemic deletion of exon 5 of the Lpla2 gene, which encodes the lipase motif essential for the phospholipase A2 activity. The survival of the Lpla2-/- mice was normal. Lpla2-/- mouse mating pairs yielded normal litter sizes, indicating that the gene deficiency did not impair fertility or fecundity. Alveolar macrophages from wild-type but not Lpla2-/- mice readily degraded radiolabeled phosphatidylcholine. A marked accumulation of phospholipids, in particular phosphatidylethanolamine and phosphatidylcholine, was found in the alveolar macrophages, the peritoneal macrophages, and the spleens of Lpla2-/- mice. By 1 year of age, Lpla2-/- mice demonstrated marked splenomegaly and increased lung surfactant phospholipid levels. Ultrastructural examination of Lpla2-/- mouse alveolar and peritoneal macrophages revealed the appearance of foam cells with lamellar inclusion bodies, a hallmark of cellular phospholipidosis. Thus, a deficiency of lysosomal phospholipase A2 results in foam cell formation, surfactant lipid accumulation, splenomegaly, and phospholipidosis in mice.
| S-EPMC1592808 | biostudies-literature
Project description:Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein-associated phospholipase A2 (Lp-PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation-related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp-PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp-PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp-PLA2 have been reported recently, while novel inhibitors were identified through a fragment-based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp-PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp-PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp-PLA2, identify more potent and selective Lp-PLA2 inhibitors, and discover the potential indications of Lp-PLA2 inhibitors.
| S-EPMC6973114 | biostudies-literature
Project description:Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovitis leading to destruction of cartilage and bone. PLA2 enzymes are key players in inflammation regulating the release of unsaturated fatty acids such as arachidonic acid (AA), a precursor of pro-inflammatory eicosanoids. Several lines of evidence point to toll-like receptors (TLRs) as drivers of synovitis and joint destruction in RA. However, few studies have addressed the implication of PLA2 activity downstream TLR activation in the synovium. Here, we aimed to characterize PLA2 enzyme involvement in TLR2-induced signaling in synovial fibroblast-like cells. TLRs1-7 and a range of sPLA2, iPLA2 and cPLA2 enzymes were found to be transcriptionally expressed in cultured synoviocytes. Activation of TLR2/1 and TLR2/6 led to phosphorylation of cPLA2α at Ser505, and induced AA release and PGE2 production; effects that were attenuated by cPLA2α inhibitors. In contrast, sPLA2 inhibitors did not affect AA or PGE2 release. cPLA2α inhibitors furthermore attenuated TLR-induced expression of IL-6, IL-8 and COX2. COX1/2 inhibitors attenuated TLR2/6-induced IL-6 transcription and protein production comparable to cPLA2α inhibition. Moreover, exogenously PGE2 added alone induced IL-6 production and completely rescued IL-6 transcription when added simultaneously with FSL-1 in the presence of a cPLA2α inhibitor. Our results demonstrate for the first time that cPLA2α is involved in TLR2/1- and TLR2/6-induced AA release, PGE2 production and pro-inflammatory cytokine expression in synoviocytes, possibly through COX/PGE2-dependent pathways. These findings expand our understanding of cPLA2α as a modulator of inflammatory molecular mechanisms in chronic diseases such as RA.
| S-EPMC4404349 | biostudies-literature
Project description:We have previously reported that the majority of phospholipase A2 (PLA2) activity in rabbit ventricular myocytes is membrane-associated, calcium-independent (iPLA2), selective for arachidonylated plasmalogen phospholipids and inhibited by the iPLA2-selective inhibitor bromoenol lactone (BEL). Here, we identified the presence of iPLA2 in rabbit ventricular myocytes, determined the full length sequences for rabbit iPLA2beta and iPLA2gamma and compared their homology to the human isoforms. Rabbit iPLA2beta encoded a protein with a predicated molecular mass of 74 kDa that is 91% identical to the human iPLA2beta short isoform. Full length iPLA2gamma protein has a predicated molecular mass of 88 kDa and is 88% identical to the human isoform. Immunoblot analysis of iPLA2beta and gamma in membrane and cytosolic fractions from rabbit and human cardiac myocytes demonstrated a similar pattern of distribution with both isoforms present in the membrane fraction, but no detectable protein in the cytosol. Membrane-associated iPLA2 activity was inhibited preferentially by the R enantiomer of bromoenol lactone [(R)-BEL], indicating that the majority of activity is due to iPLA2gamma.
| S-EPMC2831212 | biostudies-literature
Project description:BackgroundThe anti-phospholipase A2 receptor (PLA2R) antibody is a non-invasive diagnostic tool and prognosis predictor of idiopathic membranous nephropathy (IMN). Baseline hypercholesterolemia independently predicts proteinuria outcomes in IMN patients. Thus, we investigated whether hyperlipidemia is correlated with anti-PLA2R and pathological indicators.MethodsA total of 495 IMN patients identified by kidney biopsy in Wuhan Tongji Hospital, China, from January 2016 through December 2020 were enrolled in this study. Data on clinical features, pathology findings, and outcomes were collected.ResultsTotal cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were positively related to proteinuria, indicating damage to the renal glomerulus [Spearman's rank correlation coefficient = 0.432, 0.462, 0.315, and 0.289, respectively, P < 0.001 for all]. In univariate logistic regression, low HDL-C [odds ratio (OR): 0.856; 95% CI: 0.778-0.939; P = 0.001] and high TG [OR: 1.025; 95% CI: 1.006-1.044; P = 0.011] were correlated with tubular atrophy, suggesting lesions on tubules. Increased TC [adjusted OR: 1.285; 95% CI: 1.119-1.475; P < 0.001], non-HDL-C [adjusted OR: 1.284; 95% CI: 1.113-1.482; P = 0.001], and LDL-C [adjusted OR: 1.178; 95% CI: 1.009-1.376; P = 0.039] independently predicted glomerular PLA2R deposit; similar results were observed for lipids in predicting the seropositivity of anti-PLA2R antibodies. After treatment, increased HDL-C [adjusted hazard ratio (HR): 1.764; 95% CI: 1.241-2.507; P = 0.002] and decreased non-HDL-C [adjusted HR: 0.884; 95% CI: 0.795-0.983; P = 0.022] independently predicted proteinuria remission.ConclusionHypercholesterolemia is a potentially useful biomarker for disease severity, serum anti-PLA2R antibody, glomerular PLA2R deposit, and proteinuria outcome of IMN.
| S-EPMC9248763 | biostudies-literature
Project description:Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging that recapitulates many normal aging characteristics. This disorder is caused by mutation in the LMNA gene leading to the production of progerin which induces misshapen nuclei, cellular senescence, and aging. We previously showed that the phospholipase A2 receptor (PLA2R1) promotes senescence induced by replicative, oxidative, and oncogenic stress but its role during progerin-induced senescence and in progeria is currently unknown. Here, we show that knockdown of PLA2R1 prevented senescence induced by progerin expression in human fibroblasts and markedly delayed senescence of HGPS patient-derived fibroblasts. Whole-body knockout of Pla2r1 in a mouse model of progeria decreased some premature aging phenotypes, such as rib fracture and decreased bone content, together with decreased senescence marker. Progerin-expressing human fibroblasts exhibited a high frequency of misshapen nuclei and increased farnesyl diphosphate synthase (FDPS) expression compared to controls; knockdown of PLA2R1 reduced the frequency of misshapen nuclei and normalized FDPS expression. Pamidronate, a FDPS inhibitor, also reduced senescence and misshapen nuclei. Downstream of PLA2R1, we found that p53 mediated the progerin-induced increase in FDPS expression and in misshapen nuclei. These results suggest that PLA2R1 mediates key premature aging phenotypes through a p53/FDPS pathway and might be a new therapeutic target.
| S-EPMC6260922 | biostudies-literature
Project description:Phospholipases A2 (PLA2s) belong to a superfamily of enzymes responsible for hydrolysis of the sn-2 fatty acids of membrane phospholipids to release arachidonic acid. PLA2s are the rate limiting enzyme for the downstream synthesis of prostaglandins and leukotrienes that are the main mediators of inflammation. The extracellular forms of this enzyme are also called the secretary phospholipase A2 (sPLA2) and are distributed extensively in most of the tissues in the human body. Their integral role in inflammatory pathways has been the primary reason for the extensive research on this molecule. The catalytic mechanism of sPLA2 is initiated by a histidine/aspartic acid/calcium complex within the active site. Though they are known to have certain housekeeping functions, certain mutations of sPLA2 are known to be implicated in causation of certain pathologies leading to diseases such as atherosclerosis, cardiovascular diseases, benign fleck retina, neurodegeneration, and asthma. We present an overview of human sPLA2 and a comprehensive compilation of the mutations that result in various disease phenotypes. The study not only helps to have a holistic understanding of human sPLA2 mutations and their clinical implications, but is also a useful platform to initiate research pertaining to structure-function relationship of the mutations to develop effective therapies for management of these diseases.
| S-EPMC7502393 | biostudies-literature