Biology:Lipoprotein-associated phospholipase A2
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Lipoprotein-associated phospholipase A2 (Lp-PLA2) also known as platelet-activating factor acetylhydrolase (PAF-AH) is a phospholipase A2 enzyme that in humans is encoded by the PLA2G7 gene.[1][2] Lp-PLA2 is a 45-kDa protein of 441 amino acids.[3] It is one of several PAF acetylhydrolases.
Function
In the blood Lp-PLA2 travels mainly with low-density lipoprotein (LDL). Less than 20% is associated with high-density lipoprotein HDL. Several lines of evidence suggest that HDL-associated Lp-PLA2 may substantially contribute to the HDL antiatherogenic activities.[4] It is an enzyme produced by inflammatory cells and hydrolyzes oxidized phospholipids in LDL.
Lp-PLA2 is platelet-activating factor (PAF) acetylhydrolase (EC 3.1.1.47), a secreted enzyme that catalyzes the degradation of PAF to inactive products by hydrolysis of the acetyl group at the sn-2 position, producing the biologically inactive products LYSO-PAF and acetate.[5]
Clinical significance
Lp-PLA2 is involved in the development of atherosclerosis,[3] an observation that has prompted interest as a possible therapeutic target (see, e.g. the investigational drug Darapladib). In human atherosclerotic lesions, 2 main sources of Lp-PLA2 can be identified, including that which is brought into the intima bound to LDL (from the circulation), and that which is synthesized de novo by plaque inflammatory cells (macrophages, T cells, mast cells)."
It is used as a marker for cardiac disease.[6]
A meta-analysis involving a total of 79,036 participants in 32 prospective studies found that Lp-PLA2 levels are positively correlated with increased risk of developing coronary heart disease and stroke.[7]
See also
References
- ↑ "Anti-inflammatory properties of a platelet-activating factor acetylhydrolase". Nature 374 (6522): 549–53. April 1995. doi:10.1038/374549a0. PMID 7700381. Bibcode: 1995Natur.374..549T.
- ↑ "Purification, properties, sequencing, and cloning of a lipoprotein-associated, serine-dependent phospholipase involved in the oxidative modification of low-density lipoproteins". Arteriosclerosis, Thrombosis, and Vascular Biology 16 (4): 591–9. April 1996. doi:10.1161/01.ATV.16.4.591. PMID 8624782.
- ↑ 3.0 3.1 "Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target". Arteriosclerosis, Thrombosis, and Vascular Biology 25 (5): 923–31. May 2005. doi:10.1161/01.ATV.0000160551.21962.a7. PMID 15731492.
- ↑ "The role of lipoprotein-associated phospholipase A2 in atherosclerosis may depend on its lipoprotein carrier in plasma". Biochimica et Biophysica Acta 1791 (5): 327–38. May 2009. doi:10.1016/j.bbalip.2009.02.015. PMID 19272461.
- ↑ "Entrez Gene: PLA2G7 phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7941.
- ↑ "The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study". Journal of the American College of Cardiology 51 (17): 1632–41. April 2008. doi:10.1016/j.jacc.2007.11.079. PMID 18436114.
- ↑ "Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies". Lancet 375 (9725): 1536–44. May 2010. doi:10.1016/S0140-6736(10)60319-4. PMID 20435228.
- "Blood protein increases heart disease risk". BBC News. 29 April 2010. http://news.bbc.co.uk/2/hi/health/8652005.stm.
Further reading
- "Mechanisms of prionSc- and HIV-1 gp120 induced neuronal cell death". Neurotoxicology 19 (4–5): 683–8. 1998. PMID 9745929.
- "Protein-protein interactions, cytoskeletal regulation and neuronal migration". Nature Reviews. Neuroscience 2 (6): 408–16. June 2001. doi:10.1038/35077559. PMID 11389474.
- "Plasma platelet-activating factor acetylhydrolase is a secreted phospholipase A2 with a catalytic triad". The Journal of Biological Chemistry 270 (43): 25481–7. October 1995. doi:10.1074/jbc.270.43.25481. PMID 7592717.
- "Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase". The Journal of Clinical Investigation 97 (12): 2784–91. June 1996. doi:10.1172/JCI118733. PMID 8675689.
- "Loss of activity of plasma platelet-activating factor acetylhydrolase due to a novel Gln281-->Arg mutation". Biochemical and Biophysical Research Communications 236 (3): 772–5. July 1997. doi:10.1006/bbrc.1997.7047. PMID 9245731.
- "HIV and SIV envelope glycoproteins induce phospholipase A2 activation in human and macaque lymphocytes". Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 16 (1): 1–9. September 1997. doi:10.1097/00042560-199709010-00001. PMID 9377118.
- "Reduction of microtubule catastrophe events by LIS1, platelet-activating factor acetylhydrolase subunit". The EMBO Journal 16 (23): 6977–84. December 1997. doi:10.1093/emboj/16.23.6977. PMID 9384577.
- "A mutation in plasma platelet-activating factor acetylhydrolase (Val279-->Phe) is a genetic risk factor for stroke". Stroke 28 (12): 2417–20. December 1997. doi:10.1161/01.str.28.12.2417. PMID 9412624.
- "Identification of the G994--> T missense in exon 9 of the plasma platelet-activating factor acetylhydrolase gene as an independent risk factor for coronary artery disease in Japanese men". Metabolism 47 (2): 177–81. February 1998. doi:10.1016/S0026-0495(98)90216-5. PMID 9472966.
- "A mutation in plasma platelet-activating factor acetylhydrolase (Val279Phe) is a genetic risk factor for cerebral hemorrhage but not for hypertension". Thrombosis and Haemostasis 80 (3): 372–5. September 1998. doi:10.1055/s-0037-1615214. PMID 9759612.
- "Molecular analysis of an unstable genomic region at chromosome band 11q23 reveals a disruption of the gene encoding the alpha2 subunit of platelet-activating factor acetylhydrolase (Pafah1a2) in human lymphoma". Oncogene 18 (18): 2852–9. May 1999. doi:10.1038/sj.onc.1202645. PMID 10362256.
- "The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma". American Journal of Human Genetics 66 (5): 1522–30. May 2000. doi:10.1086/302901. PMID 10733466.
- "The expression and localization of plasma platelet-activating factor acetylhydrolase in endotoxemic rats". The Journal of Biological Chemistry 275 (26): 19891–6. June 2000. doi:10.1074/jbc.M001462200. PMID 10748027.
- "Platelet-activating factor acetylhydrolases: broad substrate specificity and lipoprotein binding does not modulate the catalytic properties of the plasma enzyme". Biochemistry 40 (15): 4539–49. April 2001. doi:10.1021/bi002600g. PMID 11294621.
- "Adenovirus-mediated gene transfer of human platelet-activating factor-acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice". Circulation 103 (20): 2495–500. May 2001. doi:10.1161/01.cir.103.20.2495. PMID 11369691.
- "Association of a G994 -->T missense mutation in the plasma platelet-activating factor acetylhydrolase gene with risk of abdominal aortic aneurysm in Japanese". Annals of Surgery 235 (2): 297–302. February 2002. doi:10.1097/00000658-200202000-00020. PMID 11807372.
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