Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRZ2L5A)

DOT Name Group 10 secretory phospholipase A2 (PLA2G10)
Synonyms EC 3.1.1.4; Group X secretory phospholipase A2; GX sPLA2; sPLA2-X; Phosphatidylcholine 2-acylhydrolase 10
Gene Name PLA2G10
Related Disease
Abdominal aortic aneurysm ( )
Adult respiratory distress syndrome ( )
Arteriosclerosis ( )
Asthma ( )
Astrocytoma ( )
Atherosclerosis ( )
Bronchopulmonary dysplasia ( )
Castration-resistant prostate carcinoma ( )
Chronic obstructive pulmonary disease ( )
Colitis ( )
Congenital alveolar dysplasia ( )
Coronary heart disease ( )
Craniosynostosis ( )
Hepatocellular carcinoma ( )
Hyperlipidemia ( )
Lung neoplasm ( )
Nasal polyp ( )
Neoplasm ( )
Non-small-cell lung cancer ( )
Prostate cancer ( )
Prostate carcinoma ( )
Prostate neoplasm ( )
Psoriasis ( )
Schizophrenia ( )
Tuberculosis ( )
Type-1/2 diabetes ( )
Adenovirus infection ( )
Advanced cancer ( )
Bacterial infection ( )
Cardiovascular disease ( )
Chronic renal failure ( )
Lung adenocarcinoma ( )
Lung cancer ( )
Lung carcinoma ( )
Adenocarcinoma ( )
Crohn disease ( )
Arthritis ( )
Breast cancer ( )
Breast carcinoma ( )
Cholelithiasis ( )
Colon adenocarcinoma ( )
Colon cancer ( )
Colon carcinoma ( )
Colorectal carcinoma ( )
Coronary atherosclerosis ( )
End-stage renal disease ( )
Nervous system disease ( )
Non-insulin dependent diabetes ( )
Rheumatoid arthritis ( )
UniProt ID
PA2GX_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
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PDB ID
1LE6; 1LE7; 4UY1; 5G3M; 5OW8; 5OWC; 6G5J
EC Number
3.1.1.4
Pfam ID
PF00068
Sequence
MGPLPVCLPIMLLLLLPSLLLLLLLPGPGSGEASRILRVHRRGILELAGTVGCVGPRTPI
AYMKYGCFCGLGGHGQPRDAIDWCCHGHDCCYTRAEEAGCSPKTERYSWQCVNQSVLCGP
AENKCQELLCKCDQEIANCLAQTEYNLKYLFYPQFLCEPDSPKCD
Function
Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids. Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids with preference for phosphatidylcholines and phosphatidylglycerols over phosphatidylethanolamines. Preferentially releases sn-2 omega-6 and omega-3 polyunsaturated fatty acyl (PUFA) chains over saturated fatty acyls. Contributes to phospholipid remodeling of very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles. Hydrolyzes LDL phospholipids releasing unsaturated fatty acids that regulate macrophage differentiation toward foam cells. Efficiently hydrolyzes and inactivates platelet activating factor (PAF), a potent lipid mediator present in oxidized LDL. May act in an autocrine and paracrine manner. Secreted by lung epithelium, targets membrane phospholipids of infiltrating eosinophils, releasing arachidonate and boosting eicosanoid and cysteinyl leukotriene synthesis involved in airway inflammatory response. Secreted by gut epithelium, hydrolyzes dietary and biliary phosphatidylcholines in the gastrointestinal lumen. Plays a stem cell regulator role in colon epithelium. Within intracellular compartment, mediates Paneth-like cell differentiation and its stem cell supporting functions by inhibiting the Wnt signaling pathway in intestinal stem cell (ISC). Secreted in the intestinal lumen upon inflammation, acts in an autocrine way and promotes prostaglandin E2 synthesis that stimulates Wnt signaling pathway in ISCs and tissue regeneration. May participate in hair follicle morphogenesis by regulating phosphatidylethanolamines metabolism at the outermost epithelial layer and facilitating melanin synthesis. By releasing lysophosphatidylcholines (LPCs) at sperm acrosome, controls sperm cell capacitation, acrosome reaction and overall fertility. May promote neurite outgrowth in neuron fibers involved in nociception. Contributes to lipid remodeling of cellular membranes and generation of lipid mediators involved in pathogen clearance. Cleaves sn-2 fatty acyl chains of phosphatidylglycerols and phosphatidylethanolamines, which are major components of membrane phospholipids in bacteria. Displays bactericidal activity against Gram-positive bacteria by directly hydrolyzing phospholipids of the bacterial membrane. In pulmonary epithelium, may contribute to host defense response against adenoviral infection. Prevents adenovirus entry into host cells by hydrolyzing host cell plasma membrane, releasing C16:0 LPCs that inhibit virus-mediated membrane fusion and viral infection. Likely prevents adenoviral entry into the endosomes of host cells. May play a role in maturation and activation of innate immune cells including macrophages, group 2 innate lymphoid cells and mast cells.
Tissue Specificity
Found in spleen, thymus, peripheral blood leukocytes, pancreas, lung, and colon . Expressed in neuronal fibers in dorsal root ganglia and in peripheral tissues including stomach, white adipose tissue and prostate (at protein level) .
KEGG Pathway
Glycerophospholipid metabolism (hsa00564 )
Ether lipid metabolism (hsa00565 )
Arachidonic acid metabolism (hsa00590 )
Linoleic acid metabolism (hsa00591 )
alpha-Linolenic acid metabolism (hsa00592 )
Metabolic pathways (hsa01100 )
Ras sig.ling pathway (hsa04014 )
Vascular smooth muscle contraction (hsa04270 )
Pancreatic secretion (hsa04972 )
Fat digestion and absorption (hsa04975 )
Reactome Pathway
Acyl chain remodelling of PS (R-HSA-1482801 )
Acyl chain remodelling of PE (R-HSA-1482839 )
Acyl chain remodelling of PI (R-HSA-1482922 )
Acyl chain remodelling of PG (R-HSA-1482925 )
Synthesis of PA (R-HSA-1483166 )
Acyl chain remodelling of PC (R-HSA-1482788 )

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Abdominal aortic aneurysm DISD06OF Strong Biomarker [1]
Adult respiratory distress syndrome DISIJV47 Strong Genetic Variation [2]
Arteriosclerosis DISK5QGC Strong Altered Expression [3]
Asthma DISW9QNS Strong Biomarker [4]
Astrocytoma DISL3V18 Strong Biomarker [5]
Atherosclerosis DISMN9J3 Strong Altered Expression [3]
Bronchopulmonary dysplasia DISO0BY5 Strong Altered Expression [6]
Castration-resistant prostate carcinoma DISVGAE6 Strong Biomarker [7]
Chronic obstructive pulmonary disease DISQCIRF Strong Genetic Variation [8]
Colitis DISAF7DD Strong Biomarker [9]
Congenital alveolar dysplasia DIS1IYUN Strong Altered Expression [6]
Coronary heart disease DIS5OIP1 Strong Altered Expression [10]
Craniosynostosis DIS6J405 Strong Altered Expression [11]
Hepatocellular carcinoma DIS0J828 Strong Altered Expression [12]
Hyperlipidemia DIS61J3S Strong Biomarker [13]
Lung neoplasm DISVARNB Strong Altered Expression [14]
Nasal polyp DISLP3XE Strong Altered Expression [11]
Neoplasm DISZKGEW Strong Altered Expression [7]
Non-small-cell lung cancer DIS5Y6R9 Strong Biomarker [7]
Prostate cancer DISF190Y Strong Genetic Variation [15]
Prostate carcinoma DISMJPLE Strong Biomarker [15]
Prostate neoplasm DISHDKGQ Strong Altered Expression [16]
Psoriasis DIS59VMN Strong Biomarker [17]
Schizophrenia DISSRV2N Strong Biomarker [18]
Tuberculosis DIS2YIMD Strong Biomarker [19]
Type-1/2 diabetes DISIUHAP Strong Biomarker [20]
Adenovirus infection DISUYSBZ moderate Biomarker [21]
Advanced cancer DISAT1Z9 moderate Biomarker [22]
Bacterial infection DIS5QJ9S moderate Biomarker [23]
Cardiovascular disease DIS2IQDX moderate Altered Expression [24]
Chronic renal failure DISGG7K6 moderate Altered Expression [25]
Lung adenocarcinoma DISD51WR moderate Biomarker [26]
Lung cancer DISCM4YA moderate Altered Expression [27]
Lung carcinoma DISTR26C moderate Altered Expression [27]
Adenocarcinoma DIS3IHTY Disputed Biomarker [28]
Crohn disease DIS2C5Q8 Disputed Altered Expression [29]
Arthritis DIST1YEL Limited Biomarker [30]
Breast cancer DIS7DPX1 Limited Biomarker [31]
Breast carcinoma DIS2UE88 Limited Biomarker [31]
Cholelithiasis DISERLZB Limited Biomarker [32]
Colon adenocarcinoma DISDRE0J Limited Altered Expression [33]
Colon cancer DISVC52G Limited Biomarker [28]
Colon carcinoma DISJYKUO Limited Biomarker [28]
Colorectal carcinoma DIS5PYL0 Limited Altered Expression [34]
Coronary atherosclerosis DISKNDYU Limited Altered Expression [10]
End-stage renal disease DISXA7GG Limited Altered Expression [25]
Nervous system disease DISJ7GGT Limited Biomarker [35]
Non-insulin dependent diabetes DISK1O5Z Limited Genetic Variation [20]
Rheumatoid arthritis DISTSB4J Limited Biomarker [36]
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⏷ Show the Full List of 49 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
7 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Group 10 secretory phospholipase A2 (PLA2G10). [37]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Group 10 secretory phospholipase A2 (PLA2G10). [38]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of Group 10 secretory phospholipase A2 (PLA2G10). [39]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of Group 10 secretory phospholipase A2 (PLA2G10). [40]
Permethrin DMZ0Q1G Approved Permethrin decreases the expression of Group 10 secretory phospholipase A2 (PLA2G10). [41]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Group 10 secretory phospholipase A2 (PLA2G10). [37]
Rutin DMEHRAJ Investigative Rutin decreases the expression of Group 10 secretory phospholipase A2 (PLA2G10). [42]
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⏷ Show the Full List of 7 Drug(s)

References

1 Group X secretory phospholipase A(2) augments angiotensin II-induced inflammatory responses and abdominal aortic aneurysm formation in apoE-deficient mice.Atherosclerosis. 2011 Jan;214(1):58-64. doi: 10.1016/j.atherosclerosis.2010.08.054. Epub 2010 Aug 19.
2 Secretory phospholipase A2 pathway in various types of lung injury in neonates and infants: a multicentre translational study.BMC Pediatr. 2011 Nov 8;11:101. doi: 10.1186/1471-2431-11-101.
3 Therapeutic effect of irbesartan combined with atorvastatin calcium in the treatment of rats with coronary heart disease.Exp Ther Med. 2018 Nov;16(5):4119-4123. doi: 10.3892/etm.2018.6669. Epub 2018 Aug 30.
4 Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen.JCI Insight. 2017 Nov 2;2(21):e94929. doi: 10.1172/jci.insight.94929.
5 A dangerous liaison: Leptin and sPLA2-IIA join forces to induce proliferation and migration of astrocytoma cells.PLoS One. 2017 Mar 1;12(3):e0170675. doi: 10.1371/journal.pone.0170675. eCollection 2017.
6 Cord blood Clara cell protein CC16 predicts the development of bronchopulmonary dysplasia.Eur J Pediatr. 2008 Nov;167(11):1305-12. doi: 10.1007/s00431-008-0713-2. Epub 2008 Jun 3.
7 Overexpression of secretory phospholipase A2-IIa supports cancer stem cell phenotype via HER/ERBB-elicited signaling in lung and prostate cancer cells.Int J Oncol. 2017 Jun;50(6):2113-2122. doi: 10.3892/ijo.2017.3964. Epub 2017 Apr 19.
8 A novel polymorphism in secretory phospholipase A2-IID is associated with body weight loss in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2005 Nov 1;172(9):1097-104. doi: 10.1164/rccm.200503-319OC. Epub 2005 Jul 7.
9 Group X Secreted Phospholipase A2 Releases 3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm Fertility.J Biol Chem. 2016 Mar 25;291(13):6895-911. doi: 10.1074/jbc.M116.715672. Epub 2016 Jan 31.
10 PLA2G10 Gene Variants, sPLA2 Activity, and Coronary Heart Disease Risk.Circ Cardiovasc Genet. 2015 Apr;8(2):356-62. doi: 10.1161/CIRCGENETICS.114.000633. Epub 2015 Jan 12.
11 Group II subfamily secretory phospholipase A2 enzymes: expression in chronic rhinosinusitis with and without nasal polyps.Allergy. 2007 Sep;62(9):999-1006. doi: 10.1111/j.1398-9995.2007.01381.x. Epub 2007 Jun 18.
12 Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray.Oncol Rep. 2007 Oct;18(4):943-51.
13 Thyroid hormone status regulates the expression of secretory phospholipases.Biochem Biophys Res Commun. 2014 Jan 31;444(1):56-62. doi: 10.1016/j.bbrc.2014.01.003. Epub 2014 Jan 16.
14 Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition-mediated cell death in K-ras mutant lung cancer cells.J Thorac Cardiovasc Surg. 2012 Dec;144(6):1479-85. doi: 10.1016/j.jtcvs.2012.08.064. Epub 2012 Sep 29.
15 Secretory phospholipase A2-IIa is a target gene of the HER/HER2-elicited pathway and a potential plasma biomarker for poor prognosis of prostate cancer.Prostate. 2012 Jul 1;72(10):1140-9. doi: 10.1002/pros.22463. Epub 2011 Nov 29.
16 Differential expression of secretory phospholipases A2 in normal and malignant prostate cell lines: regulation by cytokines, cell signaling pathways, and epigenetic mechanisms. Neoplasia. 2008 Mar;10(3):279-86. doi: 10.1593/neo.07965.
17 Characterization and differentiation-dependent regulation of secreted phospholipases A in human keratinocytes and in healthy and psoriatic human skin.J Invest Dermatol. 2005 Jan;124(1):204-11. doi: 10.1111/j.0022-202X.2004.23513.x.
18 Lack of association between schizophrenia and the phospholipase-A(2) genes cPLA2 and sPLA2.Am J Med Genet. 2001 Apr 8;105(3):246-9.
19 RNase 7 but not psoriasin nor sPLA2-IIA associates with Mycobacterium tuberculosis during airway epithelial cell infection.Pathog Dis. 2018 Mar 1;76(2). doi: 10.1093/femspd/fty005.
20 Polymorphism of Secretary PLA2G2A Gene Associated with Its Serum Level in Type2 Diabetes Mellitus Patients in Northern Iran.Endocr Metab Immune Disord Drug Targets. 2019;19(8):1192-1197. doi: 10.2174/1871530319666190528111225.
21 Human group III phospholipase A2 suppresses adenovirus infection into host cells. Evidence that group III, V and X phospholipase A2s act on distinct cellular phospholipid molecular species.Biochim Biophys Acta. 2007 Nov;1771(11):1389-96. doi: 10.1016/j.bbalip.2007.09.006. Epub 2007 Oct 10.
22 A Concise Update on the Relevance of Secretory Phospholipase A2 Group IIA and its Inhibitors with Cancer.Med Chem. 2017;13(7):606-615. doi: 10.2174/1573406413666170209121317.
23 The role of group IIA secretory phospholipase A2 (sPLA2-IIA) as a biomarker for the diagnosis of sepsis and bacterial infection in adults-A systematic review.PLoS One. 2017 Jul 3;12(7):e0180554. doi: 10.1371/journal.pone.0180554. eCollection 2017.
24 Tracking of secretory phospholipase A2 enzyme activity levels from childhood to adulthood: a 21-year cohort.J Pediatr (Rio J). 2019 Mar-Apr;95(2):247-254. doi: 10.1016/j.jped.2018.01.002. Epub 2018 Feb 21.
25 Increased type IIA secretory phospholipase A(2) expression contributes to oxidative stress in end-stage renal disease.J Mol Med (Berl). 2010 Jan;88(1):75-83. doi: 10.1007/s00109-009-0543-3. Epub 2009 Oct 2.
26 Inhibition of secretory phospholipase A2 IIa attenuates prostaglandin E2-induced invasiveness in lung adenocarcinoma.Mol Cell Biochem. 2019 Jun;456(1-2):145-156. doi: 10.1007/s11010-019-03500-3. Epub 2019 Jan 25.
27 Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells.Int J Oncol. 2014 Sep;45(3):978-84. doi: 10.3892/ijo.2014.2486. Epub 2014 Jun 10.
28 Distinct expression pattern of the full set of secreted phospholipases A2 in human colorectal adenocarcinomas: sPLA2-III as a biomarker candidate.Br J Cancer. 2008 Feb 12;98(3):587-95. doi: 10.1038/sj.bjc.6604184. Epub 2008 Jan 22.
29 Paneth cell antimicrobial peptides: topographical distribution and quantification in human gastrointestinal tissues.FEBS Lett. 2006 Oct 2;580(22):5344-50. doi: 10.1016/j.febslet.2006.08.083. Epub 2006 Sep 12.
30 Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA.Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):E3564-73. doi: 10.1073/pnas.1507905112. Epub 2015 Jun 23.
31 Group X secreted phospholipase A(2) induces lipid droplet formation and prolongs breast cancer cell survival.Mol Cancer. 2013 Sep 27;12(1):111. doi: 10.1186/1476-4598-12-111.
32 Secretory low-molecular-weight phospholipases A2 and their specific receptor in bile ducts of patients with intrahepatic calculi: factors of chronic proliferative cholangitis.Hepatology. 1999 Apr;29(4):1026-36. doi: 10.1002/hep.510290440.
33 Potential role of group X secretory phospholipase A(2) in cyclooxygenase-2-dependent PGE(2) formation during colon tumorigenesis.FEBS Lett. 2000 Dec 29;487(2):262-6. doi: 10.1016/s0014-5793(00)02350-4.
34 Expression of cytosolic and group X secretory phospholipase A(2) genes in human colorectal adenocarcinomas.Cancer Lett. 2002 Aug 28;182(2):175-82. doi: 10.1016/s0304-3835(02)00081-2.
35 Phospholipases A2 and inflammatory responses in the central nervous system.Neuromolecular Med. 2010 Jun;12(2):133-48. doi: 10.1007/s12017-009-8092-z. Epub 2009 Oct 24.
36 A bifunctional role for group IIA secreted phospholipase A2 in human rheumatoid fibroblast-like synoviocyte arachidonic acid metabolism.J Biol Chem. 2011 Jan 28;286(4):2492-503. doi: 10.1074/jbc.M110.123927. Epub 2010 Nov 10.
37 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
38 Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
39 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
40 Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
41 Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
42 Combination of metabolomics and network pharmacology analysis to decipher the mechanisms of total flavonoids of Litchi seed against prostate cancer. J Pharm Pharmacol. 2023 Jul 5;75(7):951-968. doi: 10.1093/jpp/rgad035.