Details of Drug Off-Target (DOT)

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

• DOT Name: Phospholipase A2 group V (PLA2G5)
• Synonyms: EC 3.1.1.4; PLA2-10; Phosphatidylcholine 2-acylhydrolase 5
• Gene Name: PLA2G5
• Related Disease:
  Familial benign flecked retina
  Adenomatous colon polyp
  Coronary atherosclerosis
  Glioma
  Neoplasm
  Obesity
  Pneumonia
  Pneumonitis
  Schizophrenia
  Acute myelogenous leukaemia
  Coronary heart disease
  High blood pressure
  Late-adult onset retinitis pigmentosa
• UniProt ID: PA2G5_HUMAN
• EC Number: 3.1.1.4
• Pfam ID: PF00068
• Sequence:
  MKGLLPLAWFLACSVPAVQGGLLDLKSMIEKVTGKNALTNYGFYGCYCGWGGRGTPKDGT
  DWCCWAHDHCYGRLEEKGCNIRTQSYKYRFAWGVVTCEPGPFCHVNLCACDRKLVYCLKR
  NLRSYNPQYQYFPNILCS
• 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 (phospholipase A2 activity), preferentially releasing fatty acyl groups with a low degree of unsaturation such as oleoyl (C18:1) and linoleoyl (C18:2) groups. Hydrolyzes low-density lipoprotein (LDL) phospholipids releasing unsaturated fatty acids that drive macrophage polarization toward an M2 phenotype. May act in an autocrine and paracrine manner. Contributes to lipid remodeling of cellular membranes at different subcellular locations and generation of lipid mediators involved in pathogen clearance. Cleaves sn-2 fatty acyl chains of cardiolipin, a major component of the inner membrane of mitochondria and bacterial membranes. Promotes phagocytosis of bacteria in macrophages through production of lysophosphatidylethanolamines. Displays bactericidal activity against Gram-positive bacteria by directly hydrolyzing phospholipids of the bacterial membrane. Promotes phagocytosis and killing of ingested fungi likely through controlling phagosome-lysosome fusion and phagosome maturation. Plays a role in biosynthesis of cysteinyl leukotrienes (CysLTs) in myeloid cells. In eosinophils, triggers perinuclear arachidonate release and LTC4 synthesis in a PLA2G4A-independent way. In neutrophils, amplifies CysLTs biosynthesis initiated by PLA2G4A. Promotes immune complex clearance in macrophages via stimulating synthesis of CysLTs, which act through CYSLTR1 to trigger phagocytosis. May regulate antigen processing in antigen-presenting cells. In pulmonary macrophages regulates IL33 production required for activation of group 2 innate lymphoid cells. May play a role in the biosynthesis of N-acyl ethanolamines that regulate energy metabolism. Hydrolyzes N-acyl phosphatidylethanolamines to N-acyl lysophosphatidylethanolamines, which are further cleaved by a lysophospholipase D to release N-acyl ethanolamines.
• Tissue Specificity: Heart, placenta and less abundantly, in lung. Detected in the outer and inner plexiform layers of the retina (at protein level) . Expressed in monocytes and macrophages .
• 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

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial benign flecked retina	DIS7TAK1	Definitive	Autosomal recessive	[1]
Adenomatous colon polyp	DISL7AGZ	Strong	Biomarker	[2]
Coronary atherosclerosis	DISKNDYU	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[4]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
Pneumonia	DIS8EF3M	Strong	Biomarker	[6]
Pneumonitis	DIS88E0K	Strong	Biomarker	[6]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[7]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[8]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[9]
High blood pressure	DISY2OHH	Limited	Genetic Variation	[9]
Late-adult onset retinitis pigmentosa	DIS1CD8L	Limited	Autosomal recessive	[10]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phospholipase A2 group V (PLA2G5).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Phospholipase A2 group V (PLA2G5).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Phospholipase A2 group V (PLA2G5).	[13]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Phospholipase A2 group V (PLA2G5).	[14]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Phospholipase A2 group V (PLA2G5).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Phospholipase A2 group V (PLA2G5).	[15]
Beta-D-Glucose	DM5IHYP	Investigative	Beta-D-Glucose decreases the activity of Phospholipase A2 group V (PLA2G5).	[17]
Fmet-leu-phe	DMQ391A	Investigative	Fmet-leu-phe increases the activity of Phospholipase A2 group V (PLA2G5).	[17]
SB-203347	DM3AWMF	Investigative	SB-203347 decreases the activity of Phospholipase A2 group V (PLA2G5).	[18]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phospholipase A2 group V (PLA2G5).	[16]

References

• [1] Biallelic mutations in PLA2G5, encoding group V phospholipase A2, cause benign fleck retina. Am J Hum Genet. 2011 Dec 9;89(6):782-91. doi: 10.1016/j.ajhg.2011.11.004. Epub 2011 Dec 1.
• [2] Three secretory phospholipase A(2) genes that map to human chromosome 1P35-36 are not mutated in individuals with attenuated adenomatous polyposis coli.Cancer Res. 1996 Mar 1;56(5):955-8.
• [3] Novel genetic approach to investigate the role of plasma secretory phospholipase A2 (sPLA2)-V isoenzyme in coronary heart disease: modified Mendelian randomization analysis using PLA2G5 expression levels.Circ Cardiovasc Genet. 2014 Apr;7(2):144-50. doi: 10.1161/CIRCGENETICS.113.000271. Epub 2014 Feb 21.
• [4] Overexpression of the phospholipase A2 group V gene in glioma tumors is associated with poor patient prognosis.Cancer Manag Res. 2019 Apr 11;11:3139-3152. doi: 10.2147/CMAR.S199207. eCollection 2019.
• [5] The adipocyte-inducible secreted phospholipases PLA2G5 and PLA2G2E play distinct roles in obesity.Cell Metab. 2014 Jul 1;20(1):119-32. doi: 10.1016/j.cmet.2014.05.002. Epub 2014 Jun 5.
• [6] Macrophages regulate lung ILC2 activation via Pla2g5-dependent mechanisms.Mucosal Immunol. 2018 May;11(3):615-626. doi: 10.1038/mi.2017.99. Epub 2017 Dec 20.
• [7] An association between the BanI polymorphism of the PLA2G4A gene for calcium-dependent phospholipase A2 and plasma glucose levels among females with schizophrenia.Prostaglandins Leukot Essent Fatty Acids. 2018 Aug;135:39-41. doi: 10.1016/j.plefa.2018.06.007. Epub 2018 Jun 30.
• [8] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [9] The (G>A) rs11573191 polymorphism of PLA2G5 gene is associated with premature coronary artery disease in the Mexican Mestizo population: the genetics of atherosclerotic disease Mexican study.Biomed Res Int. 2014;2014:931361. doi: 10.1155/2014/931361. Epub 2014 May 18.
• [10] Whole Exome Sequencing Reveals Mutations in Known Retinal Disease Genes in 33 out of 68 Israeli Families with Inherited Retinopathies. Sci Rep. 2015 Aug 26;5:13187. doi: 10.1038/srep13187.
• [11] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [12] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [13] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [14] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [15] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] Groups IV, V, and X phospholipases A2s in human neutrophils: role in eicosanoid production and gram-negative bacterial phospholipid hydrolysis. J Biol Chem. 2002 Feb 15;277(7):5061-73. doi: 10.1074/jbc.M109083200. Epub 2001 Dec 6.
• [18] Characteristics of arachidonic acid generation in human basophils: relationship between the effects of inhibitors of secretory phospholipase A2 activity and leukotriene C4 release. J Pharmacol Exp Ther. 1998 Mar;284(3):847-57.