Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6H6AMO)

• DOT Name: Platelet-activating factor acetylhydrolase (PLA2G7)
• Synonyms: PAF acetylhydrolase; EC 3.1.1.47; 1-alkyl-2-acetylglycerophosphocholine esterase; 2-acetyl-1-alkylglycerophosphocholine esterase; Group-VIIA phospholipase A2; gVIIA-PLA2; LDL-associated phospholipase A2; LDL-PLA(2); PAF 2-acylhydrolase
• Gene Name: PLA2G7
• UniProt ID: PAFA_HUMAN
• PDB ID: 3D59; 3D5E; 3F96; 3F97; 3F98; 3F9C; 5I8P; 5I9I; 5JAD; 5JAH; 5JAL; 5JAN; 5JAO; 5JAP; 5JAR; 5JAS; 5JAT; 5JAU; 5LP1; 5LYY; 5LZ2; 5LZ4; 5LZ5; 5LZ7; 5LZ8; 5LZ9; 5YE7; 5YE8; 5YE9; 5YEA; 6M06; 6M07; 6M08
• EC Number: 3.1.1.47
• Pfam ID: PF03403
• Sequence:
  MVPPKLHVLFCLCGCLAVVYPFDWQYINPVAHMKSSAWVNKIQVLMAAASFGQTKIPRGN
  GPYSVGCTDLMFDHTNKGTFLRLYYPSQDNDRLDTLWIPNKEYFWGLSKFLGTHWLMGNI
  LRLLFGSMTTPANWNSPLRPGEKYPLVVFSHGLGAFRTLYSAIGIDLASHGFIVAAVEHR
  DRSASATYYFKDQSAAEIGDKSWLYLRTLKQEEETHIRNEQVRQRAKECSQALSLILDID
  HGKPVKNALDLKFDMEQLKDSIDREKIAVIGHSFGGATVIQTLSEDQRFRCGIALDAWMF
  PLGDEVYSRIPQPLFFINSEYFQYPANIIKMKKCYSPDKERKMITIRGSVHQNFADFTFA
  TGKIIGHMLKLKGDIDSNVAIDLSNKASLAFLQKHLGLHKDFDQWDCLIEGDDENLIPGT
  NINTTNQHIMLQNSSGIEKYN
• Function: Lipoprotein-associated calcium-independent phospholipase A2 involved in phospholipid catabolism during inflammatory and oxidative stress response. At the lipid-aqueous interface, hydrolyzes the ester bond of fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity). Specifically targets phospholipids with a short-chain fatty acyl group at sn-2 position. Can hydrolyze phospholipids with long fatty acyl chains, only if they carry oxidized functional groups. Hydrolyzes and inactivates platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), a potent pro-inflammatory signaling lipid that acts through PTAFR on various innate immune cells. Hydrolyzes oxidatively truncated phospholipids carrying an aldehyde group at omega position, preventing their accumulation in low-density lipoprotein (LDL) particles and uncontrolled pro-inflammatory effects. As part of high-density lipoprotein (HDL) particles, can hydrolyze phospholipids having long-chain fatty acyl hydroperoxides at sn-2 position and protect against potential accumulation of these oxylipins in the vascular wall. Catalyzes the release from membrane phospholipids of F2-isoprostanes, lipid biomarkers of cellular oxidative damage.
• Tissue Specificity: Plasma . Secreted by macrophages (at protein level) .
• KEGG Pathway:
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis, secretion, and deacylation of Ghrelin (R-HSA-422085)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[1]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[7]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the activity of Platelet-activating factor acetylhydrolase (PLA2G7).	[8]
Orlistat	DMRJSP8	Approved	Orlistat decreases the activity of Platelet-activating factor acetylhydrolase (PLA2G7).	[8]
Vitamin B3	DMQVRZH	Approved	Vitamin B3 decreases the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[9]
Nitrous oxide	DMTHWBI	Approved	Nitrous oxide affects the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[6]
ACYLINE	DM9GRTK	Phase 2	ACYLINE increases the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[13]
PAF	DMRZAQW	Investigative	PAF increases the expression of Platelet-activating factor acetylhydrolase (PLA2G7).	[14]
RHC80267	DMC471Z	Investigative	RHC80267 decreases the activity of Platelet-activating factor acetylhydrolase (PLA2G7).	[15]

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 Platelet-activating factor acetylhydrolase (PLA2G7).	[12]

References

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• [3] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [4] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
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• [8] The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis. 2007 Aug;193(2):428-37. doi: 10.1016/j.atherosclerosis.2006.07.010. Epub 2006 Sep 5.
• [9] Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am J Cardiol. 2006 Sep 15;98(6):743-5. doi: 10.1016/j.amjcard.2006.04.011. Epub 2006 Jul 26.
• [10] Ambient air pollution and lipoprotein-associated phospholipase A? in survivors of myocardial infarction. Environ Health Perspect. 2011 Jul;119(7):921-6. doi: 10.1289/ehp.1002681. Epub 2011 Feb 28.
• [11] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [12] 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.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Lipopolysaccharide and platelet-activating factor stimulate expression of platelet-activating factor acetylhydrolase via distinct signaling pathways. Inflamm Res. 2011 Aug;60(8):735-44. doi: 10.1007/s00011-011-0326-5. Epub 2011 Mar 24.
• [15] Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling. Bioorg Med Chem Lett. 2008 Nov 15;18(22):5838-41.