Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3K7TMY)

• DOT Name: Group 3 secretory phospholipase A2 (PLA2G3)
• Synonyms: EC 3.1.1.4; Group III secretory phospholipase A2; GIII sPLA2; sPLA2-III; Phosphatidylcholine 2-acylhydrolase 3
• Gene Name: PLA2G3
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Atherosclerosis
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Myocardial infarction
  Neoplasm
  Adenocarcinoma
• UniProt ID: PA2G3_HUMAN
• EC Number: 3.1.1.4
• Pfam ID: PF05826
• Sequence:
  MGVQAGLFGMLGFLGVALGGSPALRWYRTSCHLTKAVPGNPLGYLSFLAKDAQGLALIHA
  RWDAHRRLQSCSWEDEPELTAAYGALCAHETAWGSFIHTPGPELQRALATLQSQWEACRA
  LEESPAGARKKRAAGQSGVPGGGHQREKRGWTMPGTLWCGVGDSAGNSSELGVFQGPDLC
  CREHDRCPQNISPLQYNYGIRNYRFHTISHCDCDTRFQQCLQNQHDSISDIVGVAFFNVL
  EIPCFVLEEQEACVAWYWWGGCRMYGTVPLARLQPRTFYNASWSSRATSPTPSSRSPAPP
  KPRQKQHLRKGPPHQKGSKRPSKANTTALQDPMVSPRLDVAPTGLQGPQGGLKPQGARWV
  CRSFRRHLDQCEHQIGPREIEFQLLNSAQEPLFHCNCTRRLARFLRLHSPPEVTNMLWEL
  LGTTCFKLAPPLDCVEGKNCSRDPRAIRVSARHLRRLQQRRHQLQDKGTDERQPWPSEPL
  RGPMSFYNQCLQLTQAARRPDRQQKSWSQ
• 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 without apparent head group selectivity. Contributes to phospholipid remodeling of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles. Hydrolyzes LDL phospholipids releasing unsaturated fatty acids that regulate macrophage differentiation toward foam cells. May act in an autocrine and paracrine manner. Secreted by immature mast cells, acts on nearby fibroblasts upstream to PTDGS to synthesize prostaglandin D2 (PGD2), which in turn promotes mast cell maturation and degranulation via PTGDR. Secreted by epididymal epithelium, acts on immature sperm cells within the duct, modulating the degree of unsaturation of the fatty acyl components of phosphatidylcholines required for acrosome assembly and sperm cell motility. Facilitates the replacement of fatty acyl chains in phosphatidylcholines in sperm membranes from omega-6 and omega-9 to omega-3 polyunsaturated fatty acids (PUFAs). Coupled to lipoxygenase pathway, may process omega-6 PUFAs to generate oxygenated lipid mediators in the male reproductive tract. At pericentrosomal preciliary compartment, negatively regulates ciliogenesis likely by regulating endocytotic recycling of ciliary membrane protein. Coupled to cyclooxygenase pathway provides arachidonate to generate prostaglandin E2 (PGE2), a potent immunomodulatory lipid in inflammation and tumorigenesis. At colonic epithelial barrier, preferentially hydrolyzes phospholipids having arachidonate and docosahexaenoate at sn-2 position, contributing to the generation of oxygenated metabolites involved in colonic stem cell homeostasis. Releases C16:0 and C18:0 lysophosphatidylcholine subclasses from neuron plasma membranes and promotes neurite outgrowth and neuron survival.
• Tissue Specificity: Expressed in kidney, heart, liver, and skeletal muscle. Also present in placenta and peripheral blood leukocytes. Not detected in colon, thymus, spleen and small intestine. In lung, expressed in bronchial epithelial cells and alveolar macrophages, but scarcely detected in alveolar epithelium, arterial walls and interstitial fibroblasts (at protein level). In joints of osteoarthritis and rheumatoid arthritis, expressed in endothelial cells (at protein level). In normal heart, detected in some vessels. In myocardial tissues with acute infarction, expressed in vascular endothelial cells adjacent to cardiomyocytes and those in lesions with granulation. Expression in cardiomyocytes is scarce (at protein level). In uterus, breast and colon cancers, detected in tumor cells and neighboring microvascular endothelium, but not in normal glandular tissues (at protein level) . Expressed in dermal resting mast cells (at protein level) and pulmonary mast cells . Expressed in neuronal fibers (at protein level) . Highly expressed in dorsal root ganglia neurons (at protein level) . Expressed in Purkinje cells in cerebellum (at protein level) . In stomach is preferentially expressed in neuronal fibers and in microvascular endothelium . Sparsely expressed in normal aorta (at protein level). Highly expressed in macrophages and smooth muscle cells in aorta with atheroma .
• 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 PE (R-HSA-1482839)
  Acyl chain remodelling of PG (R-HSA-1482925)
  Acyl chain remodelling of PC (R-HSA-1482788)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Group 3 secretory phospholipase A2 (PLA2G3).	[21]

3 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 affects the methylation of Group 3 secretory phospholipase A2 (PLA2G3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Group 3 secretory phospholipase A2 (PLA2G3).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Group 3 secretory phospholipase A2 (PLA2G3).	[22]

References

• [1] Cellular distribution, post-translational modification, and tumorigenic potential of human group III secreted phospholipase A(2).J Biol Chem. 2005 Jul 1;280(26):24987-98. doi: 10.1074/jbc.M502088200. Epub 2005 Apr 29.
• [2] Enhanced Phospholipase A2 Group 3 Expression by Oxidative Stress Decreases the Insulin-Degrading Enzyme.PLoS One. 2015 Dec 4;10(12):e0143518. doi: 10.1371/journal.pone.0143518. eCollection 2015.
• [3] Analyses of group III secreted phospholipase A2 transgenic mice reveal potential participation of this enzyme in plasma lipoprotein modification, macrophage foam cell formation, and atherosclerosis.J Biol Chem. 2008 Nov 28;283(48):33483-97. doi: 10.1074/jbc.M804628200. Epub 2008 Sep 18.
• [4] Group III phospholipase A(2) promotes colitis and colorectal cancer.Sci Rep. 2017 Sep 25;7(1):12261. doi: 10.1038/s41598-017-12434-z.
• [5] Phospholipase A2 Group III and Group X Have Opposing Associations with Prognosis in Colorectal Cancer.Anticancer Res. 2015 May;35(5):2983-90.
• [6] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [7] 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.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] 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.
• [14] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] 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.
• [18] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [19] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [20] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.