Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1NY7BF)

• DOT Name: Phospholipase A2, membrane associated (PLA2G2A)
• Synonyms: EC 3.1.1.4; GIIC sPLA2; Group IIA phospholipase A2; Non-pancreatic secretory phospholipase A2; NPS-PLA2; Phosphatidylcholine 2-acylhydrolase 2A
• Gene Name: PLA2G2A
• Related Disease: Colorectal cancer
• UniProt ID: PA2GA_HUMAN
• PDB ID: 1AYP; 1BBC; 1DB4; 1DB5; 1DCY; 1J1A; 1KQU; 1KVO; 1N28; 1N29; 1POD; 1POE; 3U8B; 3U8D; 3U8H; 3U8I; 5G3N
• EC Number: 3.1.1.4
• Pfam ID: PF00068
• Sequence:
  MKTLLLLAVIMIFGLLQAHGNLVNFHRMIKLTTGKEAALSYGFYGCHCGVGGRGSPKDAT
  DRCCVTHDCCYKRLEKRGCGTKFLSYKFSNSGSRITCAKQDSCRSQLCECDKAAATCFAR
  NKTTYNKKYQYYSNKHCRGSTPRC
• Function: Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids with implications in host antimicrobial defense, inflammatory response and tissue regeneration. Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) with preference for phosphatidylethanolamines and phosphatidylglycerols over phosphatidylcholines. Contributes to lipid remodeling of cellular membranes and generation of lipid mediators involved in pathogen clearance. Displays bactericidal activity against Gram-positive bacteria by directly hydrolyzing phospholipids of the bacterial membrane. Upon sterile inflammation, targets membrane phospholipids of extracellular mitochondria released from activated platelets, generating free unsaturated fatty acids such as arachidonate that is used by neighboring leukocytes to synthesize inflammatory eicosanoids such as leukotrienes. Simultaneously, by compromising mitochondrial membrane integrity, promotes the release in circulation of potent damage-associated molecular pattern molecules that activate the innate immune response. Plays a stem cell regulator role in the intestinal crypt. Within intracellular compartment mediates Paneth cell differentiation and its stem cell supporting functions by inhibiting Wnt signaling pathway in intestinal stem cell (ICS). Secreted in the intestinal lumen upon inflammation, acts in an autocrine way and promotes prostaglandin E2 synthesis that stimulates Wnt signaling pathway in ICS cells and tissue regeneration. May play a role in the biosynthesis of N-acyl ethanolamines that regulate energy metabolism and inflammation. Hydrolyzes N-acyl phosphatidylethanolamines to N-acyl lysophosphatidylethanolamines, which are further cleaved by a lysophospholipase D to release N-acyl ethanolamines. Independent of its catalytic activity, acts as a ligand for integrins. Binds to and activates integrins ITGAV:ITGB3, ITGA4:ITGB1 and ITGA5:ITGB1. Binds to a site (site 2) which is distinct from the classical ligand-binding site (site 1) and induces integrin conformational changes and enhanced ligand binding to site 1. Induces cell proliferation in an integrin-dependent manner.
• Tissue Specificity: Expressed in various tissues including heart, kidney, liver, lung, pancreas, placenta, skeletal muscle, prostate, ovary, colon and small intestine. Not detected in lymphoid organs and brain . Expressed in platelets (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)
  Antimicrobial peptides (R-HSA-6803157)
  Acyl chain remodelling of PC (R-HSA-1482788)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal cancer	DISNH7P9	No Known	Autosomal dominant	[1]

26 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 Phospholipase A2, membrane associated (PLA2G2A).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Phospholipase A2, membrane associated (PLA2G2A).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[9]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[9]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[13]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[14]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of Phospholipase A2, membrane associated (PLA2G2A).	[15]
Rofecoxib	DM3P5DA	Approved	Rofecoxib affects the expression of Phospholipase A2, membrane associated (PLA2G2A).	[15]
Dinoprostone	DMTYOPD	Approved	Dinoprostone increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[8]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[18]
Scutellarin	DMJT1E5	Preclinical	Scutellarin affects the activity of Phospholipase A2, membrane associated (PLA2G2A).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[21]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Phospholipase A2, membrane associated (PLA2G2A).	[8]
MANGIFERIN	DMWAF5Z	Investigative	MANGIFERIN decreases the activity of Phospholipase A2, membrane associated (PLA2G2A).	[22]
Petrosaspongiolide M	DMR8ZBT	Investigative	Petrosaspongiolide M decreases the activity of Phospholipase A2, membrane associated (PLA2G2A).	[22]

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, membrane associated (PLA2G2A).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
BETULINIC ACID	DMBUI2A	Phase 1	BETULINIC ACID affects the binding of Phospholipase A2, membrane associated (PLA2G2A).	[19]

References

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• [4] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
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• [8] Anti-inflammatory effects of dietary phenolic compounds in an in vitro model of inflamed human intestinal epithelium. Chem Biol Interact. 2010 Dec 5;188(3):659-67.
• [9] 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.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [12] 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.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [15] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [16] Impact of CFTR DeltaF508 mutation on prostaglandin E2 production and type IIA phospholipase A2 expression by pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L816-24. doi: 10.1152/ajplung.00466.2004. Epub 2005 Jun 17.
• [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] The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016 Feb 18;35(7):833-45.
• [19] Computational investigations of physicochemical, pharmacokinetic, toxicological properties and molecular docking of betulinic acid, a constituent of Corypha taliera (Roxb.) with Phospholipase A2 (PLA2). BMC Complement Altern Med. 2018 Feb 2;18(1):48. doi: 10.1186/s12906-018-2116-x.
• [20] Effects of flavonoids on Naja naja and human recombinant synovial phospholipases A2 and inflammatory responses in mice. Life Sci. 1994;54(20):PL333-8. doi: 10.1016/0024-3205(94)90021-3.
• [21] 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.
• [22] In vivo and in vitro anti-inflammatory activity of Mangifera indica L. extract (VIMANG). Pharmacol Res. 2004 Aug;50(2):143-9. doi: 10.1016/j.phrs.2003.12.003.