Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2IXYNX)

• DOT Name: Phospholipase A1 member A (PLA1A)
• Synonyms: EC 3.1.1.111; Phosphatidylserine-specific phospholipase A1; PS-PLA1
• Gene Name: PLA1A
• Related Disease:
  Melanoma
  Myocardial infarction
  Osteogenesis imperfecta type 1
  Venous thromboembolism
  Attention deficit hyperactivity disorder
  Autism spectrum disorder
  B-cell neoplasm
  Dementia
  Duchenne muscular dystrophy
  Gastric cancer
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Hereditary elliptocytosis
  Heritable pulmonary arterial hypertension
  Intellectual disability
  Liver cirrhosis
  Neuromuscular disease
  Osteogenesis imperfecta
  Schizophrenia
  Stomach cancer
  Spinal muscular atrophy
  Junctional epidermolysis bullosa
  Advanced cancer
  Neoplasm
• UniProt ID: PLA1A_HUMAN
• EC Number: 3.1.1.111
• Pfam ID: PF00151
• Sequence:
  MPPGPWESCFWVGGLILWLSVGSSGDAPPTPQPKCADFQSANLFEGTDLKVQFLLFVPSN
  PSCGQLVEGSSDLQNSGFNATLGTKLIIHGFRVLGTKPSWIDTFIRTLLRATNANVIAVD
  WIYGSTGVYFSAVKNVIKLSLEISLFLNKLLVLGVSESSIHIIGVSLGAHVGGMVGQLFG
  GQLGQITGLDPAGPEYTRASVEERLDAGDALFVEAIHTDTDNLGIRIPVGHVDYFVNGGQ
  DQPGCPTFFYAGYSYLICDHMRAVHLYISALENSCPLMAFPCASYKAFLAGRCLDCFNPF
  LLSCPRIGLVEQGGVKIEPLPKEVKVYLLTTSSAPYCMHHSLVEFHLKELRNKDTNIEVT
  FLSSNITSSSKITIPKQQRYGKGIIAHATPQCQINQVKFKFQSSNRVWKKDRTTIIGKFC
  TALLPVNDREKMVCLPEPVNLQASVTVSCDLKIACV
• Function: Hydrolyzes the ester bond of the acyl group attached at the sn-1 position of phosphatidylserines (phospholipase A1 activity) and 1-acyl-2-lysophosphatidylserines (lysophospholipase activity) in the pathway of phosphatidylserines acyl chain remodeling. Cleaves phosphatidylserines exposed on the outer leaflet of the plasma membrane of apoptotic cells producing 2-acyl-1-lysophosphatidylserines, which in turn enhance mast cell activation and histamine production. Has no activity toward other glycerophospholipids including phosphatidylcholines, phosphatidylethanolamines, phosphatidic acids or phosphatidylinositols, or glycerolipids such as triolein; [Isoform 2]: Hydrolyzes lyso-PS but not PS.
• Tissue Specificity: Widely expressed. Expressed in placenta, prostate and liver. Weakly or not expressed in skin, leukocytes, platelets, colon, spleen, lung, muscle and kidney.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Ras sig.ling pathway (hsa04014)
• Reactome Pathway: Acyl chain remodelling of PS (R-HSA-1482801)
• BioCyc Pathway: MetaCyc:ENSG00000144837-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Altered Expression	[1]
Myocardial infarction	DIS655KI	Definitive	Genetic Variation	[2]
Osteogenesis imperfecta type 1	DISPEDS3	Definitive	Genetic Variation	[3]
Venous thromboembolism	DISUR7CR	Definitive	Genetic Variation	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[4]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[5]
Dementia	DISXL1WY	Strong	Genetic Variation	[6]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[10]
Hereditary elliptocytosis	DISA71F4	Strong	Biomarker	[11]
Heritable pulmonary arterial hypertension	DISD1Y94	Strong	Altered Expression	[12]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[13]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[8]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[14]
Osteogenesis imperfecta	DIS7XQSD	Strong	Biomarker	[15]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Spinal muscular atrophy	DISTLKOB	moderate	Biomarker	[16]
Junctional epidermolysis bullosa	DISJRXWU	Disputed	Genetic Variation	[17]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[13]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Phospholipase A1 member A (PLA1A).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Phospholipase A1 member A (PLA1A).	[25]

8 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 Phospholipase A1 member A (PLA1A).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholipase A1 member A (PLA1A).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Phospholipase A1 member A (PLA1A).	[22]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Phospholipase A1 member A (PLA1A).	[23]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Phospholipase A1 member A (PLA1A).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Phospholipase A1 member A (PLA1A).	[23]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Phospholipase A1 member A (PLA1A).	[26]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Phospholipase A1 member A (PLA1A).	[27]

References

• [1] Association between serum autotaxin or phosphatidylserine-specific phospholipase A1 levels and melanoma.J Dermatol. 2018 May;45(5):571-579. doi: 10.1111/1346-8138.14278. Epub 2018 Mar 3.
• [2] The relationship between polymorphisms in the endothelial cell nitric oxide synthase gene and the platelet GPIIIa gene with myocardial infarction and venous thromboembolism in African Americans.Chest. 1999 Oct;116(4):880-6. doi: 10.1378/chest.116.4.880.
• [3] Nonsense mutations in the COL1A1 gene preferentially reduce nuclear levels of mRNA but not hnRNA in osteogenesis imperfecta type I cell strains.Matrix Biol. 2000 Feb;19(1):1-9. doi: 10.1016/s0945-053x(99)00056-6.
• [4] A Upf3b-mutant mouse model with behavioral and neurogenesis defects.Mol Psychiatry. 2018 Aug;23(8):1773-1786. doi: 10.1038/mp.2017.173. Epub 2017 Sep 26.
• [5] Nonsense-mediated mRNA decay: The challenge of telling right from wrong in a complex transcriptome.Wiley Interdiscip Rev RNA. 2019 Nov;10(6):e1548. doi: 10.1002/wrna.1548. Epub 2019 May 26.
• [6] NMD-12: A new machine-learning derived screening instrument to detect mild cognitive impairment and dementia.PLoS One. 2019 Mar 8;14(3):e0213430. doi: 10.1371/journal.pone.0213430. eCollection 2019.
• [7] Association Study of Exon Variants in the NF-B and TGF Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy.Am J Hum Genet. 2016 Nov 3;99(5):1163-1171. doi: 10.1016/j.ajhg.2016.08.023. Epub 2016 Oct 13.
• [8] Analysis of glycero-lysophospholipids in gastric cancerous ascites.J Lipid Res. 2017 Apr;58(4):763-771. doi: 10.1194/jlr.P072090. Epub 2017 Jan 31.
• [9] Phosphatidylserine-Specific Phospholipase A1 is the Critical Bridge for Hepatitis C Virus Assembly.Virol Sin. 2019 Oct;34(5):521-537. doi: 10.1007/s12250-019-00123-2. Epub 2019 Jun 3.
• [10] The human RNA surveillance factor UPF1 regulates tumorigenesis by targeting Smad7 in hepatocellular carcinoma.J Exp Clin Cancer Res. 2016 Jan 13;35:8. doi: 10.1186/s13046-016-0286-2.
• [11] Homozygous deletion of EPB41 genuine AUG-containing exons results in mRNA splicing defects, NMD activation and protein 4.1R complete deficiency in hereditary elliptocytosis. Blood Cells Mol Dis. 2011 Oct 15;47(3):158-65. doi: 10.1016/j.bcmd.2011.07.001. Epub 2011 Aug 11.
• [12] Abnormal trafficking of endogenously expressed BMPR2 mutant allelic products in patients with heritable pulmonary arterial hypertension.PLoS One. 2013 Nov 5;8(11):e80319. doi: 10.1371/journal.pone.0080319. eCollection 2013.
• [13] Quality and quantity control of gene expression by nonsense-mediated mRNA decay.Nat Rev Mol Cell Biol. 2019 Jul;20(7):406-420. doi: 10.1038/s41580-019-0126-2.
• [14] Next generation sequencing for molecular diagnosis of neuromuscular diseases.Acta Neuropathol. 2012 Aug;124(2):273-83. doi: 10.1007/s00401-012-0982-8. Epub 2012 Apr 18.
• [15] Type I procollagen C-propeptide defects: study of genotype-phenotype correlation and predictive role of crystal structure.Hum Mutat. 2014 Nov;35(11):1330-41. doi: 10.1002/humu.22677. Epub 2014 Oct 18.
• [16] A multi-source approach to determine SMA incidence and research ready population.J Neurol. 2017 Jul;264(7):1465-1473. doi: 10.1007/s00415-017-8549-1. Epub 2017 Jun 20.
• [17] Comprehensive analysis of gene expression profiles in keratinocytes from patients with generalized atrophic benign epidermolysis bullosa.Exp Dermatol. 2002 Feb;11(1):75-81. doi: 10.1034/j.1600-0625.2002.110108.x.
• [18] Nonsense-mediated RNA decay regulation by cellular stress: implications for tumorigenesis.Mol Cancer Res. 2010 Mar;8(3):295-308. doi: 10.1158/1541-7786.MCR-09-0502. Epub 2010 Feb 23.
• [19] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [20] 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.
• [21] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [22] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [25] 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.
• [26] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [27] Identifying qualitative differences in PPAR signaling networks in human and rat hepatocytes and their significance for next generation chemical risk assessment methods. Toxicol In Vitro. 2020 Apr;64:104463. doi: 10.1016/j.tiv.2019.02.017. Epub 2019 Oct 15.