Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHHCQ17)

• DOT Name: Group XIIA secretory phospholipase A2 (PLA2G12A)
• Synonyms: GXII sPLA2; sPLA2-XII; EC 3.1.1.4; Phosphatidylcholine 2-acylhydrolase 12A
• Gene Name: PLA2G12A
• Related Disease:
  Age-related macular degeneration
  Arteriosclerosis
  Atherosclerosis
  Autism spectrum disorder
  Schizophrenia
• UniProt ID: PG12A_HUMAN
• EC Number: 3.1.1.4
• Pfam ID: PF06951
• Sequence:
  MALLSRPALTLLLLLMAAVVRCQEQAQTTDWRATLKTIRNGVHKIDTYLNAALDLLGGED
  GLCQYKCSDGSKPFPRYGYKPSPPNGCGSPLFGVHLNIGIPSLTKCCNQHDRCYETCGKS
  KNDCDEEFQYCLSKICRDVQKTLGLTQHVQACETTVELLFDSVIHLGCKPYLDSQRAACR
  CHYEEKTDL
• Function: PA2 catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-phosphoglycerides. Does not exhibit detectable activity toward sn-2-arachidonoyl- or linoleoyl-phosphatidylcholine or -phosphatidylethanolamine.
• Tissue Specificity: Abundantly expressed in heart, skeletal muscle, kidney, liver and pancreas.
• 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

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[1]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[2]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[2]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]

14 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 Group XIIA secretory phospholipase A2 (PLA2G12A).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[13]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Group XIIA secretory phospholipase A2 (PLA2G12A).	[16]

References

• [1] Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7401-6. doi: 10.1073/pnas.0912702107. Epub 2010 Apr 12.
• [2] Quantitative trait locus mapping in mice identifies phospholipase Pla2g12a as novel atherosclerosis modifier.Atherosclerosis. 2017 Oct;265:197-206. doi: 10.1016/j.atherosclerosis.2017.08.030. Epub 2017 Sep 4.
• [3] The rs251684 Variant of PLA2G4C Is Associated with Autism Spectrum Disorder in the Northeast Han Chinese Population.Genet Test Mol Biomarkers. 2016 Dec;20(12):747-752. doi: 10.1089/gtmb.2016.0195. Epub 2016 Sep 9.
• [4] Association between PLA2G12A polymorphism and patients with schizophrenia in a southern Chinese Han population.Hum Psychopharmacol. 2018 Mar;33(2):e2654. doi: 10.1002/hup.2654. Epub 2018 Mar 11.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] 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.
• [15] 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.
• [16] 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.