Details of Drug Off-Target (DOT)

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

• DOT Name: Bifunctional coenzyme A synthase (COASY)
• Synonyms: CoA synthase; NBP; POV-2
• Gene Name: COASY
• Related Disease:
  Neurodegeneration with brain iron accumulation 6
  Pontocerebellar hypoplasia, type 12
• UniProt ID: COASY_HUMAN
• EC Number: 2.7.1.24; 2.7.7.3
• Pfam ID: PF01121 ; PF01467
• Sequence:
  MAVFRSGLLVLTTPLASLAPRLASILTSAARLVNHTLYVHLQPGMSLEGPAQPQSSPVQA
  TFEVLDFITHLYAGADVHRHLDVRILLTNIRTKSTFLPPLPTSVQNLAHPPEVVLTDFQT
  LDGSQYNPVKQQLVRYATSCYSCCPRLASVLLYSDYGIGEVPVEPLDVPLPSTIRPASPV
  AGSPKQPVRGYYRGAVGGTFDRLHNAHKVLLSVACILAQEQLVVGVADKDLLKSKLLPEL
  LQPYTERVEHLSEFLVDIKPSLTFDVIPLLDPYGPAGSDPSLEFLVVSEETYRGGMAINR
  FRLENDLEELALYQIQLLKDLRHTENEEDKVSSSSFRQRMLGNLLRPPYERPELPTCLYV
  IGLTGISGSGKSSIAQRLKGLGAFVIDSDHLGHRAYAPGGPAYQPVVEAFGTDILHKDGI
  INRKVLGSRVFGNKKQLKILTDIMWPIIAKLAREEMDRAVAEGKRVCVIDAAVLLEAGWQ
  NLVHEVWTAVIPETEAVRRIVERDGLSEAAAQSRLQSQMSGQQLVEQSHVVLSTLWEPHI
  TQRQVEKAWALLQKRIPKTHQALD
• Function: Bifunctional enzyme that catalyzes the fourth and fifth sequential steps of CoA biosynthetic pathway. The fourth reaction is catalyzed by the phosphopantetheine adenylyltransferase, coded by the coaD domain; the fifth reaction is catalyzed by the dephospho-CoA kinase, coded by the coaE domain. May act as a point of CoA biosynthesis regulation.
• Tissue Specificity: Expressed in all tissues examined including brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung and peripheral blood leukocyte. Lowest expression in peripheral blood leukocytes and highest in kidney and liver. Isoform 2 is expressed mainly in the brain.
• KEGG Pathway:
  Pantothe.te and CoA biosynthesis (hsa00770)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Coenzyme A biosynthesis (R-HSA-196783)
• BioCyc Pathway: MetaCyc:HS00931-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodegeneration with brain iron accumulation 6	DISZUO5O	Strong	Autosomal recessive	[1]
Pontocerebellar hypoplasia, type 12	DISP3DLV	Strong	Autosomal recessive	[2]

7 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 Bifunctional coenzyme A synthase (COASY).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Bifunctional coenzyme A synthase (COASY).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Bifunctional coenzyme A synthase (COASY).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bifunctional coenzyme A synthase (COASY).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Bifunctional coenzyme A synthase (COASY).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bifunctional coenzyme A synthase (COASY).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Bifunctional coenzyme A synthase (COASY).	[10]

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 Bifunctional coenzyme A synthase (COASY).	[8]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis. Eur J Hum Genet. 2018 Dec;26(12):1752-1758. doi: 10.1038/s41431-018-0233-0. Epub 2018 Aug 8.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [8] 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.
• [9] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.