Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF6FE38)

• DOT Name: Adenylosuccinate synthetase isozyme 1 (ADSS1)
• Synonyms: AMPSase 1; AdSS 1; EC 6.3.4.4; Adenylosuccinate synthetase, basic isozyme; Adenylosuccinate synthetase, muscle isozyme; M-type adenylosuccinate synthetase; Adenylosuccinate synthetase-like 1; AdSSL1; IMP--aspartate ligase 1
• Gene Name: ADSS1
• Related Disease:
  Breast carcinoma
  Cervical Intraepithelial neoplasia
  Distal myopathy
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Myopathy
  Myopathy, distal, 5
  Neoplasm
• UniProt ID: PURA1_HUMAN
• EC Number: 6.3.4.4
• Pfam ID: PF00709
• Sequence:
  MSGTRASNDRPPGAGGVKRGRLQQEAAATGSRVTVVLGAQWGDEGKGKVVDLLATDADII
  SRCQGGNNAGHTVVVDGKEYDFHLLPSGIINTKAVSFIGNGVVIHLPGLFEEAEKNEKKG
  LKDWEKRLIISDRAHLVFDFHQAVDGLQEVQRQAQEGKNIGTTKKGIGPTYSSKAARTGL
  RICDLLSDFDEFSSRFKNLAHQHQSMFPTLEIDIEGQLKRLKGFAERIRPMVRDGVYFMY
  EALHGPPKKILVEGANAALLDIDFGTYPFVTSSNCTVGGVCTGLGIPPQNIGDVYGVVKA
  YTTRVGIGAFPTEQINEIGGLLQTRGHEWGVTTGRKRRCGWLDLMILRYAHMVNGFTALA
  LTKLDILDVLGEVKVGVSYKLNGKRIPYFPANQEMLQKVEVEYETLPGWKADTTGARRWE
  DLPPQAQNYIRFVENHVGVAVKWVGVGKSRESMIQLF
• Function: Component of the purine nucleotide cycle (PNC), which interconverts IMP and AMP to regulate the nucleotide levels in various tissues, and which contributes to glycolysis and ammoniagenesis. Catalyzes the first committed step in the biosynthesis of AMP from IMP.
• Tissue Specificity: Predominantly expressed in skeletal muscle and heart, as well as in several hematopoietic cell lines and solid tumors.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Purine ribonucleoside monophosphate biosynthesis (R-HSA-73817)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[1]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Biomarker	[2]
Distal myopathy	DIS7F5R0	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[2]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[2]
Myopathy	DISOWG27	Strong	Biomarker	[3]
Myopathy, distal, 5	DISWD0BP	Strong	Autosomal recessive	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[20]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Adenylosuccinate synthetase isozyme 1 (ADSS1).	[12]

References

• [1] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [2] Adenylosuccinate synthetase 1 gene is a novel target of deletion in lung adenocarcinoma.Mol Carcinog. 2009 Dec;48(12):1116-22. doi: 10.1002/mc.20563.
• [3] Comparative transcriptome analysis of skeletal muscle in ADSSL1 myopathy.Neuromuscul Disord. 2019 Apr;29(4):274-281. doi: 10.1016/j.nmd.2018.11.003. Epub 2018 Nov 22.
• [4] ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy. Ann Neurol. 2016 Feb;79(2):231-43. doi: 10.1002/ana.24550. Epub 2015 Dec 15.
• [5] 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.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] 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.
• [15] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [19] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] 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.