Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY3TQYA)

• DOT Name: Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1)
• Synonyms: PAPS synthase 1; PAPSS 1; Sulfurylase kinase 1; SK 1; SK1
• Gene Name: PAPSS1
• UniProt ID: PAPS1_HUMAN
• PDB ID: 1X6V; 1XJQ; 1XNJ; 2OFW; 2OFX; 2PEY; 2PEZ; 2QJF
• EC Number: 2.7.1.25; 2.7.7.4
• Pfam ID: PF01583 ; PF01747 ; PF14306
• Sequence:
  MEIPGSLCKKVKLSNNAQNWGMQRATNVTYQAHHVSRNKRGQVVGTRGGFRGCTVWLTGL
  SGAGKTTVSMALEEYLVCHGIPCYTLDGDNIRQGLNKNLGFSPEDREENVRRIAEVAKLF
  ADAGLVCITSFISPYTQDRNNARQIHEGASLPFFEVFVDAPLHVCEQRDVKGLYKKARAG
  EIKGFTGIDSEYEKPEAPELVLKTDSCDVNDCVQQVVELLQERDIVPVDASYEVKELYVP
  ENKLHLAKTDAETLPALKINKVDMQWVQVLAEGWATPLNGFMREREYLQCLHFDCLLDGG
  VINLSVPIVLTATHEDKERLDGCTAFALMYEGRRVAILRNPEFFEHRKEERCARQWGTTC
  KNHPYIKMVMEQGDWLIGGDLQVLDRVYWNDGLDQYRLTPTELKQKFKDMNADAVFAFQL
  RNPVHNGHALLMQDTHKQLLERGYRRPVLLLHPLGGWTKDDDVPLMWRMKQHAAVLEEGV
  LNPETTVVAIFPSPMMYAGPTEVQWHCRARMVAGANFYIVGRDPAGMPHPETGKDLYEPS
  HGAKVLTMAPGLITLEIVPFRVAAYNKKKKRMDYYDSEHHEDFEFISGTRMRKLAREGQK
  PPEGFMAPKAWTVLTEYYKSLEKA
• Function: Bifunctional enzyme with both ATP sulfurylase and APS kinase activity, which mediates two steps in the sulfate activation pathway. The first step is the transfer of a sulfate group to ATP to yield adenosine 5'-phosphosulfate (APS), and the second step is the transfer of a phosphate group from ATP to APS yielding 3'-phosphoadenylylsulfate (PAPS: activated sulfate donor used by sulfotransferase). In mammals, PAPS is the sole source of sulfate; APS appears to be only an intermediate in the sulfate-activation pathway. Required for normal biosynthesis of sulfated L-selectin ligands in endothelial cells.
• Tissue Specificity: Expressed in testis, pancreas, kidney, thymus, prostate, ovary, small intestine, colon, leukocytes and liver. Also expressed in high endothelial venules (HEV) cells and in cartilage.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Selenocompound metabolism (hsa00450)
  Sulfur metabolism (hsa00920)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Metabolism of ingested H2SeO4 and H2SeO3 into H2Se (R-HSA-2408550)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Transport and synthesis of PAPS (R-HSA-174362)
• BioCyc Pathway: MetaCyc:HS06566-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1) decreases the response to substance of Afimoxifene.	[14]

12 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 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[6]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[12]
1,4-Dithiothreitol	DMIFOXE	Investigative	1,4-Dithiothreitol increases the activity of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Bifunctional 3'-phosphoadenosine 5'-phosphosulfate synthase 1 (PAPSS1).	[10]

References

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• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [4] 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.
• [5] Synergistic effects of arsenic trioxide combined with ascorbic acid in human osteosarcoma MG-63 cells: a systems biology analysis. Eur Rev Med Pharmacol Sci. 2014;18(24):3877-88.
• [6] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [7] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [8] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [9] 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.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [12] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [13] Human 3'-phosphoadenosine 5'-phosphosulfate synthetase (isoform 1, brain): kinetic properties of the adenosine triphosphate sulfurylase and adenosine 5'-phosphosulfate kinase domains. Biochemistry. 2004 Apr 13;43(14):4356-65.
• [14] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.