Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS2DQ0N)

• DOT Name: Pseudouridylate synthase 1 homolog (PUS1)
• Synonyms: EC 5.4.99.-; tRNA pseudouridine synthase 1; EC 5.4.99.12; tRNA pseudouridine(38-40) synthase; tRNA pseudouridylate synthase I; tRNA-uridine isomerase I
• Gene Name: PUS1
• Related Disease:
  Mitochondrial disease
  Myopathy, lactic acidosis, and sideroblastic anemia 1
  Gastric cancer
  Gastric neoplasm
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Mitochondrial myopathy
  Sideroblastic anemia
  Myopathy, lactic acidosis, and sideroblastic anemia
  Intellectual disability
• UniProt ID: PUS1_HUMAN
• PDB ID: 4IQM; 4ITS; 4J37; 4NZ6; 4NZ7
• EC Number: 5.4.99.-; 5.4.99.12
• Pfam ID: PF01416
• Sequence:
  MGLQLRALLGAFGRWTLRLGPRPSCSPRMAGNAEPPPAGAACPQDRRSCSGRAGGDRVWE
  DGEHPAKKLKSGGDEERREKPPKRKIVLLMAYSGKGYHGMQRNVGSSQFKTIEDDLVSAL
  VRSGCIPENHGEDMRKMSFQRCARTDKGVSAAGQVVSLKVWLIDDILEKINSHLPSHIRI
  LGLKRVTGGFNSKNRCDARTYCYLLPTFAFAHKDRDVQDETYRLSAETLQQVNRLLACYK
  GTHNFHNFTSQKGPQDPSACRYILEMYCEEPFVREGLEFAVIRVKGQSFMMHQIRKMVGL
  VVAIVKGYAPESVLERSWGTEKVDVPKAPGLGLVLERVHFEKYNQRFGNDGLHEPLDWAQ
  EEGKVAAFKEEHIYPTIIGTERDERSMAQWLSTLPIHNFSATALTAGGTGAKVPSPLEGS
  EGDGDTD
• Function: Pseudouridylate synthase that catalyzes pseudouridylation of tRNAs and mRNAs. Acts on positions 27/28 in the anticodon stem and also positions 34 and 36 in the anticodon of an intron containing tRNA. Also catalyzes pseudouridylation of mRNAs: mediates pseudouridylation of mRNAs with the consensus sequence 5'-UGUAG-3'. Acts as a regulator of pre-mRNA splicing by mediating pseudouridylation of pre-mRNAs at locations associated with alternatively spliced regions. Pseudouridylation of pre-mRNAs near splice sites directly regulates mRNA splicing and mRNA 3'-end processing. Involved in regulation of nuclear receptor activity through pseudouridylation of SRA1 mRNA.
• Tissue Specificity: Widely expressed . High levels of expression found in brain and skeletal muscle .

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Myopathy, lactic acidosis, and sideroblastic anemia 1	DISVX8ZU	Definitive	Autosomal recessive	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[3]
Mitochondrial myopathy	DIS9SA7V	Strong	Genetic Variation	[5]
Sideroblastic anemia	DIS4F3X1	Strong	Genetic Variation	[5]
Myopathy, lactic acidosis, and sideroblastic anemia	DISGW7N3	Supportive	Autosomal recessive	[6]
Intellectual disability	DISMBNXP	Limited	Biomarker	[6]

3 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 Pseudouridylate synthase 1 homolog (PUS1).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Pseudouridylate synthase 1 homolog (PUS1).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Pseudouridylate synthase 1 homolog (PUS1).	[20]

12 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 Pseudouridylate synthase 1 homolog (PUS1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pseudouridylate synthase 1 homolog (PUS1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Pseudouridylate synthase 1 homolog (PUS1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pseudouridylate synthase 1 homolog (PUS1).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Pseudouridylate synthase 1 homolog (PUS1).	[12]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Pseudouridylate synthase 1 homolog (PUS1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pseudouridylate synthase 1 homolog (PUS1).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Pseudouridylate synthase 1 homolog (PUS1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pseudouridylate synthase 1 homolog (PUS1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pseudouridylate synthase 1 homolog (PUS1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Pseudouridylate synthase 1 homolog (PUS1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pseudouridylate synthase 1 homolog (PUS1).	[19]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA). J Med Genet. 2007 Mar;44(3):173-80. doi: 10.1136/jmg.2006.045252. Epub 2006 Oct 20.
• [3] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [4] Scutellaria barbata polysaccharides inhibit tumor growth and affect the serum proteomic profiling of hepatoma H22bearing mice.Mol Med Rep. 2019 Mar;19(3):2254-2262. doi: 10.3892/mmr.2019.9862. Epub 2019 Jan 15.
• [5] Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).Am J Hum Genet. 2004 Jun;74(6):1303-8. doi: 10.1086/421530. Epub 2004 Apr 22.
• [6] Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA). BMJ Case Rep. 2009;2009:bcr05.2009.1889. doi: 10.1136/bcr.05.2009.1889. Epub 2009 Jun 9.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [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] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [13] Effects of aspirin on metastasis-associated gene expression detected by cDNA microarray. Acta Pharmacol Sin. 2004 Oct;25(10):1327-33.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [16] 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.
• [17] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.