Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6BQTMR)

• DOT Name: Thymidine phosphorylase
• Synonyms: TP; EC 2.4.2.4; Gliostatin; Platelet-derived endothelial cell growth factor; PD-ECGF; TdRPase
• Gene Name: TYMP
• Related Disease:
  Mitochondrial disease
  Mitochondrial DNA depletion syndrome 1
  Mitochondrial neurogastrointestinal encephalomyopathy
• UniProt ID: TYPH_HUMAN
• PDB ID: 1UOU; 2J0F; 2WK5; 2WK6
• EC Number: 2.4.2.4
• Pfam ID: PF02885 ; PF00591 ; PF07831
• Sequence:
  MAALMTPGTGAPPAPGDFSGEGSQGLPDPSPEPKQLPELIRMKRDGGRLSEADIRGFVAA
  VVNGSAQGAQIGAMLMAIRLRGMDLEETSVLTQALAQSGQQLEWPEAWRQQLVDKHSTGG
  VGDKVSLVLAPALAACGCKVPMISGRGLGHTGGTLDKLESIPGFNVIQSPEQMQVLLDQA
  GCCIVGQSEQLVPADGILYAARDVTATVDSLPLITASILSKKLVEGLSALVVDVKFGGAA
  VFPNQEQARELAKTLVGVGASLGLRVAAALTAMDKPLGRCVGHALEVEEALLCMDGAGPP
  DLRDLVTTLGGALLWLSGHAGTQAQGAARVAAALDDGSALGRFERMLAAQGVDPGLARAL
  CSGSPAERRQLLPRAREQEELLAPADGTVELVRALPLALVLHELGAGRSRAGEPLRLGVG
  AELLVDVGQRLRRGTPWLRVHRDGPALSGPQSRALQEALVLSDRAPFAAPSPFAELVLPP
  QQ
• Function: May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in vitro; Catalyzes the reversible phosphorolysis of thymidine. The produced molecules are then utilized as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis.
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Bladder cancer (hsa05219)
• Reactome Pathway:
  Pyrimidine catabolism (R-HSA-73621)
  Pyrimidine salvage (R-HSA-73614)
• BioCyc Pathway: MetaCyc:HS00442-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Mitochondrial DNA depletion syndrome 1	DISZ48YF	Strong	Autosomal recessive	[2]
Mitochondrial neurogastrointestinal encephalomyopathy	DIS5HV4H	Supportive	Autosomal recessive	[3]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gemcitabine	DMSE3I7	Approved	Thymidine phosphorylase affects the response to substance of Gemcitabine.	[28]
Pemetrexed	DMMX2E6	Approved	Thymidine phosphorylase increases the response to substance of Pemetrexed.	[29]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Deoxythymidine	DMR90HY	Investigative	Thymidine phosphorylase increases the phosphorylation of Deoxythymidine.	[30]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Thymine	DMKGXB9	Investigative	Thymidine phosphorylase increases the abundance of Thymine.	[30]

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 Thymidine phosphorylase.	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Thymidine phosphorylase.	[24]

29 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 Thymidine phosphorylase.	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Thymidine phosphorylase.	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Thymidine phosphorylase.	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Thymidine phosphorylase.	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Thymidine phosphorylase.	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Thymidine phosphorylase.	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Thymidine phosphorylase.	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Thymidine phosphorylase.	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Thymidine phosphorylase.	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Thymidine phosphorylase.	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Thymidine phosphorylase.	[7]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Thymidine phosphorylase.	[15]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Thymidine phosphorylase.	[16]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Thymidine phosphorylase.	[17]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Thymidine phosphorylase.	[7]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Thymidine phosphorylase.	[18]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Thymidine phosphorylase.	[19]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine decreases the expression of Thymidine phosphorylase.	[20]
Zalcitabine	DMH7MUV	Approved	Zalcitabine increases the expression of Thymidine phosphorylase.	[19]
Stavudine	DM6DEK9	Approved	Stavudine increases the expression of Thymidine phosphorylase.	[19]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Thymidine phosphorylase.	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Thymidine phosphorylase.	[14]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Thymidine phosphorylase.	[22]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the expression of Thymidine phosphorylase.	[23]
SB 203580	DMAET6F	Terminated	SB 203580 decreases the expression of Thymidine phosphorylase.	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Thymidine phosphorylase.	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Thymidine phosphorylase.	[26]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Thymidine phosphorylase.	[27]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide decreases the expression of Thymidine phosphorylase.	[23]

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] Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome. Mol Genet Metab. 2005 Apr;84(4):326-31. doi: 10.1016/j.ymgme.2004.12.004. Epub 2005 Jan 24.
• [3] Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain. 2011 Nov;134(Pt 11):3326-32. doi: 10.1093/brain/awr245. Epub 2011 Sep 20.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Influence of chemotherapeutic agents and cytokines on the expression of 5-fluorouracil-associated enzymes in human colon cancer cell lines. J Gastroenterol. 2006 Feb;41(2):140-50.
• [8] 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.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Combined gossypol and zoledronic acid treatment results in synergistic induction of cell death and regulates angiogenic molecules in ovarian cancer cells. Eur Cytokine Netw. 2009 Sep;20(3):121-30. doi: 10.1684/ecn.2009.0159.
• [14] 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.
• [15] Effects of aspirin on metastasis-associated gene expression detected by cDNA microarray. Acta Pharmacol Sin. 2004 Oct;25(10):1327-33.
• [16] Changes of gene expression of thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase after the administration of 5'-deoxy-5-fluorouridine, paclitaxel and its combination in human gastric cancer xenografts. Anticancer Res. 2008 May-Jun;28(3A):1593-602.
• [17] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [18] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [19] Induction of thymidine phosphorylase expression by AZT contributes to enhancement of 5'-DFUR cytotoxicity. Cancer Lett. 2006 Dec 8;244(2):239-46.
• [20] Sulfasalazine down-regulates the expression of the angiogenic factors platelet-derived endothelial cell growth factor/thymidine phosphorylase and interleukin-8 in human monocytic-macrophage THP1 and U937 cells. Mol Pharmacol. 2004 Oct;66(4):1054-60.
• [21] Synergistic effect of curcumin and cisplatin via down-regulation of thymidine phosphorylase and excision repair cross-complementary 1 (ERCC1). Mol Pharmacol. 2011 Jul;80(1):136-46.
• [22] Expression of the angiogenic factor thymidine phosphorylase in THP-1 monocytes: induction by autocrine tumor necrosis factor-alpha and inhibition by aspirin. Mol Pharmacol. 2003 Nov;64(5):1251-8. doi: 10.1124/mol.64.5.1251.
• [23] Inhibition of thymidine phosphorylase expression by Hsp90 inhibitor potentiates the cytotoxic effect of salinomycin in human non-small-cell lung cancer cells. Toxicology. 2019 Apr 1;417:54-63.
• [24] 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.
• [25] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [26] Identification of formaldehyde-responsive genes by suppression subtractive hybridization. Toxicology. 2008 Jan 14;243(1-2):224-35.
• [27] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [28] Ex vivo chemosensitivity testing and gene expression profiling predict response towards adjuvant gemcitabine treatment in pancreatic cancer. Br J Cancer. 2008 Sep 2;99(5):760-7. doi: 10.1038/sj.bjc.6604528.
• [29] A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer. Clin Cancer Res. 2007 Jun 15;13(12):3652-9. doi: 10.1158/1078-0432.CCR-06-2377.
• [30] Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors. Cancer Res. 2000 Nov 15;60(22):6298-302.