Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTO0IB8)

• DTT Name: Thymidine phosphorylase (TYMP)
• Synonyms: TdRPase; TYMP; TP; Platelet-derived endothelial cell growth factor; PDECGF; PD-ECGF; Gliostatin
• Gene Name: TYMP
• DTT Type: Successful target; [1]
• BioChemical Class: Pentosyltransferase
• UniProt ID: TYPH_HUMAN
• TTD ID: T59929
• EC Number: EC 2.4.2.4
• Sequence:
  MAALMTPGTGAPPAPGDFSGEGSQGLPDPSPEPKQLPELIRMKRDGGRLSEADIRGFVAA
  VVNGSAQGAQIGAMLMAIRLRGMDLEETSVLTQALAQSGQQLEWPEAWRQQLVDKHSTGG
  VGDKVSLVLAPALAACGCKVPMISGRGLGHTGGTLDKLESIPGFNVIQSPEQMQVLLDQA
  GCCIVGQSEQLVPADGILYAARDVTATVDSLPLITASILSKKLVEGLSALVVDVKFGGAA
  VFPNQEQARELAKTLVGVGASLGLRVAAALTAMDKPLGRCVGHALEVEEALLCMDGAGPP
  DLRDLVTTLGGALLWLSGHAGTQAQGAARVAAALDDGSALGRFERMLAAQGVDPGLARAL
  CSGSPAERRQLLPRAREQEELLAPADGTVELVRALPLALVLHELGAGRSRAGEPLRLGVG
  AELLVDVGQRLRRGTPWLRVHRDGPALSGPQSRALQEALVLSDRAPFAAPSPFAELVLPP
  QQ
• Function: 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)
  Bladder cancer (hsa05219)
• Reactome Pathway:
  Pyrimidine catabolism (R-HSA-73621)
  Pyrimidine salvage (R-HSA-73614)
• BioCyc Pathway: MetaCyc:HS00442-MON

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Uridine	DMQTREB	Depression	6A70-6A7Z	Approved	[1]

23 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-(cyclohexyl)methyl-5'-O-tritylinosine	DMS3XUC	Discovery agent	N.A.	Investigative	[2]
1-(cyclopropyl)methyl-5'-O-tritylinosine	DMDU3X7	Discovery agent	N.A.	Investigative	[2]
1-allyl-5'-O-tritylinosine	DM2J5WH	Discovery agent	N.A.	Investigative	[2]
1-benzyl-5'-O-tritylinosine	DMH0ZVR	Discovery agent	N.A.	Investigative	[2]
1-propyl-5'-O-tritylinosine	DM5P01L	Discovery agent	N.A.	Investigative	[2]
2'-aminoimidazolylmethyluracils	DMUJC2E	Discovery agent	N.A.	Investigative	[3]
5-benzyl-6-chloropyrimidine-2,4(1H,3H)-dione	DMCKODQ	Discovery agent	N.A.	Investigative	[4]
5-bromo-6-(cyclopropylamino)uracil hydrochloride	DMRY0OL	Discovery agent	N.A.	Investigative	[5]
5-bromo-6-hydrazinouracil hydrochloride	DMZJE6M	Discovery agent	N.A.	Investigative	[5]
5-butyl-6-chloropyrimidine-2,4(1H,3H)-dione	DMFKMYV	Discovery agent	N.A.	Investigative	[4]
5-chloro-6-hydrazinouracil hydrochloride	DMMT7WO	Discovery agent	N.A.	Investigative	[5]
5-fluoro-6-[(2-aminoimidazol-1-yl)methyl]uracil	DMEV0GO	Discovery agent	N.A.	Investigative	[6]
6-amino-5-bromouracil	DM5SZHR	Discovery agent	N.A.	Investigative	[7]
6-amino-5-chlorouracil hydrochloride	DMFPCSJ	Discovery agent	N.A.	Investigative	[5]
6-bromo-5-phenylpyrimidine-2,4(1H,3H)-dione	DM8A1ZU	Discovery agent	N.A.	Investigative	[4]
6-chloro-5-(2-thienyl)pyrimidine-2,4(1H,3H)-dione	DMSZML2	Discovery agent	N.A.	Investigative	[4]
6-chloro-5-heptylpyrimidine-2,4(1H,3H)-dione	DMASFR6	Discovery agent	N.A.	Investigative	[4]
6-chloro-5-hexylpyrimidine-2,4(1H,3H)-dione	DMP4V8Y	Discovery agent	N.A.	Investigative	[4]
6-chloro-5-pentylpyrimidine-2,4(1H,3H)-dione	DMUJSP7	Discovery agent	N.A.	Investigative	[4]
6-chloro-5-phenylpyrimidine-2,4(1H,3H)-dione	DM90JMN	Discovery agent	N.A.	Investigative	[4]
6-chloro-5-propylpyrimidine-2,4(1H,3H)-dione	DMB24LJ	Discovery agent	N.A.	Investigative	[4]
6-fluoro-5-phenylpyrimidine-2,4(1H,3H)-dione	DM4Q5TX	Discovery agent	N.A.	Investigative	[4]
Thymine	DMKGXB9	Discovery agent	N.A.	Investigative	[8]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Major depressive disorder	6A20	Pre-frontal cortex	6.50E-01	-0.03	-0.25

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Thymidine phosphorylase (TYMP) DME Info
• Gene Name: TYMP

4 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Capecitabine	DMTS85L	Adenocarcinoma	2D40	Approved	[9]
Floxuridine	DM04LR2	Colorectal cancer	2B91.Z	Approved	[10]
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[11]
Trifluridine	DMG2YBD	Herpetic keratitis	1F00.10	Approved	[12]

1 Investigative Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Deoxythymidine	DMR90HY	Discovery agent	N.A.	Investigative	[13]

References

• [1] Enzymatic activities of uridine and thymidine phosphorylase in normal and cancerous uterine cervical tissues. Hum Cell. 2007 Nov;20(4):107-10.
• [2] 5'-O-tritylinosine and analogues as allosteric inhibitors of human thymidine phosphorylase. J Med Chem. 2006 Sep 7;49(18):5562-70.
• [3] Potential tumor-selective nitroimidazolylmethyluracil prodrug derivatives: inhibitors of the angiogenic enzyme thymidine phosphorylase. J Med Chem. 2003 Jan 16;46(2):207-9.
• [4] Discovery of 5-substituted-6-chlorouracils as efficient inhibitors of human thymidine phosphorylase. J Med Chem. 2007 Nov 29;50(24):6016-23.
• [5] Design and synthesis of novel 5,6-disubstituted uracil derivatives as potent inhibitors of thymidine phosphorylase. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1335-7.
• [6] The role of phosphate in the action of thymidine phosphorylase inhibitors: Implications for the catalytic mechanism. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1648-51.
• [7] Xanthine oxidase-activated prodrugs of thymidine phosphorylase inhibitors. Eur J Med Chem. 2008 Jun;43(6):1248-60.
• [8] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [9] Induction of thymidine phosphorylase in both irradiated and shielded, contralateral human U87MG glioma xenografts: implications for a dual modality treatment using capecitabine and irradiation. Mol Cancer Ther. 2002 Oct;1(12):1139-45.
• [10] Enhanced cancer cell growth inhibition by dipeptide prodrugs of floxuridine: increased transporter affinity and metabolic stability. Mol Pharm. 2008 Sep-Oct;5(5):717-27.
• [11] 5-Fluorouracil pharmacogenomics: still rocking after all these years? Pharmacogenomics. 2011 Feb;12(2):251-65.
• [12] Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Invest. 2008 Oct;26(8):794-9.
• [13] Thymidine catabolism as a metabolic strategy for cancer survival. Cell Rep. 2017 May 16;19(7):1313-1321.