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Literature summary for 2.4.2.4 extracted from

  • Bera, H.; Chigurupati, S.
    Recent discovery of non-nucleobase thymidine phosphorylase inhibitors targeting cancer (2016), Eur. J. Med. Chem., 124, 992-1003 .
    View publication on PubMed

Application

Application Comment Organism
medicine thymidine phosphorylase is identified as a prime target for developing anticancer therapies Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
analysis of crystal structure of recombinant Escherichia coli TP in complex with 2'-fluoro-3'-azido-2',3'-dideoxyuridine (N3FddU) and 3'-azidothymidine (AZT) at 1.50 A and 1.52 A resolutions, respectively. Analysis of the free enzyme crystal structure at 2.8 A resolution Escherichia coli
analysis of crystal structure of recombinant human TP in complex with 5-iodouracil (5IUR) at 3.0 A and 2.5 A resolutions, respectively Homo sapiens

Protein Variants

Protein Variants Comment Organism
additional information transfection of TP into KB cells renders them highly resistant to apoptosis caused by hypoxia Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(2R,3R,4S,5R)-9-(3,4-dihydroxy-5-trityloxymethyl-tetrahydrofuran-2-yl)-1,9-dihydropurin-6-one KIN59 Escherichia coli
(2R,3R,4S,5R)-9-(3,4-dihydroxy-5-trityloxymethyl-tetrahydrofuran-2-yl)-1,9-dihydropurin-6-one KIN59 Homo sapiens
(3-benzyl-2,4,5-trioxoimidazolidin-1-yl)acetic acid
-
Homo sapiens
1-(2-phenylethyl)imidazolidine-2,4,5-trione
-
Homo sapiens
1-benzylimidazolidine-2,4,5-trione
-
Homo sapiens
1-[(2-methylphenyl)methyl]imidazolidine-2,4,5-trione
-
Homo sapiens
2'-fluoro-3'-azido-2',3'-dideoxyuridine N3FddU Escherichia coli
2-(3,4-dichlorophenyl)-5-sulfanylidene-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
-
Homo sapiens
2-(3,4-dihydroxyphenyl)quinazolin-4(3H)-one
-
Homo sapiens
2-(diphenylmethyl)-5-sulfanylidene-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
-
Homo sapiens
2-benzyl-5-sulfanylidene-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
-
Homo sapiens
2-phenyl-5-sulfanylidene-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
-
Homo sapiens
2-phenyl-7-sulfanylidene-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5(4H)-one
-
Homo sapiens
2-phenylquinazolin-4(3H)-one
-
Homo sapiens
2-phenyl[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7(4H,6H)-dione
-
Homo sapiens
2-[(3,4-dichlorophenyl)methyl]-5-sulfanylidene-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
-
Homo sapiens
2-[[(5-chloro-2-methylidene-6-oxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]sulfanyl]-7-phenyl-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
-
Homo sapiens
3'-azidothymidine AZT Escherichia coli
3,3'-(1,3,4-oxadiazole-2,5-diyl)dipyridine
-
Homo sapiens
3-(3-benzyl-2,4,5-trioxoimidazolidin-1-yl)propanamide
-
Homo sapiens
3-benzyl-1H-2-benzopyran-1-one
-
Homo sapiens
3-[(2-methoxy-6-nitroanilino)methyl]-5-(4-methylphenyl)-1,3,4-oxadiazole-2(3H)-thione
-
Homo sapiens
3-[(2-methylphenyl)methyl]-1H-2-benzopyran-1-one
-
Homo sapiens
3-[(3,4-dimethylanilino)methyl]-5-phenyl-1,3,4-oxadiazole-2(3H)-thione
-
Homo sapiens
3-[(E)-[(2,4-dichlorophenyl)imino]methyl]-4H-1-benzopyran-4-one
-
Homo sapiens
3-[(E)-[(3-methoxy-4-methylphenyl)imino]methyl]-4H-1-benzopyran-4-one
-
Homo sapiens
3-[2,4,5-trioxo-3-(2-phenylethyl)imidazolidin-1-yl]propanamide
-
Homo sapiens
3-[3-[(2-methylphenyl)methyl]-2,4,5-trioxoimidazolidin-1-yl]propanamide
-
Homo sapiens
4-oxo-4H-1-benzopyran-3-carbaldehyde
-
Homo sapiens
4-[(Z)-[(3-hydroxynaphthalen-2-yl)methylidene]amino]-1,5-dimethyl-2-phenylpyrazolidin-3-one
-
Homo sapiens
5-(4-hydroxyphenyl)-1,3,4-oxadiazole-2(3H)-thione
-
Homo sapiens
5-(benzylsulfanyl)-2-phenyl-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
-
Homo sapiens
5-(methylsulfanyl)-2-phenyl-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
-
Homo sapiens
5-chloro-6-[([4-oxo-8-[4-(pentafluoro-lambda6-sulfanyl)phenyl]-1,2,3,4-tetrahydropyrazolo[1,5-a][1,3,5]triazin-2-yl]sulfanyl)methyl]pyrimidine-2,4(1H,3H)-dione
-
Homo sapiens
5-phenyl-1,3,4-oxadiazole-2(3H)-thione
-
Homo sapiens
5-[(E)-[2-(quinoxalin-2-yl)hydrazinylidene]methyl]benzene-1,2,4-triol
-
Homo sapiens
6-amino-5-bromouracil
-
Escherichia coli
6-amino-5-bromouracil
-
Homo sapiens
6-aminothymine
-
Escherichia coli
6-aminothymine
-
Homo sapiens
7-(4-tert-butylphenyl)-2-sulfanylidene-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
-
Homo sapiens
7-(4-tert-butylphenyl)-2-[[(5-chloro-2-methylidene-6-oxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]sulfanyl]-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
-
Homo sapiens
7-(methylsulfanyl)-2-phenyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5(4H)-one
-
Homo sapiens
7-deazaxanthine
-
Escherichia coli
7-deazaxanthine
-
Homo sapiens
7-phenyl-2-sulfanylidene-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
-
Homo sapiens
7-phenylpyrazolo[1,5-a][1,3,5]triazine-2,4(1H,3H)-dione
-
Homo sapiens
8-phenyl-2-sulfanylidene-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
-
Homo sapiens
8-[4-(pentafluoro-lambda6-sulfanyl)phenyl]-2-sulfanylidene-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
-
Homo sapiens
ethyl (3-benzyl-2,4,5-trioxoimidazolidin-1-yl)acetate
-
Homo sapiens
ethyl [2,4,5-trioxo-3-(2-phenylethyl)imidazolidin-1-yl]acetate
-
Homo sapiens
ethyl [3-[(2-methylphenyl)methyl]-2,4,5-trioxoimidazolidin-1-yl]acetate
-
Homo sapiens
additional information an array of structurally diverse non-nucleobase derivatives has beens designed, synthesized and established as promising TP inhibitors, structure-function analysis, overview Escherichia coli
additional information an array of structurally diverse non-nucleobase derivatives has been designed, synthesized, and established as promising TP inhibitors, structure-function analysis, docking studies, overview. Analysis of oxadiazole and imidazolidine derivatives, pyrazolone and pyrazolo [1,5-a] [1,3,5]triazine analogues, 1,2,4-triazolo [1,5-a] [1,3,5]triazine analogues, quinazoline and quinoxaline derivatives, chromone and isocoumarin derivatives, and plant glycosides Homo sapiens
N-(4-oxo-2-sulfanylidene-8-[[4-(trifluoromethyl)phenyl]methyl]-1,2,3,4-tetrahydropyrazolo[1,5-a][1,3,5]triazin-7-yl)thiourea
-
Homo sapiens
N-(8-benzyl-4-oxo-2-sulfanylidene-1,2,3,4-tetrahydropyrazolo[1,5-a][1,3,5]triazin-7-yl)thiourea
-
Homo sapiens
symplocomoside
-
Homo sapiens
symponoside
-
Homo sapiens
TFT designated TAS-102 Homo sapiens
thymine the substrate is a non-competitive inhibitor of the enzyme Escherichia coli
thymine the substrate is a non-competitive inhibitor of the enzyme Homo sapiens
TP65
-
Escherichia coli
TP65
-
Homo sapiens
TPI
-
Homo sapiens
[2,4,5-trioxo-3-(2-phenylethyl)imidazolidin-1-yl]acetic acid
-
Homo sapiens
[3-[(2-methylphenyl)methyl]-2,4,5-trioxoimidazolidin-1-yl]acetic acid
-
Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
thymidine + phosphate Homo sapiens
-
thymine + 2-deoxy-alpha-D-ribose 1-phosphate
-
r
thymine + 2-deoxy-alpha-D-ribose 1-phosphate Escherichia coli
-
thymidine + phosphate
-
r

Organism

Organism UniProt Comment Textmining
Escherichia coli P0C037
-
-
Homo sapiens P19971
-
-

Source Tissue

Source Tissue Comment Organism Textmining
carcinoma cell the enzyme is highly upregulated in a variety of solid tumours Homo sapiens
-
endothelial cell
-
Homo sapiens
-
additional information thymidine phosphorylase (TP) expression is extremely low in healthy human tissues Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
thymidine + phosphate
-
Homo sapiens thymine + 2-deoxy-alpha-D-ribose 1-phosphate
-
r
thymine + 2-deoxy-alpha-D-ribose 1-phosphate
-
Escherichia coli thymidine + phosphate
-
r

Subunits

Subunits Comment Organism
homodimer 2 * 90000, SDS-PAGE Escherichia coli
homodimer 2 * 110000, SDS-PAGE Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.00004
-
pH and temperature not specified in the publication Homo sapiens 8-[4-(pentafluoro-lambda6-sulfanyl)phenyl]-2-sulfanylidene-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
0.00036
-
pH and temperature not specified in the publication Homo sapiens 5-chloro-6-[([4-oxo-8-[4-(pentafluoro-lambda6-sulfanyl)phenyl]-1,2,3,4-tetrahydropyrazolo[1,5-a][1,3,5]triazin-2-yl]sulfanyl)methyl]pyrimidine-2,4(1H,3H)-dione
0.0015
-
pH and temperature not specified in the publication Homo sapiens 7-(4-tert-butylphenyl)-2-[[(5-chloro-2-methylidene-6-oxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]sulfanyl]-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
0.0032
-
pH and temperature not specified in the publication Homo sapiens 5-[(E)-[2-(quinoxalin-2-yl)hydrazinylidene]methyl]benzene-1,2,4-triol
0.00382
-
pH and temperature not specified in the publication Homo sapiens N-(4-oxo-2-sulfanylidene-8-[[4-(trifluoromethyl)phenyl]methyl]-1,2,3,4-tetrahydropyrazolo[1,5-a][1,3,5]triazin-7-yl)thiourea
0.0066
-
pH and temperature not specified in the publication Homo sapiens 7-(4-tert-butylphenyl)-2-sulfanylidene-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
0.0097
-
pH and temperature not specified in the publication Homo sapiens 7-(4-tert-butylphenyl)-2-[[(5-chloro-2-methylidene-6-oxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]sulfanyl]-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
0.01084
-
pH and temperature not specified in the publication Homo sapiens 2-(3,4-dichlorophenyl)-5-sulfanylidene-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
0.013
-
pH and temperature not specified in the publication Homo sapiens 2-benzyl-5-sulfanylidene-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
0.013
-
pH and temperature not specified in the publication Homo sapiens 2-[(3,4-dichlorophenyl)methyl]-5-sulfanylidene-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
0.013
-
pH and temperature not specified in the publication Homo sapiens 2-[[(5-chloro-2-methylidene-6-oxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]sulfanyl]-7-phenyl-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
0.0144
-
pH and temperature not specified in the publication Homo sapiens 3-[(2-methoxy-6-nitroanilino)methyl]-5-(4-methylphenyl)-1,3,4-oxadiazole-2(3H)-thione
0.017
-
pH and temperature not specified in the publication Homo sapiens 6-amino-5-bromouracil
0.01977
-
pH and temperature not specified in the publication Homo sapiens 3-[(E)-[(3-methoxy-4-methylphenyl)imino]methyl]-4H-1-benzopyran-4-one
0.022
-
pH and temperature not specified in the publication Homo sapiens 4-[(Z)-[(3-hydroxynaphthalen-2-yl)methylidene]amino]-1,5-dimethyl-2-phenylpyrazolidin-3-one
0.0263
-
pH and temperature not specified in the publication Homo sapiens 8-phenyl-2-sulfanylidene-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
0.02992
-
pH and temperature not specified in the publication Homo sapiens N-(8-benzyl-4-oxo-2-sulfanylidene-1,2,3,4-tetrahydropyrazolo[1,5-a][1,3,5]triazin-7-yl)thiourea
0.035
-
pH and temperature not specified in the publication Homo sapiens TPI
0.03637
-
pH and temperature not specified in the publication Homo sapiens 2-(diphenylmethyl)-5-sulfanylidene-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
0.037
-
pH and temperature not specified in the publication Homo sapiens 3,3'-(1,3,4-oxadiazole-2,5-diyl)dipyridine
0.03824
-
pH and temperature not specified in the publication Homo sapiens 5-(4-hydroxyphenyl)-1,3,4-oxadiazole-2(3H)-thione
0.03956
-
pH and temperature not specified in the publication Homo sapiens 2-phenyl-5-sulfanylidene-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
0.04
-
pH and temperature not specified in the publication Homo sapiens 7-deazaxanthine
0.04
-
pH and temperature not specified in the publication Homo sapiens 3-[2,4,5-trioxo-3-(2-phenylethyl)imidazolidin-1-yl]propanamide
0.04029
-
pH and temperature not specified in the publication Homo sapiens 3-[(E)-[(2,4-dichlorophenyl)imino]methyl]-4H-1-benzopyran-4-one
0.04061
-
pH and temperature not specified in the publication Homo sapiens 3-[(3,4-dimethylanilino)methyl]-5-phenyl-1,3,4-oxadiazole-2(3H)-thione
0.0429
-
pH and temperature not specified in the publication Homo sapiens 2-(3,4-dihydroxyphenyl)quinazolin-4(3H)-one
0.044
-
pH and temperature not specified in the publication Homo sapiens (2R,3R,4S,5R)-9-(3,4-dihydroxy-5-trityloxymethyl-tetrahydrofuran-2-yl)-1,9-dihydropurin-6-one
0.0462
-
pH and temperature not specified in the publication Homo sapiens 2-phenylquinazolin-4(3H)-one
0.0462
-
pH and temperature not specified in the publication Homo sapiens 7-phenyl-2-sulfanylidene-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one
0.05
-
pH and temperature not specified in the publication Homo sapiens 5-phenyl-1,3,4-oxadiazole-2(3H)-thione
0.061
-
pH and temperature not specified in the publication Homo sapiens 3-[(2-methylphenyl)methyl]-1H-2-benzopyran-1-one
0.06545
-
pH and temperature not specified in the publication Homo sapiens symplocomoside
0.07
-
pH and temperature not specified in the publication Homo sapiens 6-aminothymine
0.085
-
pH and temperature not specified in the publication Homo sapiens [2,4,5-trioxo-3-(2-phenylethyl)imidazolidin-1-yl]acetic acid
0.088
-
pH and temperature not specified in the publication Homo sapiens 3-[3-[(2-methylphenyl)methyl]-2,4,5-trioxoimidazolidin-1-yl]propanamide
0.09505
-
pH and temperature not specified in the publication Homo sapiens 5-(methylsulfanyl)-2-phenyl-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
0.103
-
pH and temperature not specified in the publication Homo sapiens 1-(2-phenylethyl)imidazolidine-2,4,5-trione
0.106
-
pH and temperature not specified in the publication Homo sapiens 3-(3-benzyl-2,4,5-trioxoimidazolidin-1-yl)propanamide
0.1112
-
pH and temperature not specified in the publication Homo sapiens 5-(benzylsulfanyl)-2-phenyl-5,6-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one
0.115
-
pH and temperature not specified in the publication Homo sapiens 1-benzylimidazolidine-2,4,5-trione
0.128
-
pH and temperature not specified in the publication Homo sapiens 1-[(2-methylphenyl)methyl]imidazolidine-2,4,5-trione
0.22567
-
pH and temperature not specified in the publication Homo sapiens symponoside
0.236
-
pH and temperature not specified in the publication Homo sapiens [3-[(2-methylphenyl)methyl]-2,4,5-trioxoimidazolidin-1-yl]acetic acid
0.264
-
pH and temperature not specified in the publication Homo sapiens (3-benzyl-2,4,5-trioxoimidazolidin-1-yl)acetic acid
0.303
-
pH and temperature not specified in the publication Homo sapiens ethyl [3-[(2-methylphenyl)methyl]-2,4,5-trioxoimidazolidin-1-yl]acetate
0.342
-
pH and temperature not specified in the publication Homo sapiens ethyl (3-benzyl-2,4,5-trioxoimidazolidin-1-yl)acetate
0.357
-
pH and temperature not specified in the publication Homo sapiens ethyl [2,4,5-trioxo-3-(2-phenylethyl)imidazolidin-1-yl]acetate

Expression

Organism Comment Expression
Homo sapiens the enzyme is highly upregulated in a variety of solid tumours up

General Information

General Information Comment Organism
evolution the amino acid sequence of thymidine phosphorylase (TP) is extremely conserved. For instance, human TP shares 39% sequence identity with Escherichia coli TP Homo sapiens
evolution the amino acid sequence of thymidine phosphorylase (TP) is extremely conserved. For instance, human TP shares 39% sequence identity with Escherichia coli TP Escherichia coli
metabolism the intracellular catabolism of thymidine mediated via TP produces 2DDR-1P as a metabolic biproduct, which is subsequently converted to 2DDR by the nonenzymatic dephosphorylation. This 2DDR is then secreted from the cells to exhibit the angiogenic effects. Both TP and 2DDR directly stimulate the endothelial cell migration through the activation of focal adhesion kinase (FAK) and the formation of focal adhesions Escherichia coli
metabolism the intracellular catabolism of thymidine mediated via TP produces 2DDR-1P as a metabolic biproduct, which is subsequently converted to 2DDR by the nonenzymatic dephosphorylation. This 2DDR is then secreted from the cells to exhibit the angiogenic effects. Both TP and 2DDR directly stimulate the endothelial cell migration through the activation of focal adhesion kinase (FAK) and the formation of focal adhesions. TP and 2DDR roles in tumour development, overview Homo sapiens
physiological function thymidine phosphorylase (TP), an enzyme involved in pyrimidine salvage pathway, is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and gliostatin. The enzyme function in cancer development. TP activity is also shown to augment the levels of hypoxia-inducible factor (HIF)-1alpha during in vitro hypoxia in RT112 cells. Eventually, TP acts in concert with HIF-1a to induce VEGF secretion. Additionally, TP and VEGF are coexpressed in various human cancers and display a cooperative role in neovascularization. TP dramatically reduces the apoptotic index in various cancer cells. TP inactivates and eventually reduces the bioavailability of 5-trifluorothymidine (TFT), a clinically used anticancer drug Homo sapiens
physiological function thymidine phosphorylase (TP), an enzyme involved in pyrimidine salvage pathway, is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and gliostatin. TP activity is also shown to augment the levels of hypoxia-inducible factor (HIF)-1alpha during in vitro hypoxia in RT112 cells. Eventually, TP acts in concert with HIF-1a to induce VEGF secretion. Additionally, TP and VEGF are coexpressed in various human cancers and display a cooperative role in neovascularization. TP dramatically reduces the apoptotic index in various cancer cells Escherichia coli