Activating Compound | Comment | Organism | Structure |
---|---|---|---|
additional information | the enzyme is activated in several diseases, detailed overview | Homo sapiens |
Application | Comment | Organism |
---|---|---|
medicine | thymidine phosphorylase is a promising target for the treatment of vascular obstructive diseases, effect on cancer cells, detailed overview | Homo sapiens |
Crystallization (Comment) | Organism |
---|---|
X-ray diffraction structure determination and analysis of the free enzyme at 3.5 A resolution, and of the in complex with the small and potent inhibitor 5-chloro-6-[1-(2-iminopyrrolidinyl)methyl] uracil at 2.1 A resolution | Homo sapiens |
Protein Variants | Comment | Organism |
---|---|---|
D203A | site-directed mutagenesis, the mutant shows 60% reduced phosphorolytic activity compared to the wild-type enzyme. The mutant is inhibited by 6-aminothymine 6-amino-5-bromouracil, like the wild-type enzyme, but not by 5'-O-tritylinosine, in contrast to the wild-type enzyme | Homo sapiens |
K115E | inactive mutant | Homo sapiens |
additional information | downregulation of the enzyme by siRNA. Double knockout mutant cells, TP-/-UP-/-, lacking thymidine phosphorylase and uridine phosphorylase activities, show 100fold higher thymidine levels than the wild-type | Homo sapiens |
additional information | generation of double knockout mutant mice, TP-/-UP-/-, lacking thymidine phosphorylase and uridine phosphorylase activities, the mutant plasma thymidine levels are 5fold higher than in wild-type, but no alterations in mtDNA or pathological changes in the muscles occur in the knockout mice. Only in the brain, mitochondrial DNA depletion, respiratory chain defects and histological alterations, brain-specific phenotype, overview | Mus musculus |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
5'-O-tritylinosine | i.e. KIN59, a small-molecule inhibitor. KIN59 not only prevents the formation of new blood vessels but also promotes the degradation of small pre-existing immature blood vessels, not due to unspecific cell toxicity | Homo sapiens | |
5-amino-6-chlorouracil | - |
Homo sapiens | |
5-amino-6-chlorouracil | - |
Mus musculus | |
5-chloro-6-[1-(2-iminopyrrolidinyl)methyl] uracil | - |
Mus musculus | |
5-chloro-6-[1-(2-iminopyrrolidinyl)methyl]uracil | - |
Homo sapiens | |
6-amino-5-bromouracil | - |
Homo sapiens | |
6-amino-5-bromouracil | - |
Mus musculus | |
6-aminothymine | - |
Homo sapiens | |
6-aminothymine | - |
Mus musculus | |
7-deazaxanthine | - |
Escherichia coli | |
additional information | enzyme inhibitors can abrogate the tumorigenic and metastatic properties of the enzyme, e.g. 2-deoxy-L-ribose, which does not inhibit the enzyme but affects its biological functions | Homo sapiens |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
cytoplasm | - |
Homo sapiens | 5737 | - |
additional information | the mechanism behind the secretion of thymidine phosphorylase is possibly a posttranslational process whereby serine residues of the enzyme are covalently linked to phosphate groups of nucleotides, leading to the formation of a nucleotidylated protein that can be secreted | Homo sapiens | - |
- |
nucleus | - |
Homo sapiens | 5634 | - |
Molecular Weight [Da] | Molecular Weight Maximum [Da] | Comment | Organism |
---|---|---|---|
90000 | - |
2 * 90000 | Escherichia coli |
110000 | - |
2 * 110000 | Mus musculus |
110000 | - |
2 * 110000 | Homo sapiens |
110000 | - |
2 * 110000, about | Rattus norvegicus |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
5-fluorouracil + 2-deoxy-alpha-D-ribose 1-phosphate | Homo sapiens | the enzyme converts 5-fluorouracil to 5-fluoro-2'-deoxyuridine, activating the prodrug, overview. This action can only take place if there is enough co-substrate. 5-Fluorouracil prodrugs and metabolism, detailed overview | 5-fluoro-2'-deoxyuridine + phosphate | 5-fluoro-2'-deoxyuridine is further converted by thymidine kinase to 5-fluoro-2'-deoxyuridine 5'-monophosphate | ? | |
additional information | Homo sapiens | the enzyme stimulates formation of focal adhesions and the phosphorylation of Tyr397 of focal adhesion kinase, and it induces the expression and/or secretion of other angiogenic factors, overview. Thymidine phosphorylase promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis, detailed overview. As gliostatin from fibroma cells, the enzyme inhibits the growth of both astrocytes and glial tumor cells | ? | - |
? | |
thymidine + phosphate | Salmonella enterica subsp. enterica serovar Typhimurium | - |
thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r | |
thymidine + phosphate | Mus musculus | - |
thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r | |
thymidine + phosphate | Escherichia coli | - |
thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r | |
thymidine + phosphate | Homo sapiens | - |
thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r | |
thymidine + phosphate | Rattus norvegicus | - |
thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r | |
thymidine + phosphate | Geobacillus stearothermophilus | - |
thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Escherichia coli | - |
- |
- |
Geobacillus stearothermophilus | - |
- |
- |
Homo sapiens | - |
- |
- |
Mus musculus | - |
- |
- |
Rattus norvegicus | - |
- |
- |
Salmonella enterica subsp. enterica serovar Typhimurium | - |
- |
- |
Posttranslational Modification | Comment | Organism |
---|---|---|
additional information | the mechanism behind the secretion of thymidine phosphorylase is possibly a posttranslational process whereby serine residues of the enzyme are covalently linked to phosphate groups of nucleotides, leading to the formation of a nucleotidylated protein that can be secreted | Homo sapiens |
proteolytic modification | two alternative enzyme forms, a 27 kDa splice variant and another form containing five additional amino acids on the N-terminus, the second form is processed at Thr6 instead of Ala11 | Homo sapiens |
Purification (Comment) | Organism |
---|---|
native enzyme | Salmonella enterica subsp. enterica serovar Typhimurium |
native enzyme | Escherichia coli |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
A-431 cell | - |
Homo sapiens | - |
bladder | - |
Homo sapiens | - |
blood platelet | very high expression level | Homo sapiens | - |
brain | - |
Mus musculus | - |
brain | - |
Homo sapiens | - |
breast cancer cell | - |
Homo sapiens | - |
carcinoma cell | diverse cancer types, overview | Homo sapiens | - |
cervical carcinoma cell | - |
Homo sapiens | - |
Colo-320 cell | - |
Homo sapiens | - |
colorectal carcinoma cell | - |
Homo sapiens | - |
endometrium | thymidine phosphorylase shows a characteristic pattern of distribution dependent on the phase of the menstrual cycle: enzyme expression moves from stroma to epithelium as the cycle progresses34 and is inversely correlated with estradiol concentrations | Homo sapiens | - |
endothelial cell | - |
Homo sapiens | - |
epithelium | - |
Homo sapiens | - |
esophagus | - |
Homo sapiens | - |
fibroblast | - |
Homo sapiens | - |
glial cell | - |
Homo sapiens | - |
KB cell | epidermoid | Homo sapiens | - |
KK-47 cell | - |
Homo sapiens | - |
lung | - |
Homo sapiens | - |
lymph | - |
Homo sapiens | - |
lymphocyte | - |
Homo sapiens | - |
macrophage | very high expression level | Homo sapiens | - |
MKN-74 cell | - |
Homo sapiens | - |
additional information | the enzyme is upregulated in a wide variety of solid tumors including breast and colorectal cancers, association of the enzyme with tumor grade is evident in bladder, cervical, and renal cell cancer, but not in the other investigated cancers, in most cases, the enzyme appeared to be associated with poor prognosis, overview | Homo sapiens | - |
neurofibroma cell | - |
Homo sapiens | - |
neuron | cortical | Rattus norvegicus | - |
PC-3 cell | - |
Homo sapiens | - |
placenta | high expression level, two alternative enzyme forms, a 27 kDa splice variant and another form containing five additional amino acids on the N-terminus, the second form is processed at Thr6 instead of Ala11 | Homo sapiens | - |
rectum | - |
Homo sapiens | - |
reticulocyte | - |
Homo sapiens | - |
RT-112 cell | - |
Homo sapiens | - |
salivary gland | - |
Homo sapiens | - |
spleen | - |
Homo sapiens | - |
stromal cell | - |
Homo sapiens | - |
synoviocyte | rheumatoid athritis-associated | Homo sapiens | - |
umbilical vein endothelial cell | - |
Homo sapiens | - |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
5-fluorouracil + 2-deoxy-alpha-D-ribose 1-phosphate | the enzyme converts 5-fluorouracil to 5-fluoro-2'-deoxyuridine, activating the prodrug, overview. This action can only take place if there is enough co-substrate. 5-Fluorouracil prodrugs and metabolism, detailed overview | Homo sapiens | 5-fluoro-2'-deoxyuridine + phosphate | 5-fluoro-2'-deoxyuridine is further converted by thymidine kinase to 5-fluoro-2'-deoxyuridine 5'-monophosphate | ? | |
5-fluorouracil + 2-deoxy-alpha-D-ribose 1-phosphate | the enzyme converts 5-fluorouracil to 5-fluoro-2'-deoxyuridine, activating the prodrug, overview. This action can only take place if there is enough co-substrate | Homo sapiens | 5-fluoro-2'-deoxyuridine + phosphate | - |
? | |
additional information | the enzyme stimulates formation of focal adhesions and the phosphorylation of Tyr397 of focal adhesion kinase, and it induces the expression and/or secretion of other angiogenic factors, overview. Thymidine phosphorylase promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis, detailed overview. As gliostatin from fibroma cells, the enzyme inhibits the growth of both astrocytes and glial tumor cells | Homo sapiens | ? | - |
? | |
additional information | closing/opening motion in the presence of substrate, product, and transition state, molecular dynamic simulation | Geobacillus stearothermophilus | ? | - |
? | |
thymidine + phosphate | - |
Salmonella enterica subsp. enterica serovar Typhimurium | thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r | |
thymidine + phosphate | - |
Mus musculus | thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r | |
thymidine + phosphate | - |
Escherichia coli | thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r | |
thymidine + phosphate | - |
Homo sapiens | thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r | |
thymidine + phosphate | - |
Rattus norvegicus | thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r | |
thymidine + phosphate | - |
Geobacillus stearothermophilus | thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r | |
thymidine + phosphate | Asp203 plays an important role for loop stabilization required for efficient enzyme catalysis | Homo sapiens | thymine + 2-deoxy-alpha-D-ribose 1-phosphate | - |
r |
Subunits | Comment | Organism |
---|---|---|
homodimer | 2 * 90000 | Escherichia coli |
homodimer | 2 * 110000 | Mus musculus |
homodimer | 2 * 110000 | Homo sapiens |
homodimer | 2 * 110000, about | Rattus norvegicus |
More | each subunit contains a large mixed alpha-helical and beta-sheet domain, separated from a smaller alpha-helical domain by a large cleft. The active site consists of the thymine-binding site in the alpha-domain and the phosphate-binding site across the cleft in the a/b domain | Escherichia coli |
Synonyms | Comment | Organism |
---|---|---|
gliostatin | - |
Homo sapiens |
PD-ECGF | - |
Homo sapiens |
platelet-derived endothelial cell growth factor | - |
Homo sapiens |
IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
---|---|---|---|---|---|
0.000035 | - |
- |
Homo sapiens | 5-chloro-6-[1-(2-iminopyrrolidinyl)methyl]uracil |
Organism | Comment | Expression |
---|---|---|
Homo sapiens | the enzyme expression is is inversely correlated with estradiol concentrations in the endometrium | down |
Homo sapiens | chorionic gonadotropin36 and a combination of progesterone and transforming growth factor b1 upregulate the enzyme expression. The enzyme is also upregulated in several diseases, detailed overview | up |
General Information | Comment | Organism |
---|---|---|
malfunction | a loss-of-function mutation is involved in mitochondrial neurogastrointestinal encephalomyopathy, an autosomal recessive human disorder associated with multiple deletions of skeletal muscle mitochondrial DNA, overview. Corrleation of tumor development and progression with intratumoral thymidine phsophorylase levels, overview | Homo sapiens |
metabolism | the enzyme is the key enzyme of the pyrimidine salvage pathway | Homo sapiens |
physiological function | the enzyme plays an important role in the female reproductive cycle, and is also involved in a wide variety of chronic inflammatory diseases. Dual role of thymidine phosphorylase in cancer development and chemotherapy, acts as thymidine salvage enzyme and as platelet-derived endothelial cell growth factor inducing endothelial cell migration in vitro and angiogenesis in vivo, overview. The enzyme promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis. The enzyme is also indispensable for the activation of the extensively used 5-fluorouracil prodrug capecitabine. Role of thymidine phosphorylase in angiogenesis, mediators are matrix metalloproteinases, interleukin-8, P-selectin, and vascular epithelial growth factor, detailed overview | Homo sapiens |
physiological function | the enzyme promotes the survival and neurite outgrowth of cortical neurons | Rattus norvegicus |