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Literature summary for 2.4.2.4 extracted from

  • Bronckaers, A.; Gago, F.; Balzarini, J.; Liekens, S.
    The dual role of thymidine phosphorylase in cancer development and chemotherapy (2009), Med. Res. Rev., 29, 903-953.
    View publication on PubMed

Activating Compound

Activating Compound Comment Organism Structure
additional information the enzyme is activated in several diseases, detailed overview Homo sapiens

Application

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 (Commentary)

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

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

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

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 [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/ Products (Substrates)

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

Organism UniProt Comment Textmining
Escherichia coli
-
-
-
Geobacillus stearothermophilus
-
-
-
Homo sapiens
-
-
-
Mus musculus
-
-
-
Rattus norvegicus
-
-
-
Salmonella enterica subsp. enterica serovar Typhimurium
-
-
-

Posttranslational Modification

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 (Commentary)

Purification (Comment) Organism
native enzyme Salmonella enterica subsp. enterica serovar Typhimurium
native enzyme Escherichia coli

Source Tissue

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 and Products (Substrate)

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

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

Synonyms Comment Organism
gliostatin
-
Homo sapiens
PD-ECGF
-
Homo sapiens
platelet-derived endothelial cell growth factor
-
Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.000035
-
-
Homo sapiens 5-chloro-6-[1-(2-iminopyrrolidinyl)methyl]uracil

Expression

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

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