TYMP (thymidine phosphorylase)

2010-03-01   Irene V Bijnsdorp , Godefridus J Peters 

Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands





The TP gene encodes an angiogenic factor which promotes angiogenesis both in vitro and in vivo and is involved in nucleotide synthesis and thymidine phosphorolysis.
Atlas Image
TYMP is located on chromosome 22 of which 3 transcripts have been identified.


Thymidine phosphorylase is located at chromosome 22 in the region of q13.33. cDNA is approximately 1.8 kb long, consisting of 10 exons in a 4.3 kb region (Hagiwara et al., 1991; Stenman et al., 1992). TP was first cloned and sequenced in 1989 (Ishikawa et al., 1989). The nucleic acid sequence of TP is highly conserved, the human TP shares 39% sequence identity with that of E. coli (Barton et al., 1992).


The promoter region of the TP gene has no TATA box or CCAAT box, but has a high G-C content and seven copies of the SP-1 binding site upstream from the transcription start site. Exact TP gene regulation is unknown, but has been described to be (indirectly) regulated by NFkB, TNF-alpha and IFN-gamma (Waguri et al., 1997; Zhu et al., 2002; Zhu et al., 2003; Eda et al., 1993; de Bruin et al., 2004).



Thymidine phosphorylase was first identified as the platelet-derived endothelial cell growth factor, because it was related to endothelial cell growth (Miyazono et al., 1987; Ishikawa et al., 1989). Later on, it was found that it was identical to thymidine phosphorylase (Furukawa et al., 1992). Thymidine phosphorylase (TP) is the most correct name to refer to this protein, since it catalyzes the phopshorolysis of thymidine to thymine. TP undergoes limited post-translational modification and is not glycosylated. Covalent linkage between serine residues of TP and phosphate groups of nucleotides has been observed, which may facilitate secretion of the protein (Usuki et al., 1991). However, TP does not contain a classical secretion signal (Ishikawa et al., 1989). TP is a dimer, consisting of two identical subunits that are non-covalently associated (Desgranges et al., 1981) with its dimeric molecular mass ranging from 90 kD in Escherichia coli to 110 kD in mammals (Schwartz, 1978; Desgranges et al., 1981).


TP protein does not contain a known receptor binding region or a secretion signal (Ishikawa et al., 1989). It is implicated in nucleotide synthesis and degradation of thymidine. TP is also implicated in angiogenesis (reviewed in de Bruin et al., 2006; Liekens et al., 2007; Bronckaers et al., 2009).


TP is highly expressed in liver tissues. Furthermore, TP is often overexpressed in tumor sites and is involved in inflammatory diseases, such as rheumatoid arthritis.


TP is expressed in the cytoplasm and the nucleus (Fox et al., 1995).


TP catalyzes the phosphorolysis of thymidine (TdR) to thymine and 2-deoxy-alpha-D-ribose 1-phosphate (dR-1-P). TP can also catalyze the formation of thymidine from thymine and dR-1-P. TP also catalyzes the phosphorolysis of deoxyuridine to uracil and dR-1-P. TP also has deoxyribosyl transferase activity by which the deoxyribosyl moiety is transferred from a pyrimidine nucleoside to another pyrimidine base. Subsequently a new pyrimidine nucleoside is formed.
The sugars that are formed by degradation of thymidine are thought to play a role in the induction of angiogenesis. Deoxyribose-1-P can be converted to deoxyribose-5-phosphate or degraded to deoxyribose. Deoxyribose can be secreted, and possibly attract endothelial cells to form new blood vessels (reviewed in de Bruin et al., 2006; Liekens et al., 2007; Bronckaers et al., 2009). TP in some cancer cells can also increase their invasive potential, although the exact mechanism remains unclear.
TP can also activate or inactivate several pyrimidines or pyrimidine nucleoside analogs with antiviral and antitumoral activity, such as inactivation of trifluorothymidine (TFT) (Heidelberger et al., 1964) and 5-fluoro-2-deoxyruidine (van Laar et al., 1998), or activation of 5-fluorouracil (5-FU) (Schwartz et al., 1995) and 5-fluoro-5-deoxyuridine (5DFUR).


The TYMP gene is conserved in chimpanzee, mouse, rat, and zebrafish.



Mutations in this gene have been associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Multiple alternatively spliced variants, encoding the same protein, have been identified.

Implicated in

Entity name
Various cancer
TP in tumor sites can be expressed in the cancer cells, in the most malignant cells, tumor stromal cells (such as macrophages) or in the invasive part of the tumor (van Triest et al., 1999). A high TP expression and activity have been related to a poor outcome and increased angiogenesis. The TP gene is regulated by many other factors that are implicated in cancer, such as NFkB (de Bruin et al., 2004). TP regulates the expression of IL-8, and possibly also that of other genes, although the exact mechanism of this regulation is still unclear (Brown et al., 2000; Bijnsdorp et al., 2008). The high TP activity in the tumor can selectively activate the 5FU prodrug 5-deoxy-5-fluorouridine to 5FU. 5deoxy-5-fluorouridine is an intermediate of the oral 5FU prodrug Capecitabine (Xeloda) (de Bruin et al., 2006). On the other hand TP can inactivate the fluoropyrimidine trifluorothymidine (TFT), which is registered as the antiviral drug Viroptic® (De Clercq, 2004). An inhibitor of TP, TPI, will prevent inactivation of TFT. TAS-102 is a combination of TFT and TPI (in a molar ratio of 1:0.5) which is developed as an anticancer drug (Temmink et al., 2007).
Gastrointestinal tumors (Fox et al., 1995; Yoshikawa et al., 1999; Kimura et al., 2002; Takebayashi et al., 1996), breast cancer (Moghaddam et al., 1995), bladder cancer (OBrien et al., 1996).
High expression is often related to a poor prognosis, an increased microvessel density and increased metastasis.
Fusion protein
No fusion protein has been described.
Entity name
Rheumatoid arthritis
Elevated levels of (circulating) PD-ECGF (TP) were found in rheumatoid arthritis patients (Asai et al., 1993). In the sera and synovial fluids of patients suffering from rheumatoid arthritis PD-ECGF (TP) was detected at high levels (Asai et al., 1993). In addition, there was a significant positive correlation between PD-ECGF (TP) levels in synovial fluid and in serum (Asai et al., 1993). The elevated PD-ECGF (TP) levels presumably arise through induction of PD-ECGF (TP) in synoviocytes, resulting from aberrant production of cytokines like TNF-alpha and IL-1 (Waguri et al., 1997).
Entity name
TP is expressed in atherosclerosis. Macrophages, foam cells and giant cells from both aortic and coronary plaques expressed TP, suggesting that TP may play a role in the pathogenesis of atherosclerosis (Boyle et al., 2000).
Entity name
Increased PD-ECGF (TP) mRNA and immunoreactivity were found in lesional psoriasis compared to the non-lesional skin (Creamer et al., 1997). In another study it was reported that the thymidine phosphorylase activity was twenty-fold higher in psoriatic lesions than in normal skin (Hammerberg et al., 1991).
Entity name
Inflammatory bowel disease
In inflammatory bowel disease, TP has been found to be overexpressed, predominantly in macrophages and fibroblasts of the inflamed colonic mucosa. The grade of expression augmented with an increasing grade of inflammation. In addition, TP was found in the endothelial cells of the inflamed colonic mucosa (Giatromanolaki et al., 2003; Saito et al., 2003).
Entity name
Chronic glomerulonephritis
TP is upregulated in chronic glomerulonephritis (a renal disease characterized by inflammation of the glomeruli) where it probably plays a critical role in the progression of interstitial fibrosis (Wang et al., 2006).
Entity name
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)
An autosomal recessive disorder involving DNA alterations (Bardosi et al., 1987). Gene mutations in the TP gene include missense, splice sites microdeletions and single nucleotide insertions (Spinazzola et al., 2002; Nishino et al., 2000). These mutations are associated with a severe reduction in TP activity. This leads to increased thymidine plasma levels, and increased deoxyuridine levels (which is also a substrate for TP).
Not determined.


Pubmed IDLast YearTitleAuthors
75078051993High concentrations of immunoreactive gliostatin/platelet-derived endothelial cell growth factor in synovial fluid and serum of rheumatoid arthritis.Asai K et al
28235221987Myo-, neuro-, gastrointestinal encephalopathy (MNGIE syndrome) due to partial deficiency of cytochrome-c-oxidase. A new mitochondrial multisystem disorder.Bardosi A et al
13043671992Human platelet-derived endothelial cell growth factor is homologous to Escherichia coli thymidine phosphorylase.Barton GJ et al
186005262008The role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in tumor behavior.Bijnsdorp IV et al
110047012000Expression of angiogenic factor thymidine phosphorylase and angiogenesis in human atherosclerosis.Boyle JJ et al
194346932009The dual role of thymidine phosphorylase in cancer development and chemotherapy.Bronckaers A et al
111037872000Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors.Brown NS et al
94708991997Overexpression of the angiogenic factor platelet-derived endothelial cell growth factor/thymidine phosphorylase in psoriatic epidermis.Creamer D et al
151258672004Antiviral drugs in current clinical use.De Clercq E et al
72843781981Catabolism of thymidine in human blood platelets: purification and properties of thymidine phosphorylase.Desgranges C et al
83393821993Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5'-deoxy-5-fluorouridine.Eda H et al
76366281995Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in normal tissues: an immunohistochemical study.Fox SB et al
15700121992Angiogenic factor.Furukawa T et al
126101012003Hypoxia inducible factor 1alpha and 2alpha overexpression in inflammatory bowel disease.Giatromanolaki A et al
20059001991Organization and chromosomal localization of the human platelet-derived endothelial cell growth factor gene.Hagiwara K et al
20719391991Elevated thymidine phosphorylase activity in psoriatic lesions accounts for the apparent presence of an epidermal "growth inhibitor," but is not in itself growth inhibitory.Hammerberg C et al
24672101989Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor.Ishikawa F et al
120640132002Correlation between expression levels of thymidine phosphorylase (dThdPase) and clinical features in human gastric carcinoma.Kimura H et al
175723892007Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy.Liekens S et al
35497241987Purification and properties of an endothelial cell growth factor from human platelets.Miyazono K et al
75323081995Thymidine phosphorylase is angiogenic and promotes tumor growth.Moghaddam A et al
108525452000Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.Nishino I et al
88410011996Expression of the angiogenic factor thymidine phosphorylase/platelet-derived endothelial cell growth factor in primary bladder cancers.O'Brien TS et al
126734452003Expression of platelet-derived endothelial cell growth factor in inflammatory bowel disease.Saito S et al
76425711995Thymidine phosphorylase mediates the sensitivity of human colon carcinoma cells to 5-fluorouracil.Schwartz EL et al
3579041978Thymidine phosphorylase from Escherichia coli.Schwartz M et al
117335402002Altered thymidine metabolism due to defects of thymidine phosphorylase.Spinazzola A et al
17336671992Regional localization of the human platelet-derived endothelial cell growth factor (ECGF1) gene to chromosome 22q13.Stenman G et al
87582581996The activity and expression of thymidine phosphorylase in human solid tumours.Takebayashi Y et al
81856931994Aberrant production of gliostatin/platelet-derived endothelial cell growth factor in rheumatoid synovium.Takeuchi M et al
174419632007Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies.Temmink OH et al
19391031991Covalent linkage between nucleotides and platelet-derived endothelial cell growth factor.Usuki K et al
91339621997Gliostatin/platelet-derived endothelial cell growth factor as a clinical marker of rheumatoid arthritis and its regulation in fibroblast-like synoviocytes.Waguri Y et al
162826982006Upregulation of thymidine phosphorylase in chronic glomerulonephritis and its role in tubulointerstitial injury.Wang EH et al
100987491999Thymidine phosphorylase/platelet-derived endothelial cell growth factor is upregulated in advanced solid types of gastric cancer.Yoshikawa T et al
124669672002The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells.Zhu GH et al
145737752003Expression of the angiogenic factor thymidine phosphorylase in THP-1 monocytes: induction by autocrine tumor necrosis factor-alpha and inhibition by aspirin.Zhu GH et al
96402131998Comparison of 5-fluoro-2'-deoxyuridine with 5-fluorouracil and their role in the treatment of colorectal cancer.van Laar JA et al
107417352000Prognostic role of thymidylate synthase, thymidine phosphorylase/platelet-derived endothelial cell growth factor, and proliferation markers in colorectal cancer.van Triest B et al

Other Information

Locus ID:

NCBI: 1890
MIM: 131222
HGNC: 3148
Ensembl: ENSG00000025708


dbSNP: 1890
ClinVar: 1890
TCGA: ENSG00000025708


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Pyrimidine metabolismKEGGko00240
Drug metabolism - other enzymesKEGGko00983
Bladder cancerKEGGko05219
Pyrimidine metabolismKEGGhsa00240
Drug metabolism - other enzymesKEGGhsa00983
Bladder cancerKEGGhsa05219
Metabolic pathwaysKEGGhsa01100
Metabolism of nucleotidesREACTOMER-HSA-15869
Pyrimidine metabolismREACTOMER-HSA-73848
Pyrimidine salvage reactionsREACTOMER-HSA-73614
Pyrimidine catabolismREACTOMER-HSA-73621

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
128130272003Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency.43
190231332009Proteomics identifies thymidine phosphorylase as a key regulator of the angiogenic potential of colony-forming units and endothelial progenitor cell cultures.39
124299832002Microvessel density, mast cell density and thymidine phosphorylase expression in oral squamous carcinoma.35
187255952008Carrier erythrocyte entrapped thymidine phosphorylase therapy for MNGIE.25
193300192009Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells.18
272839042016Systemic immune-inflammation index, thymidine phosphorylase and survival of localized gastric cancer patients after curative resection.18
126399652003Thymidine phosphorylase and 2-deoxyribose stimulate human endothelial cell migration by specific activation of the integrins alpha 5 beta 1 and alpha V beta 3.17
185596002008Heterogeneous ribonucleoprotein k and thymidine phosphorylase are independent prognostic and therapeutic markers for nasopharyngeal carcinoma.17
213868402011Thymidine phosphorylase in cancer cells stimulates human endothelial cell migration and invasion by the secretion of angiogenic factors.16


Irene V Bijnsdorp ; Godefridus J Peters

TYMP (thymidine phosphorylase)

Atlas Genet Cytogenet Oncol Haematol. 2010-03-01

Online version: http://atlasgeneticsoncology.org/gene/40397/tymp-(thymidine-phosphorylase)