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.

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.