Official Full Name
Thymidine Phosphorylase
Background
An enzyme that catalyzes the reversible conversion of thymidine to thymine. Thymidine phosphorylase is part of the pyrimidine nucleoside salvage pathway. This pathway allows pyrimidine bases to be recycled for nucleotide biosynthesis, while the pentose 1-phosphates are converted to intermediates of the pentose phosphate shunt and glycolysis. The E. coli thymidine phosphorylase shares 40% sequence homology with the human sequence, which has been found to be identical to the angiogenic agent platelet-derived endothelial growth factor. The purified E. coli enzyme has been shown to stimulate blood vessel growth in chick chorioallantoic membrane assays.
Synonyms
thymidine phosphorylase; pyrimidine phosphorylase; thymidine-orthophosphate deoxyribosyltransferase; animal growth regulators# blood platelet-derived endothelial cell growth factors; blood platelet-derived endothelial cell growth factor; deoxythymidine phosphorylase; gliostatins; pyrimidine deoxynucleoside phosphorylase; thymidine:phosphate deoxy-D-ribosyltransferase; EC 2.4.2.4; 9030-23-3
Introductions
Thymidine Phosphorylase (TP) belongs to the family of glycosyltransferases, specifically the pentosyltransferases. Thymidine phosphorylase is involved in purine metabolism, pyrimidine metabolism and other metabolic pathways. Variations in thymidine phosphorylase and the TYMP gene encoding it have been associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) syndrome and bladder cancer.
Structure
TP is a homodimeric enzyme with a molecular weight of approximately 48 kDa. the structure of TP has been extensively studied and consists of two structural domains: an N-terminal domain and a C-terminal domain. the active site of TP is located in the cleft between these two structural domains, which allows it to accommodate thymidine and other substrates. The active site contains several amino acids that are essential for the catalytic activity of TP, including histidine, aspartate and serine.
Mechanism
Thymidine phosphorylase catalyzes the reversible phosphorylation of thymidine, deoxyuridine and their analogs (except deoxycytidine) to their respective bases (thymine/uracil) and 2-deoxyribose 1-phosphate. The enzyme follows a sequential mechanism, with the phosphate binding before the thymidine (or deoxyuridine, etc.) and the 2-deoxyribose 1-phosphate leaving after the nitrogenous base. Thymidine binds in a high-energy conformation, where the glycosidic bond weakens as the phosphate attacks the C1 position of the ribose ring. The enzyme can then transfer 1-phosphate deoxyribose to other nitrogenous bases.
Function
Thymidine phosphorylase plays a key role in pyrimidine salvage in order to restore nucleosides after DNA/RNA degradation. Although the reaction it catalyzes between thymidine/deoxyuridine and their respective bases is reversible, the function of the enzyme is mainly to catabolize.
Applications
TP has various applications in various fields, including cancer therapy and diagnostic imaging. one important application of TP is in cancer therapy, where it is used as a target for chemotherapy. Several nucleoside analogs, including 5-FU and capecitabine, are used to treat various types of cancer, including breast and colon cancers. These drugs are converted to their active forms by TP and are subsequently incorporated into DNA, causing DNA damage and cell death. In addition, TP is used for diagnostic imaging with positron emission tomography (PET) scans.
Clinical significance
Thymidine phosphorylase has also been found to play a dual role in the development and treatment of cancer. The angiogenic activity of this enzyme promotes tumor growth, and studies have shown that thymidine phosphorylase is much more highly expressed and active in malignant tumors (including cancers of the esophagus, stomach, colorectum, pancreas, and lung) than in adjacent non-tumor tissues. Thymidine phosphorylase in these carcinomas is upregulated by the cytokines interferon-γ and TNF-α, which are released by inflammatory cells during wound healing. The enzyme is also upregulated by low oxygen levels and low pH environments to control vascularization in hypoxic regions.
Conclusions
In conclusion, thymidine phosphorylase is an important enzyme involved in the metabolism of thymidine and folate. TP can be applied in cancer therapy and diagnostic imaging, and it has clinical implications in cancer progression and drug resistance. In addition, TP has been implicated in various inflammatory diseases, suggesting that inhibition of TP may be a potential therapeutic strategy for these diseases. Studies of TP continue to provide insights into the mechanisms of cancer and inflammation, with potential implications for the development of new therapies.
