Thymidylate phosphorylase (TP)

Thymidylate phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), is a cytosolic enzyme that plays a dual role as a metabolic catalyst and a potent angiogenic factor [1, 2]. It is responsible for the reversible phosphorolysis of thymidine to thymine and 2-deoxy-D-ribose-1-phosphate, a key step in the pyrimidine salvage pathway [1]. In many solid tumors, TP is significantly upregulated, where it promotes tumor growth, survival, and metastasis by stimulating the formation of new blood vessels [4]. This high expression is strategically exploited in oncology; TP is the essential enzyme that converts the oral prodrug capecitabine into its active cytotoxic form, 5-fluorouracil, specifically within the tumor microenvironment [3, 4]. Conversely, TP inhibitors such as tipiracil are used in combination therapies to prevent the rapid degradation of nucleoside analogs like trifluridine, thereby sustaining therapeutic drug concentrations [3]. Beyond its role in cancer, loss-of-function mutations in the TYMP gene lead to mitochondrial neurogastrointestinal encephalopathy (MNGIE), a rare disorder where the accumulation of thymidine causes mitochondrial DNA instability [2, 5].

Other names

Platelet-derived endothelial cell growth factorPD-ECGFGliostatinTYMPThymidine phosphorylaseEC 2.4.2.4TdRPase

Thymidylate phosphorylase catalyzes the reversible phosphorolysis of thymidine to thymine and 2-deoxy-D-ribose-1-phosphate [1, 2]. In cancer therapy, it acts as a metabolic activator for fluoropyrimidine prodrugs like capecitabine, performing the final conversion step into the active drug 5-fluorouracil [3]. Additionally, TP inhibitors like tipiracil are used to block the catabolism of active nucleoside analogs (e.g., trifluridine), increasing their bioavailability and anti-tumor activity [3]. The enzyme also promotes angiogenesis through its catalytic product, 2-deoxy-D-ribose, which induces endothelial cell migration and tube formation [4].