Variations in thymidine phosphorylase and the TYMP gene that encode it are associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) syndrome and bladder cancer.

The thymidine is bound in a high-energy conformation, in which the glycosidic bond weakens as the phosphate attacks the C1 position of the ribose ring, as shown below.

[2] Thymidine phosphorylase is a protein dimer with identical subunits – with a reported molecular weight of 90,000 daltons in Escherichia coli.

The terminal amino group of Lys-190, which forms a hydrogen bond with the 3′-hydroxyl of the thymidine ribose moiety is also in place to donate a proton to thymine N1 during the intermediate state.

[11] Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the thymidine phosphorylase (TP) gene.

In MNGIE disease, multiple deletions and depletion of mtDNA accumulate over time, leading to mitochondrial dysfunction.

[13] Symptoms of MNGIE disease include diarrhea and abdominal pain as a result of dysmotility, caused by neuromuscular dysfunction, as well as ptosis, ophthalmoparesis, peripheral neuropathy, and hearing loss.

[15] The enzyme's angiogenic activity promotes tumor growth, as supported by research showing much higher expression and activity of thymidine phosphorylase in malignant tumors (including carcinomas in the esophagus, stomach, colorectum, pancreas, and lung) than in adjacent non-neoplastic tissues [16] Thymidine phosphorylase in these carcinomas is up-regulated by cytokines interferon-γ and TNF-α, which are released by inflammatory cells during wound healing.