Altered thymidine metabolism due to defects of thymidine phosphorylase.

TitleAltered thymidine metabolism due to defects of thymidine phosphorylase.
Publication TypeJournal Article
Year of Publication2002
AuthorsSpinazzola, A, Martí, R, Nishino, I, Andreu, AL, Naini, A, Tadesse, S, Pela, I, Zammarchi, E, M Donati, A, Oliver, JA, Hirano, M
JournalJ Biol Chem
Date Published2002 Feb 08
KeywordsCells, Cultured, Chromosomes, Human, Pair 22, Humans, Mitochondrial Myopathies, Mutation, Thymidine, Thymidine Phosphorylase

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive human disease due to mutations in the thymidine phosphorylase (TP) gene. TP enzyme catalyzes the reversible phosphorolysis of thymidine to thymine and 2-deoxy-D-ribose 1-phosphate. We present evidence that thymidine metabolism is altered in MNGIE. TP activities in buffy coats were reduced drastically in all 27 MNGIE patients compared with 19 controls. All MNGIE patients had much higher plasma levels of thymidine than normal individuals and asymptomatic TP mutation carriers. In two patients, the renal clearance of thymidine was approximately 20% that of creatinine, and because hemodialysis demonstrated that thymidine is ultrafiltratable, most of the filtered thymidine is likely to be reabsorbed by the kidney. In vitro, fibroblasts from controls catabolized thymidine in medium; by contrast, MNGIE fibroblasts released thymidine. In MNGIE, severe impairment of TP enzyme activity leads to increased plasma thymidine. In patients who are suspected of having MNGIE, determination of TP activity in buffy coats and thymidine levels in plasma are diagnostic. We hypothesize that excess thymidine alters mitochondrial nucleoside and nucleotide pools leading to impaired mitochondrial DNA replication, repair, or both. Therapies to reduce thymidine levels may be beneficial to MNGIE patients.

Alternate JournalJ. Biol. Chem.
Citation Key10.1074/jbc.M111028200
PubMed ID11733540
Grant ListHD37529 / HD / NICHD NIH HHS / United States