Altered Thymidine Metabolism Due to Defects of Thymidine Phosphorylase

Mitochondrialneurogastrointestinalencephalomyopathy (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 thymidin...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2002-02, Vol.277 (6), p.4128-4133
Main Authors: Spinazzola, Antonella, Marti, Ramon, Nishino, Ichizo, Andreu, Antonio L., Naini, Ali, Tadesse, Saba, Pela, Ivana, Zammarchi, Enrico, Donati, M. Alice, Oliver, Juan A., Hirano, Michio
Format: Article
Language:English
Subjects:
Cells, Cultured
Chromosomes, Human, Pair 22
Humans
Mitochondrial Myopathies - genetics
Mitochondrial Myopathies - metabolism
Mutation
Thymidine
Thymidine - metabolism
Thymidine Phosphorylase - genetics
Thymidine Phosphorylase - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Mitochondrialneurogastrointestinalencephalomyopathy (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 ∼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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111028200