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SUMMARY
Transketolase proteins or transketolase enzyme activities have been related to neurodegenerative diseases, diabetes,
and cancer. Transketolase enzyme variants and reduced transketolase enzyme activities are present in patients
with the neurodegenerative disease Wernicke-Korsakoff syndrome. In Alzheimer’s disease patients transketolase
protein variants with different isoelectric points or a proteolytic cleavage leading to small transketolase
protein isoforms have been identified. In diabetes mellitus patients reduced transketolase enzyme activities have
been detected and the lipid-soluble thiamine derivative benfotiamine activates transketolase enzyme reactions,
thereby blocking three major pathways of hyperglycemic damage and preventing diabetic retinopathy. In cancer
inhibition of transketolase enzyme reactions suppresses tumor growth and metastasis. All the observed phenomena
have been interpreted solely on the basis of a single transketolase gene (TKT) encoding a single transketolase
enzyme. No mutations have been identified so far in TKT transketolase explaining the altered transketolase
proteins or transketolase enzyme activities found in neurodegenerative diseases, diabetes and cancer. We demonstrate
the presence of a second transketolase enzyme (TKTL1) in humans. During the evolution of the vertebrate
genome, mutations in this transketolase gene (TKTL1) have led to tissue-specific transcripts different in size
which encode an enzymatically active transketolase protein as well as different smaller protein isoforms. The
mutations within the TKTL1 gene caused a mutant transketolase enzyme with an altered substrate specificity and
reaction modus. Here we characterize the TKTL1 gene and its encoded TKTL1 protein(s) and discuss the medical
and clinical implications of this mutated transketolase. We furthermore postulate a novel metabolic concept for
the understanding, prevention and therapy of neurodegenerative diseases, diabetes and cancer.
(Clin. Lab. 2005;51:257-273)
entnommen aus:
Mutations in the Transketolase-like Gene TKTL1:
Clinical Implications for Neurodegenerative Diseases,
Diabetes and Cancer
JOHANNES F. COY1,2,*, DIRK DRESSLER1, JUERGEN WILDE1, PETER SCHUBERT1
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