SUMMARY

Transketolase proteins or transketolase enzyme activities have been related to neurodegenerative diseases, dia-betes, and cancer. Transketolase enzyme variants and reduced transketolase enzyme activities are present in pa-tients with the neurodegenerative disease Wernicke-Korsakoff syndrome. In Alzheimer’s disease patients trans-ketolase 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 pheno-mena have been interpreted solely on the basis of a single transketolase gene (TKT) encoding a single transketo-lase 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 demon-strate 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 an