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Thiamine Pyrophosphate-Requiring Enzymes are Altered during Pyrithiamine-Induced Thiamine Deficiency in Cultured Human Lymphoblasts^1,2,

Department of Molecular Biology ^* Department of Psychiatry, Vanderbilt University, Nashville, TN 37235

The most common of the severe complications of thiamine deficiency are beriberi and Wernicke-Korsakoff syndrome. To help clarify the biochemical basis for these disorders, a cell culture system has been established in which pyrithiamine, a potent thiamine transport inhibitor, was used to mimic different degrees of thiamine deficiency within human lymphoblasts. Activities of both transketolase and -ketoglutarate dehydrogenase (-KGDH) decreased at the same rate and to roughly the same levels in response to thiamine deficiency within a given cell line. However, variation in sensitivity to thiamine deficiency, as judged by the relative percentage of loss of enzymatic activities, was found when different cell lines were compared. When exogenous thiamine pyrophosphate was added to the activity assays, differences between transketolase and -KGDH became readily apparent. Only 25% of the lost transketolase activity was present as apo-enzyme, whereas 70% of the lost -KGDH activity was present in the apo-enzyme form. For transketolase, the non-recoverable activity was due mainly to a decrease in the synthesis rate of the protein during thiamine deficiency, suggesting that thiamine has a direct effect on the expression of the transketolase gene and/or protein.

KEY WORDS: • humans • thiamine deficiency • transketolase • synthesis rate • -ketoglutarate dehydrogenase

¹ Supported by grant AA10433-01 from the National Institute on Alcohol Abuse and Alcoholism.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

³ To whom correspondence should be addressed.

Manuscript received 10 January 1996. Revision accepted 1 April 1996.