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The Thiamine-Dependent Hysteretic Behavior of Human Transketolase: Implications for Thiamine Deficiency^1,2,

Charles K. Singleton³, Stevan R. Pekovich, Brian A. McCool and Peter R. Martin^*

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

We have investigated the hysteretic properties of human transketolase with emphasis on its dependency on thiamine pyrophosphate concentration. As demonstrated previously, the reaction progress curves revealed a slow transition from an initial low velocity to a faster final steady-state velocity, characterized by the rate constant ^-1. The rate of the transition was dependent on the concentration of the thiamine pyrophosphate cofactor, with progressively longer transition times found as the concentration of thiamine pyrophosphate was decreased. At physiological thiamine pyrophosphate concentrations, the inverse rate constant was in the range of 10 to 20 min for fibroblast-derived transketolase and increased dramatically with only small decreases from these levels of thiamine pyrophosphate. Variation in the lag was found when transketolase from different individuals was examined. Moreover, at low levels of thiamine, the rate of the transition was different between fibroblast- and lymphoblast-derived transketolase. The substantial lag in formation of active holoenzyme and the findings of interindividual variation and cell type variation in the lag period suggest mechanisms for the loss of transketolase activity during thiamine deficiency and may explain, at least in part, the differential sensitivity to deficiency demonstrated by tissues and individuals.

KEY WORDS: • thiamine pyrophosphate • transketolase • thiamine deficiency • hysteresis • humans

¹ Supported by grant AA08492 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 26 April 1994. Revision accepted 2 August 1994.