Isotopic and other studies on the molecular origins of substrate regulation of some pyruvate decarboxylases: a reconsideration†

Solvent isotope effect and beta-secondary isotope effect studies of the steady-state reaction of the pyruvate decarboxylase of Saccharomyces cerevisiae (ScPDC), which gains its full activity in a process requiring some seconds, suggested a model that ascribed the isotope effects to a reversible carbonyl-addition reaction between the 'regulatory pyruvate' molecule and the sulfhydryl group of Cys 221, occurring at the beginning and end of each catalytic cycle. The slow ('hysteretic') regulatory activation was thought to consist only of binding the regulatory molecule properly. Since the proposal of this model, much important progress in understanding both the structural and dynamic chemistry of ScPDC has been made in several laboratories. The purpose of this article is to review this new information and to evaluate the above model and others in the light of currently available evidence.