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Keywords:

  • crystal structure;
  • enzyme kinetics;
  • feedforward activation;
  • glucose-6-phosphate;
  • glycogen synthase;
  • Hill model;
  • Monod–Wyman–Changeux model;
  • phenomenological rate equation;
  • phosphorylation;
  • phosphorylation-dependent translocation

It is widely accepted that insufficient insulin-stimulated activation of muscle glycogen synthesis is one of the major components of non-insulin-dependent (type 2) diabetes mellitus. Glycogen synthase, a key enzyme in muscle glycogen synthesis, is extensively regulated, both allosterically (by glucose-6-phosphate, ATP, and others) and covalently (by phosphorylation). Although glycogen synthase has been a topic of intense study for more than 50 years, its kinetic characterization has been confounded by its large number of phosphorylation states. Questions remain regarding the function of glycogen synthase regulation and the relative importance of allosteric and covalent modification in fulfilling this function. In this review, we consider both earlier kinetic studies and more recent site-directed mutagenesis and crystal structure studies in a detailed qualitative discussion of the effects of regulation on the kinetics of glycogen synthase. We propose that both allosteric and covalent modification of glycogen synthase may be described by a Monod–Wyman–Changeux model in terms of apparent changes to L, the equilibrium constant for transition between the T and R conformers. As, with the exception of L, all parameters of this model are independent of the glycogen synthase phosphorylation state, the need to determine kinetic parameters for all possible states is eliminated; only the relationship between a particular state and L must be established. We conclude by suggesting that renewed efforts to characterize the relationship between phosphorylation and the kinetics of glycogen synthase are essential in order to obtain a better quantitative understanding of the function of glycogen synthesis regulation. The model we propose may prove useful in this regard.