Regulation of glycogen synthase from mammalian skeletalmuscle – a unifying view of allosteric and covalentregulation

摘要

It is widely accepted that insufficient insulin-stimulated activation of muscleglycogen synthesis is one of the major components of non-insulindependent(type 2) diabetes mellitus. Glycogen synthase, a key enzyme inmuscle glycogen synthesis, is extensively regulated, both allosterically (byglucose-6-phosphate, ATP, and others) and covalently (by phosphorylation).Although glycogen synthase has been a topic of intense study formore than 50 years, its kinetic characterization has been confounded by itslarge number of phosphorylation states. Questions remain regarding thefunction of glycogen synthase regulation and the relative importance ofallosteric and covalent modification in fulfilling this function. In thisreview, we consider both earlier kinetic studies and more recent site-directedmutagenesis and crystal structure studies in a detailed qualitative discussionof the effects of regulation on the kinetics of glycogen synthase.We propose that both allosteric and covalent modification of glycogen synthasemay be described by a Monod–Wyman–Changeux model in terms ofapparent changes to L, the equilibrium constant for transition between theT and R conformers. As, with the exception of L, all parameters of thismodel are independent of the glycogen synthase phosphorylation state, theneed 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 relationshipbetween phosphorylation and the kinetics of glycogen synthase areessential in order to obtain a better quantitative understanding of the functionof glycogen synthesis regulation. The model we propose may proveuseful in this regard.