Regulation of glycogen synthase from mammalian skeletal muscle – a unifying view of allosteric and covalent regulation

Abstract

It is widely accepted that insufficient insulin-stimulated activation of muscle glycogen synthesis is one of the major components of non-insulindependent (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.Abbreviations ADP-Glc, ADP-glucose; AMPK, AMP-activated protein kinase; AtGS, Agrobacterium tumefaciens glycogen synthase; CaMKII, calmodulindependent protein kinase II; CK1, casein kinase 1; CK2, casein kinase 2; D form, glucose-6-phosphate-dependent form of glycogen synthase; DYRK, dual-specificity tyrosine-phosphorylated and tyrosine-regulated protein kinase; EcGS, Escherichia coli glycogen synthase; G6P, glucose-6-phosphate; GP, glycogen phosphorylase; GS, glycogen synthase; GSK3, glycogen synthase kinase 3; I form, glucose-6-phosphate-independent form of glycogen synthase; MWC, Monod-Wyman-Changeux; p38MAPK, mitogen-activated protein kinase; PaGS, Pyrococcus abyssi glycogen synthase; PASK, Per/Arnt/Sim domain-containing protein kinase; PhK, phosphorylase kinase; PKA, cAMPdependent protein kinase; PP1, protein phosphatase 1; PP2A, protein phosphatase 2A; ScGS, Saccharomyces cerevisiae glycogen synthase; UDP-Glc, uridine diphosphate glucose.

Incorporating covalent and allosteric effects into rate equations: the case of muscle glycogen synthase

“…In a recent review of the kinetics and regulation of GS [13], we suggested that the available kinetic data of this enzyme are compatible with what is predicted for an MWC (Monod-Wyman-Changeux)-type enzyme in which allosteric and covalent modification alter the apparent equilibrium between the T (taut) and R (relaxed) conformations of the enzyme. The proposed model promises to simplify the kinetic characterization of GS significantly, because the effect of phosphorylation is described by a single parameter.…”

“…Of the three models we will here limit ourselves to the MWC model. We have previously argued [13] that both the Hill and Koshland-Némethy-Filmer models have features that are either incompatible with GS kinetics or result in equations that are too complex.…”

“…Justifications for these assumptions are discussed at length in our recent review of GS kinetics [13] and, for the sake of brevity, will not be dealt with here individually.…”

Double Knockout Mutants of Arabidopsis Grown under Normal Conditions Reveal that the Plastidial Phosphorylase Isozyme Participates in Transitory Starch Metabolism

“…Later, both starch and glycogen synthases have been discovered that utilize either ADPglucose or UDPglucose (or both; Deschamps et al, 2006) as hexosyl donor. Ample evidence has been presented that these enzymes are essential biosynthetic enzymes (Ballicora et al, 2003;Zeeman et al, 2010;Roach et al, 2012;Palm et al, 2013). Furthermore, it is widely accepted that in glycogenstoring cells, phosphorylase is indispensible for the degradation of the storage polysaccharide (Hwang et al, 1989;Alonso-Casajús et al, 2006;Wilson et al, 2010;Roach et al, 2012;Gazzerro et al, 2013).…”

Metabolic regulation of myocardial adaptation to exercise.

“…The activities of ancillary pathways of glucose metabolism are regulated in part through expression of their rate-limiting or committed-step enzymes, cofactor availability, allosterism, and/or post-translational modifications [e.g., [252][253][254][255][256][257][258] ]. Flux through these pathways may be regulated by other means as well.…”