Protein phosphorylation can regulate metabolite concentrations rather than control flux: The example of glycogen synthase

Despite dramatic increases in glucose influx during the transition from fasting to fed states, plasma glucose concentration remains tightly controlled. This constancy is in large part due to the capacity of skeletal muscle to absorb excess glucose and store it as glycogen. The magnitude of this capacity is controlled by insulin by way of regulated insertion of glucose transporters into the muscle cell membrane. Here, we examine the mechanism by which muscle cells are able to tolerate large flux increases across their transporters without significantly changing their own metabolite pools. MCA was used to probe data sets that measured the effects of changing plasma glucose and/or insulin concentrations on the rates of glycogen synthesis and the concentrations of metabolites, particularly glucose-6-phosphate. We find that homeostasis is achieved by insulin-dependent phosphorylation changes in GSase sensitivity to the upstream metabolite glucose-6-phosphate. The centrality of GSase to homeostasis resolves the paradox of its sensitivity to allosteric and covalent regulation despite its minimal role in flux control. The importance of this role for enzymatic phosphorylation to diabetes pathology is discussed, and its general applicability is suggested.