Structural basis for 2′-phosphate incorporation into glycogen by glycogen synthase

Abstract

Significance Glycogen is a branched glucose polymer found in most animals, fungi, bacteria, and archaea as an osmotically neutral means of energy storage. Glycogen also contains minor amounts of phosphate which can be removed by a dual specificity phosphatase, laforin. Accumulation of phosphate results in highly insoluble glycogen deposits and underlies Lafora disease, a devastating form of myoclonus epilepsy. In this paper, we present structural and kinetic data that support a plausible mechanism by which phosphate is directly incorporated into glycogen by glycogen synthase.

Glycogen Phosphomonoester Distribution in Mouse Models of the Progressive Myoclonic Epilepsy, Lafora Disease

“…This mechanism has been challenged (27), but it is supported by other independent experiments. Glycogen synthase can catalyze the formation of the fast ester from UDP-glucose in vitro (41), and by x-ray crystallography, the active site of glycogen synthase can accommodate fast ester and its cognate reaction product UMP (41). A similar pathway might account for phosphorylation at C3, but there is no supporting evidence (26).…”

Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation

“…This reordered segment pushes the arginine regulatory helices apart from each other across the subunit interface and coincidently induces large scale translational and rotational movements of the subunits that promote better access for glycogen chains to reach the catalytic site 10 . These conformational transitions that lead to opening of the tetrameric interfaces are critical in order to permit full closure of the N-terminal domain upon the C-terminal domain and generate the catalytically competent ternary complex between the enzyme and both the donor and acceptor substrates 14 .…”

Structural biology of glucan phosphatases from humans to plants

“…Glycogen clearly contains monoester phosphate on the C2, C3, and C6 positions and laforin is definitively a glycogen phosphatase, but the origin of that phosphate is unknown [53–55]. Some suggest that C2 and perhaps C3 phosphate is due to a metabolic error by glycogen synthase [54,56,57]. Alternatively, others have proposed that a kinase similar to GWD phosphorylates glycogen, but no candidate has been reported [53].…”