title: Structural basis for 2'-phosphate incorporation into glycogen by glycogen synthase.
abstract: Glycogen is a glucose polymer that contains minor amounts of covalently attached phosphate. Hyperphosphorylation is deleterious to glycogen structure and can lead to Lafora disease. Recently, it was demonstrated that glycogen synthase catalyzes glucose-phosphate transfer in addition to its characteristic glucose transfer reaction. Glucose-1,2-cyclic-phosphate (GCP) was proposed to be formed from UDP-Glc breakdown and subsequently transferred, thus providing a source of phosphate found in glycogen. To gain further insight into the molecular basis for glucose-phosphate transfer, two structures of yeast glycogen synthase were determined; a 3.0-Å resolution structure of the complex with UMP/GCP and a 2.8-Å resolution structure of the complex with UDP/glucose. Structural superposition of the complexes revealed that the bound ligands and most active site residues are positioned similarly, consistent with the use of a common transfer mechanism for both reactions. The N-terminal domain of the UDP-glucose complex was found to be 13.3° more closed compared with a UDP complex. However, the UMP · GCP complex was 4.8° less closed than the glucose complex, which may explain the low efficiency of GCP transfer. Modeling of either α- or β-glucose or a mixture of both anomers can account for the observed electron density of the UDP-glucose complex. NMR studies of UDP-Glc hydrolysis by yeast glycogen synthase were used to verify the stereochemistry of the product, and they also showed synchronous GCP accumulation. The similarities in the active sites of glycogen synthase and glycogen phosphorylase support the idea of a common catalytic mechanism in GT-B enzymes independent of the specific reaction catalyzed.
authors: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202.
authors: Vimbai M
authors: VM
authors: Chikwana
authors: May
authors: M
authors: Khanna
authors: Sulochanadevi
authors: S
authors: Baskaran
authors: Vincent S
authors: VS
authors: Tagliabracci
authors: Christopher J
authors: CJ
authors: Contreras
authors: Anna
authors: A
authors: DePaoli-Roach
authors: Peter J
authors: PJ
authors: Roach
authors: Thomas D
authors: TD
authors: Hurley
mesh_terms: D003461:Crystallography; D006003:Glycogen / Q000737:chemistry* / Q000378:metabolism; D006006:Glycogen Synthase / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D016296:Mutagenesis; D010710:Phosphates / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010710:Phosphates; D006003:Glycogen; D006006:Glycogen Synthase
keywords: crystallography; glycosyltransfer