Crystal structure of glycogen synthase: homologous enzymes catalyze glycogen synthesis and degradation

Abstract

Glycogen and starch are the major readily accessible energy storage compounds in nearly all living organisms. Glycogen is a very large branched glucose homopolymer containing about 90% a-1,4-glucosidic linkages and 10% a-1,6 linkages. Its synthesis and degradation constitute central pathways in the metabolism of living cells regulating a global carbon/energy buffer compartment. Glycogen biosynthesis involves the action of several enzymes among which glycogen synthase catalyzes the synthesis of the a-1,4-glucose backbone. We now report the first crystal structure of glycogen synthase in the presence and absence of adenosine diphosphate. The overall fold and the active site architecture of the protein are remarkably similar to those of glycogen phosphorylase, indicating a common catalytic mechanism and comparable substratebinding properties. In contrast to glycogen phosphorylase, glycogen synthase has a much wider catalytic cleft, which is predicted to undergo an important interdomain 'closure' movement during the catalytic cycle. The structures also provide useful hints to shed light on the allosteric regulation mechanisms of yeast/mammalian glycogen synthases.

The glgX gene product of Corynebacterium glutamicum is required for glycogen degradation and for fast adaptation to hyperosmotic stress

“…Glycogen consists of a-1,4-a-1,6-linked glucose residues (Manners, 1991), and serves as a major reserve polysaccharide in eukaryotes and in a variety of bacteria (Ball & Morell, 2003;Iglesias & Preiss, 1992). Although there have been some investigations of enzymes or genes involved in glycogen synthesis and degradation in other bacteria (Buschiazzo et al, 2004;Horcajada et al, 2006;Yeo & Chater, 2005), most studies have been done with Escherichia coli (Ballicora et al, 2003;Preiss, 1996). In this organism, glycogen is synthesized in a two-step process.…”

Multiple Glycogen-binding Sites in Eukaryotic Glycogen Synthase Are Required for High Catalytic Efficiency toward Glycogen

“…Recent structural studies have shown that the enzyme folds into two Rossmann foldlike domains, with a deep cleft in between harboring the active site (1)(2)(3). Although the basic fold is conserved between the prokaryotic, archaeal, and eukaryotic enzymes, there are multiple sequence insertions in the eukaryotic enzymes.…”

Lyase activity of glycogen synthase: Is an elimination/addition mechanism a possible reaction pathway for retaining glycosyltransferases?

“…Although the initial stereochemical course of this reaction differs from that proposed in Fig. 4, since the protonation of D-glucal at C2 occurs from the a-side, we interpret this finding as the demonstration that a stable glucosyl derivative bearing a C1-C2 double bond is chemically and kinetically competent for the transfer reaction catalyzed by GP or MalP, whose active site machineries are very similar to that of GS and other retaining GTs of the GT-B fold (22). Remarkably, a glucose-derived intermediate also lacking the 1-hydroxyl group was found in the active site of MalP in a complex with maltopentaose and a phosphate ion, produced by rapid soaking and freezing (PDB 2asv).…”

“…Fungal and animal GSs, classed in family GT3, have only one representative, Saccharomyces cerevisiae GS, of known crystal structure (21), while three enzymes of the GT5 family, which comprises prokariotyc and archaeal GSs, as well as starch synthases, have been solved: those from Agrobacterium tumefaciens (22), Pyrococcus abyssi glycogen synthase (PaGS) (23), and Escherichia coli glycogen synthase (EcGS) (24). The crystal structure of the complex between EcGS and ADP-Glc showed that the enzyme is able to cleave its donor substrate into ADP and an unknown glucosyl species.…”