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J. Biol. Chem., Vol. 279, Issue 14, 13764-13768, April 2, 2004

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Glycogen Synthase Sensitivity to Glucose-6-P Is Important for Controlling Glycogen Accumulation in Saccharomyces cerevisiae^*

Bartholomew A. Pederson, Wayne A. Wilson, and Peter J. Roach

From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Indiana University Center for Diabetes Research, Indianapolis, Indiana 46202

Glycogen is a storage form of glucose utilized as an energy reserve by many organisms. Glycogen synthase, which is essential for synthesizing this glucose polymer, is regulated by both covalent phosphorylation and the concentration of glucose-6-P. With the yeast glycogen synthase Gsy2p, we recently identified two mutants, R579A/R581A/R582A and R586A/R588A/R591A, in which multiple arginine residues were mutated to alanine that were completely insensitive to activation by glucose-6-P in vitro (Pederson, B. A., Cheng, C., Wilson, W. A., and Roach, P. J. (2000) J. Biol. Chem. 275, 27753–27761). We report here the expression of these mutants in Saccharomyces cerevisiae and, as expected from our findings in vitro, they were not activated by glucose-6-P. The R579A/R581A/R582A mutant, which is also resistant to inhibition by phosphorylation, caused hyperaccumulation of glycogen. In contrast, the mutant R586A/R588A/R591A, which retains the ability to be inactivated by phosphorylation, resulted in lower glycogen accumulation when compared with wild-type cells. When intracellular glucose-6-P levels were increased by mutating the PFK2 gene, glycogen storage due to the wild-type enzyme was increased, whereas that associated with R579A/R581A/R582A was not greatly changed. This is the first direct demonstration that activation of glycogen synthase by glucose-6-P in vivo is necessary for normal glycogen accumulation.

Received for publication, November 11, 2003 , and in revised form, January 12, 2004.

^* This work was supported in part by National Institutes of Health Grant DK42576 and the Indiana University Diabetes Research and Training Center (supported by National Institutes of Health Grant DK20542). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a mentor-based postdoctoral research award from the American Diabetes Association (to P. J. R.).

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122; Tel.: 317-274-1582; Fax: 317-274-4686; E-mail: proach{at}iupui.edu.

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