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. 1996 Jul 23;93(15):7491–7495. doi: 10.1073/pnas.93.15.7491

Enzymatic phosphorylation of muscle glycogen synthase: a mechanism for maintenance of metabolic homeostasis.

R G Shulman 1, D L Rothman 1
PMCID: PMC38772  PMID: 8755501

Abstract

We recently analyzed experimental studies of mammalian muscle glycogen synthesis using metabolic control analysis and concluded that glycogen synthase (GSase) does not control the glycogenic flux but rather adapts to the flux which is controlled bv the activity of the proximal glucose transport and hexokinase steps. This model did not provide a role for the well established relationship between GSase fractional activity, determined by covalent phosphorylation, and the rate of glycogen synthesis. Here we propose that the phosphorylation of GSase, which alters the sensitivity to allosteric activation by glucose 6-phosphate (G6P), is a mechanism for controlling the concentration of G6P instead of controlling the flux. When the muscle cell is exposed to conditions which favor glycogen synthesis such as high plasma insulin and glucose concentrations the fractional activity of GSase is increased in coordination with increases in the activity of glucose transport and hexokinase. This increase in GSase fractional activity helps to maintain G6P homeostasis by reducing the G6P concentration required to activate GSase allosterically to match the flux determined by the proximal reactions. This role for covalent phosphorylation also provides a novel solution to the Kacser and Acarenza paradigm which requires coordinated activity changes of the enzymes proximal and distal to a shared intermediate, to avoid unwanted flux changes.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Farrace S., Rossetti L. Hyperglycemia markedly enhances skeletal muscle glycogen synthase activity in diabetic, but not in normal conscious rats. Diabetes. 1992 Nov;41(11):1453–1463. doi: 10.2337/diab.41.11.1453. [DOI] [PubMed] [Google Scholar]
  2. Fell D. A. Metabolic control analysis: a survey of its theoretical and experimental development. Biochem J. 1992 Sep 1;286(Pt 2):313–330. doi: 10.1042/bj2860313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Fell D. A., Thomas S. Physiological control of metabolic flux: the requirement for multisite modulation. Biochem J. 1995 Oct 1;311(Pt 1):35–39. doi: 10.1042/bj3110035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Guinovart J. J., Salavert A., Massagué J., Ciudad C. J., Salsas E., Itarte E. Glycogen synthase: a new activity ratio assay expressing a high sensitivity to the phosphorylation state. FEBS Lett. 1979 Oct 15;106(2):284–288. doi: 10.1016/0014-5793(79)80515-3. [DOI] [PubMed] [Google Scholar]
  5. Hubbard M. J., Cohen P. On target with a new mechanism for the regulation of protein phosphorylation. Trends Biochem Sci. 1993 May;18(5):172–177. doi: 10.1016/0968-0004(93)90109-z. [DOI] [PubMed] [Google Scholar]
  6. Kacser H., Acerenza L. A universal method for achieving increases in metabolite production. Eur J Biochem. 1993 Sep 1;216(2):361–367. doi: 10.1111/j.1432-1033.1993.tb18153.x. [DOI] [PubMed] [Google Scholar]
  7. Kacser H., Burns J. A. The control of flux. Symp Soc Exp Biol. 1973;27:65–104. [PubMed] [Google Scholar]
  8. Okubo M., Bogardus C., Lillioja S., Mott D. M. Glucose-6-phosphate stimulation of human muscle glycogen synthase phosphatase. Metabolism. 1988 Dec;37(12):1171–1176. doi: 10.1016/0026-0495(88)90196-5. [DOI] [PubMed] [Google Scholar]
  9. Piras R., Rothman L. B., Cabib E. Regulation of muscle glycogen synthetase by metabolites. Differential effects on the I and D forms. Biochemistry. 1968 Jan;7(1):56–66. doi: 10.1021/bi00841a009. [DOI] [PubMed] [Google Scholar]
  10. Piras R., Staneloni R. In vivo regulation of rat muscle glycogen synthetase activity. Biochemistry. 1969 May;8(5):2153–2160. doi: 10.1021/bi00833a056. [DOI] [PubMed] [Google Scholar]
  11. Price T. B., Perseghin G., Duleba A., Chen W., Chase J., Rothman D. L., Shulman R. G., Shulman G. I. NMR studies of muscle glycogen synthesis in insulin-resistant offspring of parents with non-insulin-dependent diabetes mellitus immediately after glycogen-depleting exercise. Proc Natl Acad Sci U S A. 1996 May 28;93(11):5329–5334. doi: 10.1073/pnas.93.11.5329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Quant P. A. Experimental application of top-down control analysis to metabolic systems. Trends Biochem Sci. 1993 Jan;18(1):26–30. doi: 10.1016/0968-0004(93)90084-z. [DOI] [PubMed] [Google Scholar]
  13. Roach P. J., Larner J. Rabbit skeletal muscle glycogen synthase. II. Enzyme phosphorylation state and effector concentrations as interacting control parameters. J Biol Chem. 1976 Apr 10;251(7):1920–1925. [PubMed] [Google Scholar]
  14. Rossetti L., Giaccari A. Relative contribution of glycogen synthesis and glycolysis to insulin-mediated glucose uptake. A dose-response euglycemic clamp study in normal and diabetic rats. J Clin Invest. 1990 Jun;85(6):1785–1792. doi: 10.1172/JCI114636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Rothman D. L., Magnusson I., Cline G., Gerard D., Kahn C. R., Shulman R. G., Shulman G. I. Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):983–987. doi: 10.1073/pnas.92.4.983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Rothman D. L., Shulman R. G., Shulman G. I. 31P nuclear magnetic resonance measurements of muscle glucose-6-phosphate. Evidence for reduced insulin-dependent muscle glucose transport or phosphorylation activity in non-insulin-dependent diabetes mellitus. J Clin Invest. 1992 Apr;89(4):1069–1075. doi: 10.1172/JCI115686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Shulman R. G., Bloch G., Rothman D. L. In vivo regulation of muscle glycogen synthase and the control of glycogen synthesis. Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8535–8542. doi: 10.1073/pnas.92.19.8535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Srere P. A. 17th Fritz Lipmann Lecture. Wanderings (wonderings) in metabolism. Biol Chem Hoppe Seyler. 1993 Sep;374(9):833–842. [PubMed] [Google Scholar]
  19. Villar-Palasi C. Substrate specific activation by glucose 6-phosphate of the dephosphorylation of muscle glycogen synthase. Biochim Biophys Acta. 1991 Nov 12;1095(3):261–267. doi: 10.1016/0167-4889(91)90109-b. [DOI] [PubMed] [Google Scholar]
  20. Yki-Järvinen H., Sahlin K., Ren J. M., Koivisto V. A. Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients. Diabetes. 1990 Feb;39(2):157–167. doi: 10.2337/diab.39.2.157. [DOI] [PubMed] [Google Scholar]

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