BIOMAT Database Logo BIOMAT Database Logo

In vivo regulation of muscle glycogen synthase and the control of glycogen synthesis. 1995

R G Shulman, and G Bloch, and D L Rothman
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06510, USA.

The activity of glycogen synthase (GSase; EC 2.4.1.11) is regulated by covalent phosphorylation. Because of this regulation, GSase has generally been considered to control the rate of glycogen synthesis. This hypothesis is examined in light of recent in vivo NMR experiments on rat and human muscle and is found to be quantitatively inconsistent with the data under conditions of glycogen synthesis. Our first experiments showed that muscle glycogen synthesis was slower in non-insulin-dependent diabetics compared to normals and that their defect was in the glucose transporter/hexokinase (GT/HK) part of the pathway. From these and other in vivo NMR results a quantitative model is proposed in which the GT/HK steps control the rate of glycogen synthesis in normal humans and rat muscle. The flux through GSase is regulated to match the proximal steps by "feed forward" to glucose 6-phosphate, which is a positive allosteric effector of all forms of GSase. Recent in vivo NMR experiments specifically designed to test the model are analyzed by metabolic control theory and it is shown quantitatively that the GT/HK step controls the rate of glycogen synthesis. Preliminary evidence favors the transporter step. Several conclusions are significant: (i) glucose transport/hexokinase controls the glycogen synthesis flux; (ii) the role of covalent phosphorylation of GSase is to adapt the activity of the enzyme to the flux and to control the metabolite levels not the flux; (iii) the quantitative data needed for inferring and testing the present model of flux control depended upon advances of in vivo NMR methods that accurately measured the concentration of glucose 6-phosphate and the rate of glycogen synthesis.

UI MeSH Term Description Entries
D008954 Models, Biological Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment. Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D009132 Muscles Contractile tissue that produces movement in animals. Muscle Tissue,Muscle,Muscle Tissues,Tissue, Muscle,Tissues, Muscle
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D003924 Diabetes Mellitus, Type 2 A subclass of DIABETES MELLITUS that is not INSULIN-responsive or dependent (NIDDM). It is characterized initially by INSULIN RESISTANCE and HYPERINSULINEMIA; and eventually by GLUCOSE INTOLERANCE; HYPERGLYCEMIA; and overt diabetes. Type II diabetes mellitus is no longer considered a disease exclusively found in adults. Patients seldom develop KETOSIS but often exhibit OBESITY. Diabetes Mellitus, Adult-Onset,Diabetes Mellitus, Ketosis-Resistant,Diabetes Mellitus, Maturity-Onset,Diabetes Mellitus, Non-Insulin-Dependent,Diabetes Mellitus, Slow-Onset,Diabetes Mellitus, Stable,MODY,Maturity-Onset Diabetes Mellitus,NIDDM,Diabetes Mellitus, Non Insulin Dependent,Diabetes Mellitus, Noninsulin Dependent,Diabetes Mellitus, Noninsulin-Dependent,Diabetes Mellitus, Type II,Maturity-Onset Diabetes,Noninsulin-Dependent Diabetes Mellitus,Type 2 Diabetes,Type 2 Diabetes Mellitus,Adult-Onset Diabetes Mellitus,Diabetes Mellitus, Adult Onset,Diabetes Mellitus, Ketosis Resistant,Diabetes Mellitus, Maturity Onset,Diabetes Mellitus, Slow Onset,Diabetes, Maturity-Onset,Diabetes, Type 2,Ketosis-Resistant Diabetes Mellitus,Maturity Onset Diabetes,Maturity Onset Diabetes Mellitus,Non-Insulin-Dependent Diabetes Mellitus,Noninsulin Dependent Diabetes Mellitus,Slow-Onset Diabetes Mellitus,Stable Diabetes Mellitus
D005958 Glucosephosphates
D006003 Glycogen
D006006 Glycogen Synthase An enzyme that catalyzes the transfer of D-glucose from UDPglucose into 1,4-alpha-D-glucosyl chains. EC 2.4.1.11. Glycogen (Starch) Synthase,Glycogen Synthetase,Glycogen Synthase I,Synthase D,Synthase I,UDP-Glucose Glycogen Glucosyl Transferase,Synthase, Glycogen,Synthetase, Glycogen,UDP Glucose Glycogen Glucosyl Transferase
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000494 Allosteric Regulation The modification of the reactivity of ENZYMES by the binding of effectors to sites (ALLOSTERIC SITES) on the enzymes other than the substrate BINDING SITES. Regulation, Allosteric,Allosteric Regulations,Regulations, Allosteric
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

R G Shulman, and G Bloch, and D L Rothman
Regulation of glycogen synthesis in human skeletal muscle: does cellular glycogen control glycogen synthase phosphatase activity?
September 1991, Biochemistry international,
R G Shulman, and G Bloch, and D L Rothman
Allosteric regulation of glycogen synthase controls glycogen synthesis in muscle.
November 2010, Cell metabolism,
R G Shulman, and G Bloch, and D L Rothman
Regulation of GLUT4 protein and glycogen synthase during muscle glycogen synthesis after exercise.
March 1998, Acta physiologica Scandinavica,
R G Shulman, and G Bloch, and D L Rothman
Control of glycogen synthesis is shared between glucose transport and glycogen synthase in skeletal muscle fibers.
February 2000, American journal of physiology. Endocrinology and metabolism,
R G Shulman, and G Bloch, and D L Rothman
Glycogen synthetase and control of glycogen synthesis in muscle.
July 1964, Biochemical and biophysical research communications,
R G Shulman, and G Bloch, and D L Rothman
Regulation of glycogen synthesis in rat skeletal muscle after glycogen-depleting contractile activity: effects of adrenaline on glycogen synthesis and activation of glycogen synthase and glycogen phosphorylase.
November 1999, The Biochemical journal,
R G Shulman, and G Bloch, and D L Rothman
In vivo regulation of liver and skeletal muscle glycogen synthase activity by glucose and insulin.
June 1986, Diabetes,
R G Shulman, and G Bloch, and D L Rothman
Control of glycogen content in retina: allosteric regulation of glycogen synthase.
January 2012, PloS one,
R G Shulman, and G Bloch, and D L Rothman
Shared control of hepatic glycogen synthesis by glycogen synthase and glucokinase.
November 2000, The Biochemical journal,
R G Shulman, and G Bloch, and D L Rothman
Calcium-dependent regulation of glycogen synthase activity in a muscle glycogen particle.
December 1980, Archives of biochemistry and biophysics,
Copied contents to your clipboard!