Definition
Glycogen Synthase is a rate-determining enzyme in the glycogenesis process, that catalyzes the transfer of D-glucose from UDPglucose into 1,4-alpha-D-glucosyl chains.
Related peptides
Mammals express 2 isoforms of Glycogen synthase encoded by the GYS 1 and GYS 2 genes. GYS 1 gene encodes the muscle isoform (737 amino acids; 83786 Da) and is expressed in skeletal muscle, cardiac muscle, adipose tissue, kidneys and the brain, while GYS 2 expresses the liver isoform (703 amino acids; 80957 Da)1.
Discovery
Glycogen synthesis was first demonstrated by Leloir et al (1959) 2. Glycogen synthase was the third enzyme shown to be regulated by a phosphorylation- dephosphorylation mechanism. Following the discovery that Glycogen phosphorylase and phosphorylase kinase were activated by phosphorylation, Larner and Co-workers found that Glycogen synthase existed in two forms in the Skeletal muscle (Glucose 6-Phosphate dependent and independent forms, respectively) 3.
Structural characteristics
The apparent molecular weight of the human glycogen synthase is found to be approximately 83,000 Daltons, by gel electrophoresis. The smallest active species is a tetramer with identical subunits3.The human liver glycogen synthase is truncated by 34 amino acids compared to the human muscle enzyme. The amino acid similarity between human liver and human muscle glycogen synthase is only 69%. It is least similar in the N and C terminal regions of the molecule. Two highly conserved regions are present in all published amino acid sequences for glycogen synthase. These regions include the amino acid sequences from 201 to 400 and 501 to 600. This high conservation suggests that the catalytic site and the glucose-6-P and nucleotide allosteric sites are included in these regions4,5.
Mechanism of action
Glycogen Synthase is phosphorylated by Protein Kinase A as well as by Phosphorylase Kinase via a cAMP mediated signal transduction pathway. Phosphorylation of Glycogen Synthase promotes the "b" (less active) conformation. The cAMP cascade thus inhibits glycogen synthesis. Insulin, produced in response to high blood glucose, triggers a separate signal cascade that leads to activation of Phosphoprotein Phosphatase. This phosphatase catalyzes removal of regulatory phosphate residues from Glycogen Synthase. Thus insulin antagonizes effects of the cAMP cascade induced by glucagon and epinephrine. Glucose-6-phosphate is the allosteric activator of Glycogen synthase. Glycogen synthase requires glucose-6-phosphate as an allosteric activator in the phosphorylated state only6.
Functions
In both muscle and liver, glycogen concentrations are regulated by the complementary activities of glycogen phosphorylase and glycogen synthase. Excess carbohydrate is stored as glycogen. Glycogen synthase incorporates glucose units into the glycogen particle7. It catalyses the transfer of the glycosyl residue from uridine diphosphate glucose (UDPG) to the non-reducing end of -1,4-glucan.
References
1. Dilmec.F, Atas A(2009). Characterisation of the human GYS2 gene and its product using bioinformatic tools.Turk J Med Sci, 39 (1): 1-6.
2. Discoveries in plant biology. By Shain-dow Kung, Shang-Fa Yang
3. The enzymes. By Paul D. Boyer, Edwin G. Krebs, D. S. Sigman, Fuyuhiko Tamanoi, David D. Hackney, Ross E. Dalbey, Steven G. Clarke.
4. Nuttall FQ, Gannon MC, Bai G, Lee EY (1994). Primary structure of human liver glycogen synthase deduced by cDNA cloning. Arch Biochem Biophys, 311(2):443-449.
5. Westphal SA, Nuttall FQ(1992).Comparative characterization of human and rat liver glycogen synthase. Arch Biochem Biophys. 292(2): 479-486.
6. Dr. K. A. Watson. Glycogen Synthase. In collaboration with R. Schinzel (Germany) Laboratory Journal 2000. Laboratory of Molecular Biophysics. Oxford University.
7. Jensen J, Lai YC(2009).Regulation of muscle glycogen synthase phosphorylation and kinetic properties by insulin, exercise, adrenaline and role in insulin resistance.Archives of Physiology and Biochemistry, 115(1):13-21.