|glycogen (starch) synthase|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
Glycogen synthase (UDP-glucose-glycogen glucosyltransferase) is an enzyme involved in converting glucose to glycogen. It takes short polymers of glucose and converts them into long polymers of glycogen.
In other words, this enzyme converts excess glucose residues one by one into a polymeric chain for storage as glycogen. Glycogen synthase concentration is highest in the bloodstream 30 to 60 minutes following intense exercise. It is a key enzyme in glycogenesis.
Much research has been done on glycogen degradation through studying the structure and function of glycogen phosphorylase, the key regulatory enzyme of glycogen degradation. On the other hand, much less is known about the structure of glycogen synthase, the key regulatory enzyme of glycogen synthesis. The crystal structure of glycogen synthase from Agrobacterium tumefaciens, however, has been determined at 2.3 A resolution. In its asymmetric form, glycogen synthase is found as a dimer, whose monomers are composed of two Rossmann-fold domains. This structural property, among others, is shared with related enzymes, such as glycogen phosphorylase and other glycosyltransferases of the GT-B superfamily.
Glycogen synthase can be classified in two general protein families. The first family (GT3), which is from mammals and yeast, is approximately 80 kDa, uses UDP-glucose as a sugar donor, and is regulated by phosphorylation and ligand binding. The second family (GT5), which is from bacteria and plants, is approximately 50 kDA, uses ADP-glucose as a sugar donor, and is unregulated.
Although the catalytic mechanisms used by glycogen synthase are not well known, structural similarities to glycogen phosphorylase at the catalytic and substrate binding site suggest that the mechanism for synthesis is similar in glycogen synthase and glycogen phosphorylase.
In a recent study of transgenic mice, an overexpression of glycogen synthase and an overexpression of phosphatase both resulted in excess glycogen storage levels. This suggests that glycogen synthase plays an important biological role in regulating glycogen/glucose levels and is activated by dephosphorylation.
|glycogen synthase 1 containing carbon elements||muscle and other tissues||GYS1|
|glycogen synthase 2||liver||GYS2|
The liver enzyme expression is restricted to the liver, whereas the muscle enzyme is widely expressed. Liver glycogen serves as a storage pool to maintain the blood glucose level during fasting, whereas muscle glycogen synthesis accounts for disposal of up to 90% of ingested glucose. The role of muscle glycogen is as a reserve to provide energy during bursts of activity.
The reaction is highly regulated by allosteric effectors such as glucose-6-phosphate, by phosphorylation reactions, and indirectly triggered by the hormone insulin, which is secreted by the pancreas. Phosphorylation of glycogen synthase decreases its activity. The enzyme also cleaves the ester bond between the C1 position of glucose and the pyrophosphate of UDP itself.
The control of glycogen synthase is a key step in regulating glycogen metabolism and glucose storage. Glycogen synthase is directly regulated by glycogen synthase kinase 3 (GSK-3), AMPK, protein kinase A (PKA), and casein kinase 2 (CK2). Each of these protein kinases lead to phosphorylated and catalytically inactive glycogen synthase. The phosphorylation sites of glycogen synthase are summarized below.
|Site 2||Serine 7||AMPK||,|
|Site 2a||Serine 10||CK2|
|Site 3a||Serine 641||GSK3|||
|Site 3b||Serine 645||GSK3|||
|Site 3c||Serine 649||GSK3|||
|Site 3d||Serine 653||GSK3|||
|Site 4||Serine 727|
For enzymes in the GT3 family, these regulatory kinases inactivate glycogen synthase by phosphorylating it at the N-terminal of the 25th residue and the C-terminal of the 120th residue. Glycogen synthase is also regulated by protein phosphatase 1 (PP1), which activates glycogen synthase via dephosphorylation. PP1 is targeted to the glycogen pellet by four targeting subunits, GM, GL, PTG and R6. These regulatory enzymes are regulated by insulin and glucagon signaling pathways.
Mutations in the GYS1 gene are associated with glycogen storage disease type 0. In humans, defects in the tight control of glucose uptake and utilization are also associated with diabetes and hyperglycemia. Patients with type 2 diabetes normally exhibit low glycogen storage levels because of impairments in insulin-stimulated glycogen synthesis and suppression of glycogenolysis. Insulin stimulates glycogen synthase by inhibiting glycogen synthase kinases or/and activating protein phosphatase 1 (PP1) among other mechanisms .
|Glucose tolerance test||Abnormal|
|Auditory brainstem response||Normal|
|Peripheral blood lymphocytes||Normal|
|All tests and analysis from|
Model organisms have been used in the study of GYS2 function. A conditional knockout mouse line, called Gys2tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out and two significant phenotypes were reported. Homozygous mutant male adults displayed impaired glucose tolerance, whereas females had a significant decrease in circulating glucose levels as determined by clinical chemistry.
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