Glycogen synthase
Encyclopedia
Glycogen synthase is an enzyme
involved in converting glucose
to glycogen
. It takes short polymers of glucose and converts them into long polymers.
It is a glycosyltransferase
enzyme
that catalyses the reaction of UDP-glucose and (1,4-α-D-glucosyl)n to yield UDP
and (1,4-α-D-glucosyl)n+1.
In other words, this enzyme converts excess glucose
residue
s one by one into a polymeric chain for storage as glycogen
. Its presence in the bloodstream is highest in the 30 to 60 minutes following intense exercise. It is a key enzyme in glycogenesis
.
, 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.
at the catalytic and substrate binding site
suggest that the mechanism for synthesis is similar in glycogen synthase and glycogen phosphorylase.
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.
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.
, 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 and protein kinase A (PKA). Each of these protein kinases lead to phosphorylated and catalytically inactive glycogen synthase. The phosphorylation sites of glycogen synthase are summarized below.
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.
.
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, and this indicates that insulin activates glycogen synthase by inhibiting its kinases.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
involved in converting glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
to glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
. It takes short polymers of glucose and converts them into long polymers.
It is a glycosyltransferase
Glycosyltransferase
Glycosyltransferases are enzymes that act as a catalyst for the transfer of a monosaccharide unit from an activated nucleotide sugar to a glycosyl acceptor molecule, usually an alcohol....
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that catalyses the reaction of UDP-glucose and (1,4-α-D-glucosyl)n to yield UDP
Uridine diphosphate
Uridine diphosphate, abbreviated UDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside uridine. UDP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase uracil.-See also:* Nucleoside...
and (1,4-α-D-glucosyl)n+1.
In other words, this enzyme converts excess glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
residue
Residue (chemistry)
In chemistry, residue is the material remaining after a distillation or an evaporation, or to a portion of a larger molecule, such as a methyl group. It may also refer to the undesired byproducts of a reaction....
s one by one into a polymeric chain for storage as glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
. Its presence in the bloodstream is highest in the 30 to 60 minutes following intense exercise. It is a key enzyme in glycogenesis
Glycogenesis
Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage. This process is activated during rest periods following the Cori cycle, in the liver, and also activated by insulin in response to high glucose levels, for example after a...
.
Structure
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 tumefaciensAgrobacterium tumefaciens
Agrobacterium tumefaciens is the causal agent of crown gall disease in over 140 species of dicot. It is a rod shaped, Gram negative soil bacterium...
, 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
Glycogen phosphorylase
Glycogen phosphorylase is one of the phosphorylase enzymes . Glycogen phosphorylase catalyzes the rate-limiting step in the degradation of glycogen in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond...
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
Glucose-1-phosphate adenylyltransferase
In enzymology, a glucose-1-phosphate adenylyltransferase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are ATP and alpha-D-glucose 1-phosphate, whereas its two products are diphosphate and ADP-glucose....
as a sugar donor, and is unregulated.
Mechanism
Although the catalytic mechanisms used by glycogen synthase are not well known. Structural similarities to glycogen phosphorylaseGlycogen phosphorylase
Glycogen phosphorylase is one of the phosphorylase enzymes . Glycogen phosphorylase catalyzes the rate-limiting step in the degradation of glycogen in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond...
at the catalytic and substrate binding site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...
suggest that the mechanism for synthesis is similar in glycogen synthase and glycogen phosphorylase.
Function
In a recent study of transgenicGenetically modified organism
A genetically modified organism or genetically engineered organism is an organism whose genetic material has been altered using genetic engineering techniques. These techniques, generally known as recombinant DNA technology, use DNA molecules from different sources, which are combined into one...
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.
Isozymes
In humans, there are two paralogous isozymes of glycogen synthase:| isozyme | tissue distribution | gene |
|---|---|---|
| glycogen synthase 1 | muscle and other tissues | |
| glycogen synthase 2 | liver |
The liver enzyme expression is restricted to the liver, whereas the muscle enzyme is widely expressed. Liver glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
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.
Regulation
The reaction is highly regulated by allosteric effectors such as glucose-6-phosphateGlucose-6-phosphate
Glucose 6-phosphate is glucose sugar phosphorylated on carbon 6. This compound is very common in cells as the vast majority of glucose entering a cell will become phosphorylated in this way....
, by phosphorylation reactions, and indirectly triggered by the hormone insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, which is secreted by the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
. Phosphorylation of glycogen synthase decreases its activity. The enzyme also cleaves the ester bond between the C1 position of glucose and the pyrophosphate
Pyrophosphate
In chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Any salt or ester containing two phosphate groups is called a diphosphate. As a food additive, diphosphates are known as E450.- Chemistry :...
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 and protein kinase A (PKA). Each of these protein kinases lead to phosphorylated and catalytically inactive glycogen synthase. The phosphorylation sites of glycogen synthase are summarized below.
| Name | Phosphorylation Site | Kinase | Reference(s) |
|---|---|---|---|
| Site 1a | PKA | , | |
| Site 1b | PKA | , | |
| 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
Protein phosphatase 1
Phosphoprotein phosphatase 1 belongs to a certain class of phosphatases known as protein serine/ threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases and aspartate-based phosphatases...
), which activates glycogen synthase via dephosphorylation. PP1 is targeted to the glycogen pellet by four targeting subunits, GM
PPP1R3A
Protein phosphatase 1 regulatory subunit 3A is an enzyme that in humans is encoded by the PPP1R3A gene.-Further reading:...
, GL, PTG
PPP1R3C
Protein phosphatase 1 regulatory subunit 3C also known as PTG is an enzyme that in humans is encoded by the PPP1R3C gene.- Function :...
and R6. These regulatory enzymes are regulated by insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
and glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
signaling pathways.
Pathology
Mutations in the GYS2 gene are associated with glycogen storage disease type 0Glycogen storage disease type 0
Glycogen storage disease type 0 is characterized by a deficiency in the glycogen synthase enzyme. Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is often classified with the GSDs because it is another defect of glycogen storage and can cause...
.
In humans, defects in the tight control of glucose uptake and utilization are also associated with diabetes and hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
. Patients with type 2 diabetes normally exhibit low glycogen storage levels, and this indicates that insulin activates glycogen synthase by inhibiting its kinases.