Glycogen Synthesis and Andersen’s Disease
Introduction
Glucose is a major fuel source for most organisms that is broken down in the process of glycolysis to form adenosine triphosphate (ATP). To protect themselves from potential fuel shortage, organisms have developed a process that converts excess glucose into another form to be stored as “high molecular mass glucans” (Voet & Voet, 1995) that can be converted back into glucose when needed. Plants convert the fuel into starches made up of the -1,4-linked glucan -amylose and amylopectin, while animals convert it to glycogen (Voet & Voet, 1995).
Figure 1: Structures of Glycogen, Amylopectin, and Amylose showing the increased branching in glycogen versus the starch, amylopectin.
Glycogen is similar to starch in its structure, but has more -1,6 branches, occurring every 8 to 12 residues, whereas amylopectin branches every 24 to 30 residues (Voet & Voet, 1995). The molecule is rather large, occurring in “100- to 400-Ȧ-diameter cytoplasmic granules, which contain up to 120,000 glucose units” (Voet & Voet, 1995). Glycogen can be found in all tissues and is especially numerous in skeletal muscle and liver cells. This is the case due to the increased need and use of glycogen by these tissues (Voet & Voet, 1995).
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When tissues need glucose, a process called glycogenolysis breaks down glycogen into glucose precursors for further metabolism. When there is too much glucose in the blood, a process called glycogenesis converts the glucose into glycogen to be stored. Glycogen is made and broken down by different pathways (Royals, 2018). It is important that we have discovered this difference because one mishap in either system can lead to major metabolic issues.
Steps of the Pathway
Glycogenesis is a three-step pathway catalyzed by three major enzymes: Uridine diphosphate-glucose (UDP-glucose) pyrophosphorylase, glycogen synthase, and glycogen branching enzyme (Royals, 2018). Since the conversion of glucose-1-phosphate (G1P) to glycogen and orthophosphate (Pi) is “thermodynamically unfavorable under all physiological Pi concentrations” (Voet & Voet, 1995), an additional exergonic step is required that creates UDP-glucose. This process was discovered by Luis Leloir in 1957 when he found that UDP-glucose is higher in energy and serves as a glucosyl donor for glycogen chains. This conversion is the first step in glycogenesis (Voet & Voet, 1995).
Figure 2: Steps of glycogenesis
Step 1: Uridine disphosphate-glucose pyrophosphorylase
To convert G1P to UDP-glucose, G1P is combined with uridine triphosphate (UTP) and catalyzed by UDP-glucose pyrophosphorylase. The “phosphoryl oxygen of G1P attacks the α phosphorous atom of UTP to form UDP-glucose and pyrophosphatase (PPi)” (Voet & Voet, 1995). The PPi is then hydrolyzed by the enzyme inorganic phosphatase to release two Pi. The reaction is rendered irreversible by this hydrolysis (Royals, 2018).
Figure 3: Reaction between glucose 1-phosphate and UTP to form UDP-glucose and PPi. From this point, PPi is hydrolyzed to form 2 Pi.
Step 2: Glycogen synthase
The next step of glycogen synthesis is the addition of a glycosyl unit from UDP-glucose to a growing glycogen chain (Royals, 2018). Glycogen synthase catalyzes the transfer of the glucose residue to the C4-OH group on one of glycogen’s nonreducing ends and forms an α-1,6-glycosidic bond. Glycogen synthase cannot link together two glucose residues. It can only extend the pre-existing α-1,4-linked glucan chain (Voet & Voet, 1995). To initiate glycogen synthesis, a primer of polysaccharide with more than four glycosyl residues, called glycogenin, is required (Royals, 2018). Glycogenin catalyzes the addition of up to seven glycosyl units to form the glucose polymer that serves as the primer. Only at this point can glycogen synthesis be initiated and continue, using the primer as a template. However, once the glycogen unit has reached a certain size, the protein dissociates (Voet & Voet, 1995). Studies that have analyzed glycogen granules found that glycogenin and glycogen synthase molecules are present in a one to one ratio within a single glycogen (Voet & Voet, 1995). This means that every glycogen granule contains a single glycogen molecule, as well as one glycogenin protein and glycogen synthase enzyme molecule (Voet & Voet, 1995).
Step 3: Branching enzyme
At the end of step two, glycogen synthase catalyzed the formation of α-amylose from α-1,4-linkage. As heavy branching is characteristic of glycogen, the final step of glycogenesis is catalyzed by the branching enzyme, amylo-1,4-1,6-transglycosylase (Voet & Voet, 1995). The enzyme, also known as glycogen transferase, transfers a six to seven residue terminal glycogen chain to the C6-OH group of an interior glucose residue of the same or another glycogen chain (Royals, 2018). Existing α-1,4-glycosidic bonds are broken and α-1,6-linkages are formed. The transferred segment must have come from a chain consisting of at least eleven residues and must be transferred four residues away from another branching point (Voet & Voet, 1995).
Figure 4: The branching of glycogen. Branches are formed by transferring a six to seven glucose residue from the terminal end of the glycogen chain to the C6-OH group of an interior glucose residue.
While glycogen transferase creates branching, synthase simultaneously extends both nonreducing ends of the glycogen chain to allow more space for branching to occur. Copious branching allows glycogen to be more soluble and increases the number of nonreducing ends. This increases the amount of glucose that is stored in the glycogen unit and can be quickly released when needed (Royals, 2018).
Regulation of the Pathway
If glycogen synthesis and degradation were to run simultaneously, the body would waste essential minerals and enzymes required to run cellular metabolism. There must be a way to regulate glycogen phosphorylase, a key enzyme in glycogen breakdown, and glycogen synthase so that the body is either storing or utilizing glucose according to its needs. Control happens through allosteric regulation, substrate cycles, and “enzyme-catalyzed covalent modifications of both glycogen synthase and glycogen phosphorylase” (Voet & Voet, 1995).
Allosteric Regulation
Glycogen phosphorylase and glycogen synthase catalyze opposite reactions. The rates of both enzymes are allosterically regulated by glucose, glucose 6-phosphate (G6P), ATP, and adenosine monophosphate (AMP). During glycogenolysis, glycogen phosphorylase is activated by AMP and inhibited by ATP and G6P. Glycogen synthase during glycogenesis is activated by G6P (Voet & Voet, 1995). When the body is low on ATP and G6P and high in AMP, glycogen phosphorylase is activated, and glycogen synthase is inhibited, so glycogen degradation is favored. When ATP and G6P levels are high, glycogen phosphorylase is inhibited, and glycogen synthase is activated, and glycogen synthesis is favored (Voet & Voet, 1995).
Bicyclic Cascade
Both enzymes can be interconverted between two forms with different properties through reactions known as a cyclic cascade. Interconverting the enzymes involves enzyme-catalyzed covalent modification and demodification reactions. Glycogen phosphorylase exists in two forms: one that must be activated by AMP and one that does not (Voet & Voet, 1995). Glycogen phosphorylase a is usually active and glycogen phosphorylase b is usually inactive. Each form exists in equilibrium between tense (T) and relaxed (R) conformational states. The transition between the active R and less-active T states is controlled by the energetic charge of the muscle cell (Royals, 2018). Glycogen synthase exists in two forms: the modified (m), phosphorylated form that is inactive (b) and the original (o), dephosphorylated form that is active (a). The transition between the a and b forms is controlled by GDP concentrations in tissues. The balance between the interconverted forms of glycogen phosphorylase and glycogen synthase relies on the bicyclic cascades between the two enzymes. They are very closely related and when one is high, the other is low (Voet & Voet, 1995). They are linked by “[cyclic AMP]-dependent protein kinase and phosphorylase kinase which, through phosphorylation, activate phosphorylase as they inactivate glycogen synthase” (Voet & Voet, 1995).
Hormonal Control
The enzyme-catalyzed covalent modifications are largely controlled by hormones. Glycogen metabolism in the liver is mostly controlled by a hormone called glucagon, and in the muscles and other tissues is controlled by insulin and an adrenal hormone called epinephrine (Voet & Voet, 1995). When blood glucose levels drop too low, glucagon and epinephrine levels in the blood increase to stimulate glycogen degradation and inhibit glycogen synthesis. The breakdown of glycogen to glucose in the liver raises blood sugar levels in the blood. When these levels get too high, insulin levels in the blood increase to stimulate glycogen synthesis and inhibit glycogen degradation. Glucose is pulled from the blood and stored as glycogen in tissue cells (Royals, 2018).
Figure 5: Illustrated flow chart showing blood glucose regulation by hormones
Difference in Prokaryotes and Eukaryotes
The distant prokaryotic relative of humans, bacteria, have an average glycogen chain length of eight to twelve glucose units with a molecular size of about 107 to 108 Daltons. Yeast, an organism used in copious studies done on eukaryotic glycogen metabolism, have a similar structure with eleven to twelve glucose residues per chain and a molecule diameter of about 20 nanometers (Wilson et al., 2010).
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In yeast, glycogen synthesis is functionally the same as in prokaryotic organisms, but includes many small, yet important differences. Glycogen formation is stimulated by decreased levels of carbon, nitrogen, phosphorous, or sulfur (Wilson et al., 2010). Yeast synthesize and degrade copious amounts of glycogen during the sporulation process as UDP-glucose is a crucial element of cell wall formation (Wilson et al., 2010).
Eukaryotic organisms cannot initiate glycogen synthesis without glycogenin. Yeast are different in the sense that they contain two isoforms of glucogenin – GLG1 and GLG2 (Wilson et al., 2010). While the proteins are significantly different in size, with one being 64 kDa and the other being 43 kDa, they appear to function the same and deletion of one or the other has no effect on synthesis. However, it has been discovered that glg1 glg2 double mutants are glycogen-deficient (Wilson et al., 2010).
Like the two forms of glycogenin, yeast also contain two isoforms of glycogen synthase, GSY1 and GSY2. The proteins have been found to be 80% identical, but when GSY2 is deleted, glycogen synthase activity reduced by approximately 90% (Wilson et al., 2010). Further studies discovered that gsy2 mutant cells contained significantly less glycogen as compared to wild type, leading researchers to believe that gsy2 is the major form of glycogen synthase (Wilson et al., 2010).
Despite having small differences in enzymes, glycogenesis is relatively the same in prokaryotes and eukaryotic organism, yeast.
Relation to the Central Metabolic Pathway
Before glucose can be transformed into glycogen, it must first be synthesized itself. The synthesis of glucose is called gluconeogenesis. Gluconeogenesis is a two-stage process made up of eleven reactions that turns pyruvate into glucose. The majority (~90%) of gluconeogenesis occurs in the liver while the remainder (~10%) occurs in the kidney (Royals, 2018).
When blood sugar levels get too high in the blood, insulin is released to stimulate the formation of glycogen, which is partially stored in the liver, where most of gluconeogenesis occurs (Royals, 2018). When blood sugar levels get too low, glucagon and epinephrine levels increase to stimulate glycogenolysis, the counterpart to glycogenesis (Voet & Voet, 1995).
Associated Diseases
Glycogen metabolism is a finely tuned system that must be functioning in a very specific way in order to be functioning correctly. Naturally, there exist several genetic disorders that cause enzymatic imbalances and throw off glycogen metabolism. These diseases are called glycogen storage diseases (GSDs). While many of these diseases affect glycogen degradation, there are a few that affect glycogen synthesis. Of the nine glycogen storage diseases, types one, four, and nine pertain to glycogenesis (Voet & Voet, 1995).
Glycogen Storage Disease Type IV
Glycogen Storage Disease Type Four (GSD IV) is one of the most severe, and most commonly fatal, glycogen storage diseases. This uncommon disease, also known as Andersen’s disease, causes those affected to form abnormal glycogen molecules with fewer branches and 
longer chains (Chen, 2001). The chains highly resemble amylopectin, the major storage sugar in beans and peas. The abnormal chains result from decreased or absent glycogen branching enzymes in the body (Magoulas & El-Hattab, 2013).
Figure 6: The structure of glycogen in those affected by GBE1 mutation causing Glycogen Storage Disease Type IV. There are less branches and longer chains that cause decreased solubility of the unit.
While GSD IV does not cause increased glycogen levels in the liver, the resulting glycogen is less soluble due to decreased branching and, thus, glycogen accumulation in the liver occurs (Özen, 2007). This insoluble glycogen triggers the immune system to treat the abnormal units as foreign bodies and leads to cellular destruction and organ dysfunction (Özen, 2007). This immune response is responsible for cirrhosis of the liver commonly seen in GSD IV patients (Chen, 2001). The response is so strong that many patients affected do not survive past the age of four due to liver dysfunction (Voet & Voet, 1995).
The lack of glycogen branching enzymes results from mutations in the gene that codes for the enzyme. Connections between phenotype and genotype have not been determined, so many that show symptoms and earlier onset of decreased GBE activity have been associated with GBE1 mutations (“Glycogen,” 2018).
Disease Population Expression
Since Glycogen Storage Disease Type IV patients don’t typically live past young childhood, the disease is commonly associated with children. However, Andersen’s disease is an autosomal recessive trait, meaning both parents have to be carriers in order to pass it onto their children and have a 25 percent subsequent risk of affection for each pregnancy (“Glycogen,” 2018). Siblings of affected individuals have a 25 percent chance of being affected, a 50 percent chance of being a carrier, and a 25 percent chance of not being affected or a carrier (Magoulas & El-Hattab, 2013). There is an adult-onset form that is less common and usually affects individual of Ashkenazi Jewish ancestry (“Glycogen,” 2018).
Treatments
Patients with GSD IV require medical treatment for liver dysfunction after being tested for abnormal findings and laboratory evidence of organ dysfunction (Özen, 2007). Currently, the only definitive treatment for Andersen’s disease is liver transplantation and that is limited by complications with transplantation and the possibility of disease progression in other organs (“Glycogen,” 2018). Treatment for those patients with the adult-onset form of GSD IV includes medications and transplantation (“Glycogen,” 2018).
Classic GSD IV leads to death, most commonly caused by liver failure, by age four in those that did not undergo transplantation. The adult-onset form has better long-term prognosis for those with the neuromuscular subtype (Magoulas & El-Hattab, 2013).
Those that feel they are at-risk or may be affected based on the diagnosis of a family member are able to seek genetic counseling, prenatal diagnosis, and preimplantation genetic diagnosis for the prevention of GSD IV (Magoulas & El-Hattab, 2013).
Conclusion
Cellular metabolism is an intimately interconnected web made up of several pathways that are all crucial to keeping cells running efficiently. While glycolysis turns glucose into ATP to help fuel the body and gluconeogenesis creates glucose from noncarbohydrate precursors, glycogenesis takes excess glucose and converts it to glycogen for later metabolic usage. However smooth the pathways may be, the slightest difference can cause major issues within the cell. Glycogen Storage Diseases affect millions worldwide, yet no cures have been found. Copious studies have been done to uncover the mysteries behind what keeps the body running, yet so much has yet to be discovered.
References
- Chen, Y. (2001). Glycogen Storage Diseases. In The Metabolic and Molecular Bases of Inherited Disease (8th ed.). NY: McGraw.
- Glycogen storage disease type IV. (2018, November 27). Retrieved November 30, 2018.
- Magoulas, P. L., & El-Hattab, A. W. (2013). Glycogen Storage Disease Type IV. GeneReviews. Retrieved November 30, 2018.
- Özen, H. (2007). Glycogen storage diseases: New perspectives. World Journal of Gastroenterology,13(17), 2541-2553. doi:10.3748/wjg.v13.i18.2541
- Royals, B. (2018). Glycogen Degradation/Synthesis [Powerpoint slides]. Retrieved from https://canvas.park.edu/courses/37435/files/folder/Lectures?preview=4742661.
- Voet, D., & Voet, J. G. (1995). Glycogen Metabolism. In Biochemistry: Second Edition (2nd ed., pp. 484-512). NY: John Wiley & Sons.
- Wilson, W. A., Roach, P. J., Montero, M., Baroja-Fernández, E., Muñoz, F. J., Eydallin, G., . . . Pozueta-Romero, J. (2010). Regulation of glycogen metabolism in yeast and bacteria. FEMS Microbiology Reviews, 34(6), 952-985. doi:10.1111/j.1574-6976.2010.00220.x
Picture Sources:
Figure 2: Royals, B. (2018). Glycogen Degradation/Synthesis [Powerpoint slides]. Slide 19
Figure 3: Royals, B. (2018). Glycogen Degradation/Synthesis [Powerpoint slides]. Slide 17
Figure 4: http://oregonstate.edu/instruct/bb350/ahernmaterials/a18.html
Figure 5: Royals, B. (2018). Glycogen Degradation/Synthesis [Powerpoint slides]. Slide 33
Figure 6: https://pt.wikipedia.org/wiki/Glicogen%C3%B3lise#/media/File:Glycogen.png
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