Glycogens are animals’ energy reserves and are highly branched glucose polymers. They are similar to starch, which is present as an energy reservoir in plant cells. The liver contains a high concentration of glycogen. However, muscle tissues contain the most glycogen by weight. The process of glycogen formation from an excessive glucose molecule is called glycogenesis.
Glycogenesis occurs mainly in liver and muscle cells. Two primary bonds that connect glucose residues in glycogen are ɑ-1,4-glycosidic bonds (usually present in linear strands) and ɑ-1,6-glycosidic bonds (usually at junction points).
Glycogen’s branchings are responsible for its quick metabolism and high solubility. Glycogens help maintain glucose homeostasis in animal bodies, so their metabolism is regulated primarily by glucagon and insulin. Insulin promotes glycogen synthesis or glycogenesis, while glucagon promotes glycogen breakdown (glycogenolysis).
Table of Contents
Enzymes Required for Glycogenesis
The conversion of glucose to glycogen requires different enzymes to work in coordination. The conversion occurs mainly in liver and muscle cells during high energy demands and low blood glucose levels. The enzymes include hexokinase, phosphoglucomutase, UDP-glucose pyrophosphorylase, glycogenin, glycogen synthase, and glycogen branching enzyme.
In addition to these specialized proteins, glucose transporters are required for transporting glucose from blood to liver or muscle cells. Glycogenesis occurs mostly when there is an abundant amount of glucose in the blood, like after a good meal.
Hexokinase
Like in glycolysis (the breakdown of glucose), hexokinase is responsible for the phosphorylation of glucose molecules. Without phosphorylation, the synthesis of glycogen can be halted.
Phosphorylation is the addition of a phosphate group to a glucose molecule. A glucose molecule converts to Glucose-6-phosphate in the presence of this enzyme and ATP (Adenosine triphosphate) molecule furing glycogenesis.
In liver cells, hexokinase is referred to as glucokinase. Although its work is phosphorylation, glucokinase can phosphorylate glucose molecules but not other hexose sugars.
Phosphoglucomutase
This enzyme is responsible for the conversion of glucose-6-phosphate to glucose-1-phosphate in glycogenesis. So, phosphoglucomutase or PGM’s role is the conversion of glucose-6-phosphate to glucose-1-phosphate and vice versa.
UDP-glucose pyrophosphorylase
In glycogenesis, UDP-glucose pyrophosphorylase (UGPase) catalyzes the formation of UPD-glucose from the reaction between UTP (Uridine Triphosphate) and glucose-1-phosphate. Its primary substrates are glucose-1-phosphate and UTP. This enzyme also participates in different synthesis pathways of nucleotide sugars for various biological processes. Glycogenin
Glycogenin is a dimeric protein that acts as an autocatalytic primer for glycogen synthesis. It has two identical subunits: one enzymatic and the other non-enzymatic.
It catalyzes the transfer of glucose to oneself from the UDP-glucose. The glucose is transferred to the -OH group of tyrosine residue within its structure.
Glycogenin can also catalyze the formation of ɑ-1,4-glycosidic bond between the first bound glucose molecule and the new glucose molecule. Once the primer reaches a specific size, glycogen synthase and glycogen branching enzymes take over the elongation and branching of glycogen.
Glycogen synthase
Once the primer reaches the desired size, the glycogen synthase (GYS) enzyme adds further glucose molecules by forming an ɑ-1,4-glycosidic bond between the reducing side (C1) of the new glucose molecule and the non-reducing side (C4) of an already existing glucose molecule. This enzyme is crucial for the elongation of the chain.
Glycogen branching enzyme
This enzyme is the common name of 1,4-glucan:1,4-glucan 6-glucanotransferase or amylo-(1,4 to 1,6)-transglycosylase. This enzyme catalyzes the branching reaction. Once the oligosaccharide chain reaches a certain height (usually 8-12 glucose residues), a portion of the chain is transferred to a different position, forming a ɑ-1,6-glycosidic bond.
This reaction helps form typical glycogen branching, which aids in the efficient storage of glucose.
Glucose transporters
Although these are not enzymes, they help transport glucose across cell membranes. Hence, glucose transporters (GLUTs) are essential for the synthesis of glycogen. There are up to 12 types of GLUT (GLUT1 to GLUT12) in the human body. The liver uptakes glucose molecules from the blood with the help of GLUT1 and GLUT2. GLUT4 helps transport glucose to muscle cells.
Mechanism of Glycogenesis
Glycogenesis is a complex enzymatic process and occurs in the following steps:
Uptake of glucose
Cells that store glucose as glycogen need to uptake glucose from the bloodstream using GLUTs or glucose transporters. GLUT2 is responsible for the uptake of glucose from the blood to the liver, and GLUT4 helps in the uptake of glucose in muscle cells.
Glucose Conversion
After entering the desired cell, glucose needs to be converted to glucose-6-phosphate for the synthesis of glycogen. This conversion occurs by phosphorylation reaction. Hexokinase (in muscle and other cells) and glucokinase (in the liver) catalyze this reaction. The phosphate for the addition of phosphorylation comes from the ATP molecule, which changes into the ADP (Adenosine Diphosphate) molecule.
Reaction summary; Glucose + ATP → Glucose-6-phosphate + ADP; in presence of hexokinase or glucokinase
Isomerization
The glucose-6-phosphate is isomerized to glucose-1-phosphate with the enzyme phosphoglucomutase. This step is essential for incorporating glucose into the growing glycogen chain.
Summary Reaction; Glucose-6-phosphate ⇄ Glucose-1-phosphate; in presence of phosphoglucomutase
UDP-glucose synthesis
A two-step reaction forms the UDP-glucose.
- Glucose-1-phosphate reacts to UTP (uridine triphosphate) in the presence of UDP-glucose pyrophospholase to form UDP-glucose-PPi (pyrophosphate).
- The hydrolysis of PPi to two single phosphate molecules provides energy for further reaction, releasing UDP-glucose.
Reaction summary: Glucose-1-phosphate + UTP ⇄ UDP-Glucose + PPi in the presence of UDP-glucose pyrophospholase.
Initiation of Glycogen chain
Glycogenin (an autocatalytic primer) reacts with UDP-glucose. The reducing (C1) of glucose attaches to the -OH group of a tyrosine residue in glycogen. Here, glycogenin facilitates the addition of further glucose molecules to the C4 or non-reducing side of the glucose by forming ɑ-1,4-glycosidic bond.
Elongation of Glycogen chain
After the formation of 8-10 glucose residues in the glycogen chain, the enzyme glycogen synthase takes over its elongation. This helps form the ɑ-1,4-glycosidic bond between C1 of a new glucose molecule and C4 of the old glucose molecule.
Branching of Glycogen
The characteristic branching of the glycogen chain is the final step in glycogenesis. Here, the glycogen branching enzyme added branches to the glycogen molecule. The enzyme cleaves a segment of the glycogen chain from the non-reducing end and translocates it to the C6 of an adjacent glucose molecule by forming an α-1,6-glycosidic bond.
Formation of Glycogen Granules
The addition of multiple chains of glucose to the glycogen leads to the formation of a granule-like structure. The structure has a center of highly branched glycogen surrounded by several less branched outer layers.
Regulation of Glycogenesis
The regulation of glycogenesis is essential for energy storage and utilization in cells. The whole process is regulated tightly. The regulatory mechanism includes the signaling from hormones like insulin and glucagon and the regulation of enzymes involved in the process, like glycogen synthase.
Regulation by Hormones
- Insulin is the primary hormone promoting glycogenesis in liver and muscle cells. After meal consumption, blood glucose levels increase, triggering pancreatic beta cells to release insulin. The hormone binds to receptors on target cells that activate the signaling pathways. The pathways activate protein phosphatase 1 (PP1), which dephosphorylates and activates glycogen synthase. The enzyme can now catalyze the addition of glucose to the growing glycogen chain.
- Another hormone influencing glycogenesis is glucagon. This hormone works opposite to insulin and promotes glycogenolysis (the breakdown of glycogen). It also suppresses gluconeogenesis.
- Epinephrine or adrenaline also affects glycogenesis. During stressful times or exercise, the adrenal glands release this hormone. Glycogen breakdown is essential for a quick supply of energy, so the hormone triggers glycogenolysis. A signaling mechanism helps inhibit glycogen synthase by phosphorylating and activating glycogen phosphorylase.
Regulation of Glycogen Synthase
Several metabolites and signaling molecules are responsible for the allosteric regulation of the enzyme glycogen synthase. Glucose-6-phosphate and AMP (Adenosine monophosphate) stimulate glycogen synthase activity. AMP reflects low energy status, whereas glucose-6-phosphate shows high cellular energy and availability of substrate. ATP and phosphorylated intermediates (G6P during glycogenolysis) inhibit glycogen synthase activity.
Likewise, reversible phosphorylation of glycogen synthase can regulate its activity. Phosphorylation of glycogen synthase by glycogen synthase kinase-3 (GSK-3) converts it to a less active form, glycogen synthase b. Insulin signaling promotes dephosphorylation of glycogen synthase, converting glycogen synthase b to glycogen synthase a.
Glucagon and epinephrine also activate GSK-3 and inhibit glycogen synthase, decreasing glycogenesis.
Glucose Availability
The availability of glucose within the cell can affect the rate of glycogen synthesis. It is influenced by dietary intake and cellular glucose uptake. Glucose-6-phosphate is a derivative of glucose after phosphorylation, and its presence inside the cell stimulates glycogenesis. G6P serves as a precursor for glycogenesis and allosterically activates glycogen synthase.
Glycogenin Activity
Another regulated step is glycogenin’s initiation of glycogen synthesis. Glycogenin self-glucosylation activity is essential for generating the initial glycogen primer. However, the precise regulatory mechanisms governing glycogenin activity are not as well understood as those governing glycogen synthase.
References
- Froese, D. S., Michaeli, A., McCorvie, T. J., Krojer, T., Sasi, M., Melaev, E., Goldblum, A., Zatsepin, M., Lossos, A., Álvarez, R., Escribá, P. V., Minassian, B. A., von Delft, F., Kakhlon, O., & Yue, W. W. (2015). Structural basis of glycogen branching enzyme deficiency and pharmacologic rescue by rational peptide design. Human molecular genetics, 24(20), 5667–5676. https://doi.org/10.1093/hmg/ddv280
- Visuttijai, K., Hedberg-Oldfors, C., Thomsen, C., Glamuzina, E., Kornblum, C., Tasca, G., Hernandez-Lain, A., Sandstedt, J., Dellgren, G., Roach, P., & Oldfors, A. (2020). Glycogenin is Dispensable for Glycogen Synthesis in Human Muscle, and Glycogenin Deficiency Causes Polyglucosan Storage. The Journal of clinical endocrinology and metabolism, 105(2), 557–566. https://doi.org/10.1210/clinem/dgz075
- Chadt, A., & Al-Hasani, H. (2020). Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Archiv : European journal of physiology, 472(9), 1273–1298. https://doi.org/10.1007/s00424-020-02417-x
- Patino SC, Orrick JA. Biochemistry, Glycogenesis. [Updated 2024 Jan 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549820/
- Daghlas SA, Mohiuddin SS. Biochemistry, Glycogen. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539802/
