Glycogen is an extensively branched glucose polymer that is used by animals as an energy reserve. It is the animal analog to starch. It is highly concentrated in the liver, although skeletal muscles have significant content as well. It is also present in lower levels in other tissues, such as kidney, heart, and brain. The glucose residues within glycogen connect via two principal bonds, the alpha-1,4 and alpha-1,6 glycosidic bonds in strands and at junction points, respectively. The branching is a crucial aspect of glycogen as it increases its solubility and allows it to get metabolized more quickly. Importantly, glycogen is used to maintain glucose homeostasis. Because of this, its metabolism is highly regulated primarily by insulin and glucagon and molecules in their downstream signaling pathways. Insulin and glucagon promote glycogen synthesis and breakdown, respectively. Pathologies that target enzymes involved in glycogen synthesis, degradation, and/or regulation may have significant adverse effects on the body.
Key Fundamental Points:
Broadly, glycogen is either synthesized or broken down depending on the needs of the body. It is an essential molecule for maintaining glucose homeostasis. Two major peptide hormones involved in its regulation are insulin and glucagon, which promote anabolism and catabolism respectively. Understanding the broad effects of these two hormones is important in the context of glycogen. Insulin signals a high energy state, thus its downstream effects include the synthesis of lipids and glycogen. Glucagon signals a low energy state; thus its downstream effects are the reverse of insulin actions. Therefore, increased glucagon release will result in the downstream effect of increased lipolysis and glycogenolysis to meet the body’s needs.
Specifically, insulin and glucagon’s downstream effects alter the activity of several enzymes oppositely involved in glycogen metabolism via dephosphorylation and phosphorylation, respectively. Insulin associates with the activation of protein phosphatase 1 (PP1) and Protein Kinase B (PKB). Glucagon associates with the cAMP-mediated pathway that activates Protein Kinase A (PKA). In glycogen synthesis, glycogen synthase is the primary enzyme regulated by PP1 as mentioned above, PKB, and PKA enzymes.
Glycogen synthase has two major forms, which are glycogen synthase a and glycogen synthase b, which are the active and inactive forms, respectively. The significant difference between them is that glycogen synthase b is more phosphorylated than glycogen synthase a. In the insulin-mediated pathway, PP1 dephosphorylates glycogen synthase b to convert it to glycogen synthase a. PKB accomplishes this indirectly by inactivating an enzyme known as glycogen synthase kinase 3 (GSK3), which would otherwise phosphorylate glycogen synthase a. In the glucagon-mediated pathway, PKA phosphorylates PP1, preventing PP1 from activating glycogen synthase b to glycogen synthase a.
Two major forms of glycogen phosphorylase are glycogen phosphorylase a and b, which are the active and inactive forms, respectively. The glucagon associated PKA activates glycogen phosphorylase kinase, which subsequently phosphorylates and activates glycogen phosphorylase. The insulin associated PP1 dephosphorylates glycogen phosphorylase, converting it to its b form. It is important to note that the liver isoform of glycogen phosphorylase a needs glucose to bind to an allosteric site to allow PP1 to dephosphorylate it. Thus, the liver glycogen phosphorylase is typically considered a “glucose sensor.”
There is glycogen metabolic regulation specific to skeletal muscle. Glycogen phosphorylase kinase b increases its activity in the presence of calcium in the cytoplasm released from the sarcoplasmic reticulum during muscle contraction. It contains calmodulin subunits, which have a high affinity for calcium. Low energy state compounds such as AMP, IMP, and Pi are known to be positive allosteric regulators of glycogen phosphorylase, which promotes its conversion from glycogen phosphorylase b to glycogen phosphorylase a.
Glycogenesis or glycogen synthesis is a multi-step process that begins with the conversion of glucose to glucose-6-phosphate via hexokinase or the liver isoform of hexokinase known as glucokinase. This process is an important step as the addition of a phosphate group traps glucose within the cell.G6P is subsequently converted to glucose-1-phosphate (G1P) via phosphoglucomutase. G1P converts to UDP glucose via glucose-1-phosphate uridyltransferase, which requires UTP as an additional substrate.In this step, G1P’s phosphate group performs a nucleophilic attack on the alpha phosphate of UTP, resulting in the release of pyrophosphate (PPi), which a highly reactive molecule that is quickly subject to hydrolysis. The release of PPi helps to push the reaction forward. Glycogen synthase creates an alpha-1,4 glycosidic bond between UDP-glucose and a growing glycogen strand.
However, before glycogen synthase works, it requires a glycogen primer. Glycogenin synthesizes this initial primer for glycogen synthase. Briefly, glycogenin acts by attaching a UDP-glucose molecule at its 1C position to a hydroxyl group on a tyrosine residue, which causes UDP to exit, and the primer subsequently grows to 10 to 20 glucose residues long.
Branching subsequently occurs via a glycogen branching enzyme, which has two catalytic activities, which include a transferase and alpha-1,6 glycosidase that forms the branch bond. Once the glycogen chain is roughly 11 glucose residues long, the glycogen branching enzyme begins to add branches. On average, an eight glucose residue segment transfers and gets placed as a branch of a nearby strand. This branching is an important component as it increases solubility and sites in which glucose can be extracted from the glycogen polymer.
Glycogenolysis or glycogen breakdown it primarily requires glycogen phosphorylase and debranching enzyme. Glycogen phosphorylase requires the entry of phosphate (Pi) and PLP, a cofactor derived from Vitamin B6. It ultimately removes one glucose residue from glycogen in the form of G1P. However, glycogen phosphorylase is unable to break down alpha-1,4 bonds as it approaches a junction point; thus, the glycogen debranching enzyme takes over four glucose residues before the junction point is reached. Like the branching enzyme, it has two catalytic properties. In this case, they are a transferase and alpha-1,6 glucosidase which transfer the three distal glucose molecules to a proximal longer chain and hydrolysis of the alpha-1,6 glycosidic bond, respectively. The hydrolysis of the alpha-1,6 glycosidic bond yields a glucose unit instead of G1P. The ratio of G1P to glucose generate from glycogenolysis is considered to be 10:1. Once G1P is extracted from glycogen, it can be converted to G6P via phosphoglucomutase , to be utilized for other processes such as glycolysis or the pentose phosphate pathway (PPP). Alternatively, it can be converted to glucose. In order to do so, it must be broken down via glucose-6-phosphatase which is located on the endoplasmic reticulum membrane. It is important to know that muscle does not express glucose-6-phosphatase (G6Pase).
There are a multitude of glycogen storage diseases (GSD) that are caused by a genetic mutation in enzymes directly involved the anabolism and catabolism of glycogen. Many of these are inherited in an autosomal recessive pattern and often present in early childhood. The major GSDs and the enzymes perturbed are as follows:
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