Study Guide - Glycogenesis Course
A comprehensive review of glycogen synthesis: pathway chemistry, enzyme roles, hormonal control, clinical correlates, and quick checks for exam prep.
Test your knowledge with the Glycogenesis Game.
| Term | Definition |
|---|---|
| Glycogenesis | Anabolic pathway that polymerizes glucose into glycogen for storage, mainly in liver and skeletal muscle |
| Glycogenolysis | Catabolic breakdown of glycogen to glucose-1-phosphate (and in liver, ultimately blood glucose) - opposed to glycogenesis during fasting and exercise |
| Glycogen | Highly branched polymer of glucose with alpha-1,4 backbone linkages and alpha-1,6 branch points, stored in cytosolic granules |
| Glycogenin | Self-glucosylating primer protein that attaches the first glucose oligomer and remains covalently linked at the core of each glycogen molecule |
| Glycogen synthase (GSa / GSb) | Rate-limiting enzyme of glycogenesis; GSa denotes the more active, dephosphorylated form, GSb the less active, phosphorylated form |
| Branching enzyme | Amylo-(1,4→1,6)-transglycosylase that transfers a segment of an alpha-1,4 chain to form an alpha-1,6 branch, increasing non-reducing ends |
| UDP-glucose | Activated glucose donor for glycogen elongation; formed from glucose-1-phosphate and UTP with release of pyrophosphate |
| UDP-glucose pyrophosphorylase | Catalyzes G1P + UTP → UDP-glucose + PPi; also called UGPase - commits glucose to glycogen (and other UDP-sugar) pathways |
| Phosphoglucomutase | Interconverts glucose-6-phosphate and glucose-1-phosphate, linking glycolytic intermediates to glycogenesis and glycogenolysis |
| Alpha-1,4-glycosidic bond | Linkage between C1 of one glucose and C4 of the next along a linear glycogen chain - substrate for synthase elongation and phosphorylase release of G1P |
| Alpha-1,6-glycosidic bond | Branch linkage attaching a side chain to a prior residue; created by branching enzyme and hydrolyzed by the debranching enzyme during glycogenolysis |
| Non-reducing end | Terminal glucose whose anomeric C1 is tied up in a glycosidic bond - the site where glycogen synthase adds UDP-glucose and phosphorylase removes G1P |
| Protein phosphatase 1 (PP1) | Major phosphatase that dephosphorylates and activates glycogen synthase and inactivates phosphorylase - promoted in the fed, insulin-stimulated state |
| GSK-3 | Glycogen synthase kinase-3; phosphorylates glycogen synthase toward the inactive state - restrained by insulin-Akt signaling |
| Insulin | Pancreatic beta-cell hormone of the fed state; increases glucose uptake and flux into glycogenesis and activates glycogen synthase via phosphatases and reduced GSK-3 activity |
| Glucagon | Pancreatic alpha-cell hormone that signals fasting in the liver; raises cAMP, activates PKA, favors glycogen breakdown and suppresses glycogenesis |
Fed state
Insulin dominates. Signaling favors protein phosphatase 1 (PP1), which dephosphorylates glycogen synthase to the more active GSa form. Insulin-Akt signaling also inhibits GSK-3, reducing phosphorylation of synthase. Glycogen breakdown is suppressed; glucose is stored as glycogen when substrate and energy are abundant.
Fasted state (liver)
Glucagon (low insulin) raises hepatic cAMP, activating protein kinase A (PKA). PKA phosphorylates glycogen synthase toward the less active GSb form and activates the phosphorylase cascade, shifting flux toward glycogenolysis and gluconeogenesis rather than glycogenesis.
| Type | Name | Enzyme / defect | Key features |
|---|---|---|---|
| 0 (liver) | Glycogen synthase deficiency | Hepatic glycogen synthase | Fasting hypoglycemia, ketosis; liver may store little glycogen |
| Ia | von Gierke | Glucose-6-phosphatase | Severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperlipidemia, hyperuricemia |
| Ib | von Gierke variant | G6P transporter (T1) into ER | Similar to Ia with neutropenia and inflammatory bowel-like issues |
| II | Pompe | Lysosomal acid alpha-glucosidase (GAA) | Glycogen accumulates in lysosomes; infantile cardiomyopathy and hypotonia; later-onset myopathy |
| III | Cori / Forbes | Debranching enzyme (glycogen debranching enzyme) | Limit dextrin accumulation; hepatomegaly, hypoglycemia; muscle involvement in some subtypes |
| IV | Andersen | Branching enzyme | Poorly branched polyglucosan; progressive liver disease / cirrhosis; variable neuromuscular forms |
| V | McArdle | Muscle glycogen phosphorylase | Exercise intolerance, second-wind phenomenon, myoglobinuria; normal resting blood glucose |
| VI | Hers | Liver glycogen phosphorylase | Milder hepatomegaly and fasting hypoglycemia compared to type I |
| VII | Tarui | Muscle phosphofructokinase-1 (PFKM) | Exercise intolerance, hemolytic tendency (RBC PFK affected); glycogen and glucose-6-phosphate may rise in muscle |
| IX | Phosphorylase kinase deficiency | Phosphorylase kinase (liver PHKA2 X-linked common) | Hepatomegaly, variable hypoglycemia, delayed motor milestones in some cases |
Liver glycogen
Muscle glycogen
Q1.Why can hepatic glycogen raise blood glucose after a meal is absorbed, but muscle glycogen cannot replenish systemic glucose during exercise recovery?
Hepatocytes express glucose-6-phosphatase in the endoplasmic reticulum, so G6P from glycogenolysis can be converted to free glucose and exported. Skeletal muscle lacks this enzyme, so G6P enters glycolysis locally. Muscle glycogen therefore supports contraction but not blood glucose export.
Q2.What is the biochemical role of UDP-glucose in glycogenesis, and which enzyme forms it from G1P?
UDP-glucose is the activated donor that supplies glucosyl units for glycogenin priming and for glycogen synthase elongation. UDP-glucose pyrophosphorylase (UGPase) catalyzes G1P + UTP → UDP-glucose + PPi; pyrophosphatase hydrolysis of PPi makes the step effectively irreversible.
Q3.Contrast glycogen synthase GSa and GSb and explain how insulin shifts the balance toward synthesis in the liver.
GSa refers to the more active, dephosphorylated synthase; GSb is the less active, multiply phosphorylated form. Insulin signaling activates phosphatases such as PP1, which dephosphorylates synthase toward GSa. Insulin also signals through Akt to phosphorylate and inhibit GSK-3, reducing inhibitory phosphorylation of synthase. Concurrently, glycogen breakdown is switched off.
Q4.A child has severe fasting hypoglycemia, hepatomegaly, elevated lactate, and hyperlipidemia. Which glycogen storage disease classically fits, and what enzyme is deficient?
This pattern matches glycogen storage disease type Ia (von Gierke disease), caused by deficiency of glucose-6-phosphatase. G6P cannot be converted to free glucose for export, so hypoglycemia occurs while G6P is diverted to glycolysis (lactate) and to alternative pathways that raise lipids and uric acid.
Q5.What does branching enzyme do, and why would its deficiency lead to abnormal glycogen with fewer branch points?
Branching enzyme (amylo-(1,4→1,6)-transglycosylase) transfers a terminal fragment from an alpha-1,4 chain and attaches it with an alpha-1,6 linkage, creating branches. Without it, glycogen has long outer chains and fewer non-reducing ends - as seen in type IV (Andersen disease), producing poorly branched polyglucosan material.
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