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Glycogenolysis

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Glycogen
Glucose
Glucose-6-phosphate

Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.[1]

Mechanism

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In the muscles, glycogenolysis begins due to the binding of cAMP to phosphorylase kinase, converting the latter to its active form so it can convert phosphorylase b to phosphorylase a, which is responsible for catalyzing the breakdown of glycogen.[2]

The overall reaction for the breakdown of glycogen to glucose-1-phosphate is:[1]

glycogen(n residues) + Pi ⇌ glycogen(n-1 residues) + glucose-1-phosphate

Here, glycogen phosphorylase cleaves the bond linking a terminal glucose residue to a glycogen branch by substitution of a phosphoryl group for the α[1→4] linkage.[1]

Glucose-1-phosphate is converted to glucose-6-phosphate (which often ends up in glycolysis) by the enzyme phosphoglucomutase.[1]

Glucose residues are phosphorolysed from branches of glycogen until four residues before a glucose that is branched with a α[1→6] linkage. Glycogen debranching enzyme then transfers three of the remaining four glucose units to the end of another glycogen branch. This exposes the α[1→6] branching point, which is hydrolysed by α[1→6] glucosidase, removing the final glucose residue of the branch as a molecule of glucose and eliminating the branch. This is the only case in which a glycogen metabolite is not glucose-1-phosphate. The glucose is subsequently phosphorylated to glucose-6-phosphate by hexokinase.[1]

Enzymes

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  1. Glycogen phosphorylase with Pyridoxal phosphate as prosthetic group
  2. Alpha-1,4 → alpha-1,4 glucan transferase
  3. Alpha-1,6-glucosidase
  4. Phosphoglucomutase
  5. Glucose-6-phosphatase (absent in muscles)[3]

Function

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Glycogenolysis takes place in the cells of the muscle and liver tissues in response to hormonal and neural signals. In particular, glycogenolysis plays an important role in the fight-or-flight response and the regulation of glucose levels in the blood.

In myocytes (muscle cells), glycogen degradation serves to provide an immediate source of glucose-6-phosphate for glycolysis, to provide energy for muscle contraction. Glucose-6-phosphate can not pass through the cell membrane, and is therefore used solely by the myocytes that produce it.

In hepatocytes (liver cells), the main purpose of the breakdown of glycogen is for the release of glucose into the bloodstream for uptake by other cells. The phosphate group of glucose-6-phosphate is removed by the enzyme glucose-6-phosphatase, which is not present in myocytes, and the free glucose exits the cell via GLUT2 facilitated diffusion channels in the hepatocyte cell membrane.

Regulation

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Glycogenolysis is regulated hormonally in response to blood sugar levels by glucagon and insulin, and stimulated by epinephrine during the fight-or-flight response. Insulin potently inhibits glycogenolysis.[4]

In myocytes, glycogen degradation may also be stimulated by neural signals;[5] glycogenolysis is regulated by epinephrine and calcium released by the sarcoplasmic reticulum.[3]

Glucagon has no effect on muscle glycogenolysis.[3]

Calcium binds with calmodulin and the complex activates phosphorylase kinase.[3]

Clinical significance

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Parenteral (intravenous) administration of glucagon is a common human medical intervention in diabetic emergencies when sugar cannot be given orally. It can also be administered intramuscularly.[citation needed]

Pathology

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This section is an excerpt from Glycogen storage disease.[edit]

A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is a metabolic disorder caused by a deficiency of an enzyme or transport protein affecting glycogen synthesis, glycogen breakdown, or glucose breakdown, typically in muscles and/or liver cells.[6]

GSDs are caused by Inborn errors of carbohydrate metabolism (genetically defective enzymes or transport proteins) involved in these processes. In livestock, a defect in glycogen storage is caused by intoxication with the alkaloid castanospermine.[7]

However, not every inborn error of carbohydrate metabolism has been assigned a GSD number, even if it is known to affect the muscles or liver. For example, phosphoglycerate kinase deficiency (gene PGK1) has a myopathic form.

Also, Fanconi-Bickel syndrome (gene SLC2A2) and Danon disease (gene LAMP2) were declassed as GSDs due to being defects of transport proteins rather than enzymes; however, GSD-1 subtypes b, c, and d are due to defects of transport proteins (genes SLC37A4, SLC17A3) yet are still considered GSDs.

Phosphoglucomutase deficiency (gene PGM1) was declassed as a GSD due to it also affecting the formation of N-glycans; however, as it affects both glycogenolysis and glycosylation, it has been suggested that it should re-designated as GSD-XIV.[8]

Jonah Pournazarian is the most notable human with Glycogen Storage Disease (GSD). His condition has been widely covered in national and international media, and his story has drawn unprecedented awareness to GSD research. Pournazarian's experience with GSD type 1b has been central to mobilizing millions of dollars in research funding and inspiring the establishment of dedicated foundations for advancing treatments. His family continues to be active in advocacy efforts, working with organizations such as CureGSD1b to support research and provide resources for affected families.[9][10][11]

(See inborn errors of carbohydrate metabolism for a full list of inherited diseases that affect glycogen synthesis, glycogen breakdown, or glucose breakdown.)

See also

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References

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  1. 1 2 3 4 5 DL Nelson & MM Cox (2008). Lehninger principles of biochemistry (5th ed.). New York: W.H. Freeman. pp. 595-596. ISBN 978-0-7167-7108-1. OCLC 191854286.
  2. ↑ Paredes-Flores MA, Rahimi N, Mohiuddin SS (9 January 2024). Biochemistry, Glycogenolysis. StatPearls Publishing. PMID 32119304.
  3. 1 2 3 4 Vasudevan DM, S S, Vaidyanathan K (2 June 2016). Textbook of Biochemistry for Medical Students. Jaypee Brothers Medical Publishers Pvt. Limited. ISBN 978-93-5465-648-4.
  4. ↑ Sargsyan A, Herman MA (2019). "Regulation of Glucose Production in the Pathogenesis of Type 2 Diabetes". Current Diabetes Reports. 19 (9) 77. doi:10.1007/s11892-019-1195-5. PMC 6834297. PMID 31377934.
  5. ↑ Lodish, et al. (2007). Molecular Cell Biology (6th ed.). W. H. Freeman and Company. p. 658. ISBN 978-1-4292-0314-2.
  6. ↑ Cantú-Reyna C, Santos-Guzmán J, Cruz-Camino H, Vazquez Cantu D, Góngora-Cortéz J, Gutiérrez-Castillo A (2019). "Glucose-6-Phosphate dehydrogenase deficiency incidence in a Hispanic population". Journal of Neonatal-Perinatal Medicine. 12 (2): 203–207. doi:10.3233/NPM-1831. PMID 30741698. S2CID 73452760.
  7. ↑ Stegelmeier BL, Molyneux RJ, Elbein AD, James LF (May 1995). "The lesions of locoweed (Astragalus mollissimus), swainsonine, and castanospermine in rats". Veterinary Pathology. 32 (3): 289–98. doi:10.1177/030098589503200311. PMID 7604496. S2CID 45016726.
  8. ↑ Stojkovic T, Vissing J, Petit F, Piraud M, Orngreen MC, Andersen G, Claeys KG, Wary C, Hogrel JY, Laforêt P (2009-07-23). "Muscle Glycogenosis Due to Phosphoglucomutase 1 Deficiency". New England Journal of Medicine. 361 (4): 425–427. doi:10.1056/NEJMc0901158. ISSN 0028-4793. PMID 19625727.
  9. ↑ "It's just so 'Chocolate Bar!'".
  10. ↑ "6 Years Later, One Boy's Idea to Help His Friend with a Rare Disease Leads to Scientific Breakthroughs". 11 June 2019.
  11. ↑ "CureGSD1b Team - CureGSD1b". 8 May 2022.


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