Glycogen phosphorylase
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Glycogen phosphorylase is one of the phosphorylase enzymes (EC 2.4.1.1). Glycogen phosphorylase catalyzes the rate limiting step in the degradation of glycogen in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond.
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[edit] Isozymes
In mammals, the major isozymes of glycogen phosphorylase are found in muscle, liver and brain. The brain type is predominant in adult brain and embryonic tissues, while the liver and muscle types are predominant in adult liver and skeletal muscle, respectively.[1]
[edit] Clinical significance
Mutations in the muscle isoform of glycogen phosphorylase (PYGM) are associated with McArdle disease (glycogen storage disease type V). More than 65 mutations in the PYGM gene that lead to McArdle disease have been identified to date.[2][3]
Mutations in the liver isoform of glycogen phosphorylase (PYGL) are associated with Hers disease (glycogen storage disease type VI).[4][5]
The brain isoform of glycogen phosphorylase (PYGLB) has been proposed as a biomarker for gastric cancer.[6]
[edit] Mechanism
Glycogen phosphorylase breaks up glycogen into glucose subunits. Glycogen is left with one less glucose molecule, and the free glucose molecule is in the form of glucose-1-phosphate. In order to be used for metabolism, it must be converted to glucose-6-phosphate by the enzyme phosphoglucomutase.
Glycogen phosphorylase can only act on linear chains of glycogen (α1-4 glycosidic linkage). Its work will immediately come to a halt four residues away from α1-6 branch (which are exceedingly common in glycogen). In these situations, a debranching enzyme is necessary, which will straighten out the chain in that area. Additionally, the enzyme transferase shifts a block of 3 glucosyl residues from the outer branch to the other end and then an α1-6 glucosidase enzyme is required to break the remaining (single glucose) α1-6 residue that remains in the new linear chain. After all this is done, glycogen phosphorylase can continue. The enzyme is specific to α1-4 chains as the molecule contains a 30 angstrom long crevice with the same radius as the helix formed by the glycogen chain, this accommodates 4-5 glucosyl residues, but is too narrow for branches. This crevice connects the glycogen storage site to the active, catalytic site.
Glycogen phosphorylase has a pyridoxal phosphate (PLP derived from Vitamin B6) at each catalytic site. Pyridoxal phosphate links with basic residues and covalently forms a Schiff base which helps attack the substrate. PLP is covalently linked to the protein via the ε-amino group of a lysyl residue. PLP therefore stabilizes the attacking phosphate group.
[edit] Regulation
Glycogen phosphorylase is regulated by both allosteric control and by phosphorylation (covalent modification).
Hormones such as epinephrine and glucagon regulate glycogen phosphorylase using second messenger amplification systems that are linked to G proteins. Epinephrine activates adenylate cyclase through a G-protein that in turn increases levels of cAMP. cAMP binds to and releases an active form of protein kinase A (PKA). Next, PKA phosphorylates phosphorylase kinase which in turn phosphorylates glycogen phosphorylase b, transforming it into the active glycogen phosphorylase a. This phosphorylation is added onto the glycogen phosphorylase a seryl 14. In the liver, epinephrine activates another G-protein linked receptor that triggers a different cascade resulting in the activation of Phospholipase C (PLC). PLC indirectly causes the release of calcium from the hepatocytes endoplasmic reticulum into the cytosol. The increased calcium availability binds to the calmodulin subunit and activates glycogen phosphorylase kinase. Glycogen phosphorylase kinase activates glycogen phosphorylase in the same manner mentioned previously.
Glycogen phosphorylase b is not always inactive in muscle, as it can be activated allosterically by AMP. An increase in AMP concentration, which occurs during strenuous exercise, signals energy demand. AMP activates glycogen phosphorylase b by changing its conformation from a taut to a relaxed form. This relaxed form has similar enzymatic properties as the phosphorylated enzyme. An increase in ATP concentration opposes this activation by displacing AMP from the nucleotide binding site, indicating sufficient energy stores.
Upon eating a meal there is a release of insulin, signaling glucose availability in the blood. Insulin indirectly activates PP-1 and phosphodiesterase. The PP-1 directly dephosphorylates glycogen phosphorylase a reforming the inactive glycogen phosphorylase b. The phosphodiesterase converts cAMP to AMP. This activity removes the second messenger (generated by glucagon and epinephrine) and inhibits PKA. In this manner, PKA can no longer cause the phosphorylation cascade that ends with formation of (active) glycogen phosphorylase a. These modifications initiated by insulin end glycogenolysis in order to preserve what glycogen stores are left in the cell and trigger glycogenesis (rebuilding of glycogen).
Phosphorylase a and b each exist in two forms a T (tense) inactive state and R (relaxed) state. Phosphorylase b is normally in the T state, inactive due to the physiological presence of ATP and Glucose 6 phosphate, and Phosphorylase a is normally in the R state (active)
An isoenzyme of glycogen phosphorylase exists in the liver sensitive to glucose concentration as the liver acts as a glucose exporter. Essentially, liver phosphorylase is responsive to glucose which causes a very responsive transition from the R to T form, inactivating it, furthermore, liver phosphorylase is insensitive to AMP.
[edit] See also
- McArdle's Disease (deficiency of (muscle) myophosphorylase)
- Hers' Disease (deficiency of liver phosphorylase)
[edit] References
- ^ David ES, Crerar MM (January 1986). "Quantitation of muscle glycogen phosphorylase mRNA and enzyme amounts in adult rat tissues". Biochim. Biophys. Acta 880 (1): 78–90. PMID 3510670.
- ^ Nogales-Gadea G, Arenas J, Andreu AL (January 2007). "Molecular genetics of McArdle's disease". Curr Neurol Neurosci Rep 7 (1): 84–92. doi:. PMID 17217859.
- ^ Andreu AL, Nogales-Gadea G, Cassandrini D, Arenas J, Bruno C (July 2007). "McArdle disease: molecular genetic update". Acta Myol 26 (1): 53–7. PMID 17915571.
- ^ Burwinkel B, Bakker HD, Herschkovitz E, Moses SW, Shin YS, Kilimann MW (April 1998). "Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI". Am. J. Hum. Genet. 62 (4): 785–91. doi:. PMID 9529348.
- ^ Chang S, Rosenberg MJ, Morton H, Francomano CA, Biesecker LG (May 1998). "Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI". Hum. Mol. Genet. 7 (5): 865–70. doi:. PMID 9536091.
- ^ Shimada S, Matsuzaki H, Marutsuka T, Shiomori K, Ogawa M (July 2001). "Gastric and intestinal phenotypes of gastric carcinoma with reference to expression of brain (fetal)-type glycogen phosphorylase". J. Gastroenterol. 36 (7): 457–64. doi:. PMID 11480789.
[edit] Further reading
- Voet, Judith G.; Voet, Donald (1995). "Chapter 17: Glycogen Metabolism". Biochemistry (2nd ed.). New York: J. Wiley & Sons. ISBN 0-471-58651-X.
- Voet, Judith G.; Voet, Donald (2004). "Chapter 18: Glycogen Metabolism". Biochemistry (3rd ed.). New York: J. Wiley & Sons. ISBN 0-471-19350-X.
[edit] External links
- MeSH Glycogen+phosphorylase
- Diwan JJ. "Glycogen Metabolism". Molecular Biochemistry I. Rensselaer Polytechnic Institute. http://rpi.edu/dept/bcbp/molbiochem/MBWeb/mb1/part2/glycogen.htm#animat1. Retrieved on 2009-01-10.
- Goodsell DS (2001-12-01). "Glycogen Phosphorylase". Molecule of the Month. RCSB Protein Data Bank. http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb24_1.html. Retrieved on 2009-01-10.
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