Glycogen phosphorylase and its relation to type 2 diabetes

By Jenny Tang

    Glycogen phosphorylase is an enzyme that catalyzes the breakdown of glycogen to glucose-1-phosphate, where it then enters the glycolysis cycle. It releases glucose-1-phosphate from its terminal α-1,4 glycosidic bond (Livanova, 2002). It is highly regulated, by the phosphorylation, through a kinase cascade that occurs in the liver. 

Regulation of glycogen phosphorylase

 The activation of glycogen phosphorylase goes through a cascade of multiple activations. Protein kinase A (PKA) is activated through the conformational change through the binding of cAMP. Protein kinase A continues to go phosphorylate phosphorylase kinase (PK), which continues to be phosphorylated, and activates Glycogen phosphorylase (Mutalik and Venkatesh, 2005).

 Glycogen phosphorylase exists in two forms, them being glycogen phosphorylase b and glycogen phosphorylase b. In order to be utilized, glycogen phosphorylase needs to be phosphorylated into its active form, glycogen phosphorylase a. In this way, it is highly monitored as it requires to go through many different enzymes and relies on the phosphorylation of the enzymes.  

 Glycogen phosphorylase is highly monitored, as it is able to switch on and off from its forwards and backwards reaction to prevent futile enzyme activity, and to prevent glycogen synthesis and glycogen breakdown at the same time. If the reaction constantly performed both glycogen breakdown and glycogen synthesis at the same rate, it would result in a net product of 0, and result in futile usage of energy. 

Relationship between glycogen phosphorylase and diabetes

Glycogen is regulated by the combination of glycogen synthesis which is performed by glycogen synthase and the breakdown of glycogen, performed by glycogen phosphorylase. These two enzymes are important in hepatic glucose homeostasis. These are combined with signal transduction pathways like cyclic adenosine 3,5-monophosphate (cAMP) and assist through post translational modification, depending on the needs of the human body. When there is an imbalance in glucose, either abnormally high or abnormally low hepatic glycogen output, where both glycogen synthase and glycogen phosphorylase play a large role in (Baker, Timmons and Greenhaff, 2005).

   Glycogen synthase is regulated by phosphorylation sites and allosterically by glucose-6-phosphate, and it is needed for normal glycogen levels. It converts glucose to glycogen, where glycogen is then stored in the liver. Over expression of glycogen synthase can result in glycogen storage levels, which contribute to diabetes (Azpiazu, 2000). This was found in a study done with transgenic mice, where three lines of mice were monitored with glycogen synthase expression and the glycogen content. As there was overexpression of glycogen synthase, the amount of glycogen accumulation increased (Manchester, 1993).

 In order to treat diabetes, the patients have to be able to control their blood glucose levels, which is why they are commonly prescribed hypoglycemic drugs. In type 2 diabetes patients, they have high levels of glycogen output in their liver. The process of the breakdown of glycogen into glucose, called glycogenolysis which occurs in both muscle and liver cells, utilizes glycogen phosphorylase to catalyse the breakdown of glycogen. 

 Glycogen phosphorylase inhibitors can potentially assist in the stabilization of the amount of glucose output in the liver, hence being able to monitor diabetes 2 (Baker, Timmons and Greenhaff, 2005). It was tested with a glucose-based inhibitor named KB228, which was tested under normal conditions and diabetic conditions, on mice. What was observed was that both the diabetic mice that had a high hepatic glucose intake and non-diabetic mice had better glucose sensitivity. This insinuates that these glycogen phosphorylase inhibitors can help reduce glucose levels under both normal and hyperglycemic conditions (Nagy, 2013). The glucose phosphorylase inhibitor additionally assists the build-up of glycogen in muscles and liver which consequently leads to lower blood glucose levels. 

  Glucose phosphorylation is critical for the function of stable glucose levels, and works in conjunction with glycogen synthase to maintain glycogen homeostasis. Though it is highly monitored and regulated by the phosphorylation of different enzymes, and can be switched on and off to maintain its productivity and to prevent futile activity. Glucose phosphatase manipulation through using a glucose phosphatase inhibitor may be benefical, and be a potential tool against regulating the blood sugar, hence assisting in monitoring in diabetes. 

References:

Azpiazu, I. et al., 2000. Control of glycogen synthesis is shared between glucose transport and glycogen synthase in skeletal muscle fibers. American Journal of Physiology-Endocrinology and Metabolism. Available at: https://journals.physiology.org/doi/full/10.1152/ajpendo.2000.278.2.E234 [Accessed December 8, 2020]. 

Baker, D.J., Timmons, J.A. & Greenhaff, P.L., 2005. Glycogen Phosphorylase Inhibition in Type 2 Diabetes Therapy. Diabetes. Available at: https://diabetes.diabetesjournals.org/content/54/8/2453?patientinform-links=yes [Accessed December 8, 2020]. 

J. K.. Parnas, T.B. et al., 1970. Pyridoxal 5″-Phosphate as a Catalytic and Conformational Cofactor of Muscle Glycogen Phosphorylase b. Biochemistry (Moscow). Available at: https://link.springer.com/article/10.1023/A:1020978825802 [Accessed December 8, 2020]. 

Manchester, J. et al., 1996. Increased glycogen accumulation in transgenic mice overexpressing glycogen synthase in skeletal muscle. Proceedings of the National Academy of Sciences of the United States of America. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC38219/ [Accessed December 9, 2020]. 

Mutalik, V.K. & Venkatesh, K.V., 2005. Quantification of the glycogen cascade system: the ultrasensitive responses of liver glycogen synthase and muscle phosphorylase are due to distinctive regulatory designs. Theoretical biology & medical modelling. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1180476/ [Accessed December 8, 2020]. 

Nagy, L. et al., Glycogen Phosphorylase Inhibitor N-(3,5-Dimethyl-Benzoyl)-N’-(β-D-Glucopyranosyl)Urea Improves Glucose Tolerance under Normoglycemic and Diabetic Conditions and Rearranges Hepatic Metabolism. PLOS ONE. Available at: https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0069420 [Accessed December 8, 2020].