Glycogen phosphorylase (GP) (GP)

Glycogen phosphorylase is a critical metabolic enzyme that serves as the rate-limiting step in glycogenolysis, the process of breaking down glycogen into glucose-1-phosphate. It exists in three primary isoforms—liver (PYGL), muscle (PYGM), and brain (PYGB)—which are encoded by distinct genes and regulated by hormonal signals like glucagon and epinephrine, as well as allosteric effectors like AMP and glucose. In the liver, the enzyme plays a pivotal role in maintaining blood glucose levels during fasting, making it a prominent therapeutic target for the treatment of hyperglycemia in Type 2 diabetes. Inhibition of liver glycogen phosphorylase is intended to reduce excessive hepatic glucose production, a major contributor to elevated fasting blood sugar in diabetic patients. Genetic deficiencies in specific isoforms lead to glycogen storage diseases, such as McArdle disease (muscle) and Hers disease (liver). Despite significant pharmaceutical interest and the development of several small-molecule allosteric inhibitors, clinical progress has been challenged by the need for high isoform selectivity to avoid adverse effects related to muscle function and liver health.

Other names

Alpha-glucan phosphorylasePhosphorylaseGlycogen phosphorylase, liver form (PYGL)Glycogen phosphorylase, muscle form (PYGM)Glycogen phosphorylase, brain form (PYGB)1,4-alpha-D-glucan:phosphate alpha-D-glucosyltransferase

Allosteric inhibition of the enzyme activity by binding to specific sites (such as the AMP-binding site, the indole site, or the catalytic site), thereby stabilizing the enzyme in its inactive T-state and preventing the breakdown of glycogen into glucose-1-phosphate.