Glykogenfosforylas

Glykogenfosforylas, or glycogen phosphorylase, is a cytosolic enzyme that catalyzes the rate-limiting step of glycogenolysis. It cleaves glucose units from glycogen by phosphorolysis, producing glucose-1-phosphate and a shortened glycogen chain. The reaction is glycogen(n) + Pi -> glucose-1-phosphate + glycogen(n−1). The enzyme requires pyridoxal phosphate (PLP) as a cofactor and acts on the alpha-1,4-glycosidic bonds of glycogen.

In mammals, there are three tissue-specific isoforms: PYGL (liver), PYGM (muscle), and PYGB (brain). The enzyme exists in two states: glycogen phosphorylase b (inactive, dephosphorylated) and glycogen phosphorylase a (active, phosphorylated on serine 14 by phosphorylase kinase). Regulation occurs through covalent modification and allosteric control.

Covalent regulation links to hormonal signaling. Phosphorylation of glycogen phosphorylase by phosphorylase kinase is activated by hormones such as glucagon and epinephrine (in liver and muscle, respectively) via a cAMP/PKA pathway, promoting glycogen breakdown. Insulin promotes dephosphorylation and inactivation via protein phosphatase 1, reducing glycogenolysis.

Allosteric regulation complements the covalent control. AMP activates glycogen phosphorylase b, enhancing activity when cellular energy is low. Glucose and glucose-6-phosphate inhibit the enzyme, with liver isoforms showing sensitivity to glucose to help control hepatic glucose output; in muscle, the enzyme preferentially channels glucose-1-phosphate toward glycolysis for energy rather than glucose release.

Biological role and clinical relevance: glycogen phosphorylase drives glycogen breakdown to supply glucose-1-phosphate for energy or blood glucose homeostasis. Deficiency of the liver isoform (PYGL) causes Hers disease (glycogen storage disease type VI), characterized by hepatomegaly and mild fasting hypoglycemia. Phosphorylase kinase defects can cause glycogen storage disease type IX.