Glycogenolysis (glycogen breakdown to glucose-1/6-phosphate) — GSD III/V/VI, PGM1-CDG

Glycogenolysis is the cytosolic breakdown of stored glycogen to release glucose units for glycolysis (muscle) or blood-glucose maintenance (liver). Glycogen phosphorylase (the rate-limiting, PLP-dependent enzyme; muscle PYGM, liver PYGL, brain PYGB isoforms) sequentially phosphorolyses the alpha-1,4-glycosidic bonds at the non-reducing ends of glycogen, releasing glucose-1-phosphate, until it stalls about four glucose residues from an alpha-1,6 branch point (leaving a "limit dextrin"). The bifunctional glycogen debranching enzyme (AGL) then remodels the branch: its 4-alpha-glucanotransferase activity transfers a maltotriosyl unit to a nearby chain, exposing the single alpha-1,6-linked glucose, which its amylo-alpha-1,6-glucosidase activity hydrolyses to free glucose — restoring a linear chain that phosphorylase can continue to degrade. Finally phosphoglucomutase (PGM1) reversibly isomerises the glucose-1-phosphate to glucose-6-phosphate (via a glucose-1,6-bisphosphate intermediate, Mg2+-dependent), which enters glycolysis or, in liver/kidney, is dephosphorylated by the glucose-6-phosphatase system for export as free glucose. Inherited defects define glycogen storage diseases: PYGM deficiency causes GSD V (McArdle disease, exercise intolerance/myoglobinuria); PYGL deficiency GSD VI (Hers disease, hepatomegaly/hypoglycemia); AGL deficiency GSD III (Cori/Forbes disease, with abnormal limit-dextrin-like glycogen); and PGM1 deficiency PGM1-CDG (a mixed glycogenosis and congenital disorder of glycosylation).