Glycogenolysis (Glycogen Breakdown)

1. 1

   Glycogen(n) + Pi → glycogen(n−1) + glucose-1-phosphate

   Glycogen phosphorylase 2.4.1.1 ST-0035 Irreversible/directional rate-limiting PLP (B6) Pi
   In Glycogen(n) Pi

   Out Glycogen(n-1) Glucose-1-phosphate
   › Notes

   Glycogen phosphorylase uses inorganic phosphate (Pi) and the cofactor pyridoxal phosphate (PLP; vitamin B6) to phosphorolyze successive alpha(1→4) bonds at nonreducing ends. It stops four residues before an alpha(1→6) branch (a limit dextrin); this is the principal rate-limiting step and conserves the bond energy in glucose-1-phosphate rather than using ATP.

2. 2

   Limit dextrin: transfer of a three-residue alpha(1→4)-linked segment to a neighboring nonreducing end

   Glycogen debranching enzyme (AGL) - 4-alpha-glucanotransferase activity 2.4.1.25 ST-0036 Irreversible/directional
   In Glycogen limit dextrin

   Out Glycogen limit dextrin (transferred branch)
   › Notes

   The 4-alpha-glucanotransferase activity of the bifunctional glycogen debranching enzyme moves a block of three glucosyl residues from the short branch to another alpha(1→4) chain. No nucleotide cofactor is required.

3. 3

   Remaining alpha(1→6)-linked branch glucose + H2O → free glucose

   ↪ 6)-linked branch glucose + H2O → free glucose

   Glycogen debranching enzyme (AGL) - amylo-alpha(1,6)-glucosidase activity 3.2.1.33 ST-0037 Irreversible H2O
   In Remaining alpha(1→6)-linked branch glucose H2O

   Out Free glucose
   › Notes

   The amylo-alpha(1,6)-glucosidase activity of the same glycogen debranching enzyme hydrolyzes the single branch-point residue using water. Approximately one glucose per branch is released free; the reaction is effectively irreversible.

4. 4

   Glucose-1-phosphate ↔ glucose-6-phosphate

   Phosphoglucomutase ST-0038 Reversible
   In Glucose-1-phosphate

   Out Glucose-6-phosphate
   › Notes

   Cytosolic phosphoglucomutase reversibly transfers the phosphate via glucose-1,6-bisphosphate. In muscle, glucose-6-phosphate enters glycolysis; in liver it is prepared for export.

5. 5

   Glucose-6-phosphate + H2O → glucose + Pi

   Glucose-6-phosphatase (G6PC + G6PT translocase) 3.1.3.9 ST-0039 Irreversible H2O Pi
   In Glucose-6-phosphate H2O

   Out Glucose Pi
   › Notes

   In liver and renal cortex, the endoplasmic-reticulum glucose-6-phosphatase system hydrolyzes glucose-6-phosphate after its transport into the ER lumen. This irreversible step enables release of glucose to blood; it is absent from skeletal muscle, explaining why muscle glycogen cannot directly correct hypoglycemia.

Showing all 5 steps.

Overview

Glycogenolysis mobilizes glucosyl units from glycogen as glucose-1-phosphate, with limited free glucose released at branch points. In liver it maintains circulating glucose during early fasting; in skeletal muscle it rapidly supplies glucose-6-phosphate for glycolysis during contraction. The pathway is activated by energy demand and counter-regulatory hormones.

Cellular location

Glycogenolysis occurs on cytosolic glycogen granules in hepatocytes and skeletal muscle, with final glucose-6-phosphatase-dependent release of glucose occurring in the endoplasmic reticulum of liver and renal cortex. Muscle lacks glucose-6-phosphatase, so its glucose-6-phosphate remains intracellular. Lysosomal acid alpha-glucosidase also degrades a small fraction of glycogen in lysosomes but is distinct from the main cytosolic pathway.

Net energetics

Most residues are released as glucose-1-phosphate and converted to glucose-6-phosphate without ATP expenditure; therefore, their anaerobic glycolytic conversion to lactate yields net 3 ATP per glucosyl residue, one more than free glucose entering glycolysis. Branch-point residues released by alpha(1,6)-glucosidase are free glucose and require hexokinase if metabolized in muscle, yielding the usual net 2 ATP anaerobically. Glycogenolysis itself directly produces no NADH, NADPH, FADH2, or GTP.

Clinical significance

Hormonal and allosteric control allows liver to respond to systemic hypoglycemia and muscle to respond locally to AMP and Ca2+ during contraction. Hepatic glucose-6-phosphatase deficiency causes GSD I (von Gierke disease), with severe fasting hypoglycemia, lactic acidosis, hyperuricemia, and hepatomegaly. Muscle glycogen phosphorylase deficiency causes GSD V (McArdle disease), characterized by exercise intolerance, cramps, myoglobinuria, and a "second-wind" phenomenon; lysosomal acid alpha-glucosidase deficiency causes Pompe disease (GSD II), a separate lysosomal glycogen disorder with cardiomyopathy and myopathy.