Glycogen Degradation

  • Glycogen phosphorylase is the main enzyme involved in glycogen degradation
  • It catalyses the phosphorolysis of the terminal -1,4 glycosidic linkage at the non-reducing ends, with the release of glucose 1-phosphate and a glycogen chain which has been shortened by one glucose residue.
  • The -1,6 glycosidic linkages are removed by a debranching enzyme.
  • The glucose 1-phosphate is readily converted to glucose 6-phosphate by phosphoglucomutase and can thus be exported as glucose after hydrolysis by Glcose-6-phosphatase by the liver or used for glycolysis by the muscle.

Glu-1-PGlu-1,6-P2Glu-6-P

  • Glycogen degradation to glucose 6-phosphate is a readily reversible set of reactions in theory, but in vivo the reaction proceeds in the direction of glycogen breakdown because of the excess of Pi compared to Glucose 1-phosphate.

Glycogen Synthesis

  • In contrast to glycogen degradation, the synthesis is an energy requiring pathway which is distinct from allowing for the reciprocal control of the synthesis and degradation.
  • Synthetic pathway involves a high-energy intermediate UDP-glucose, which acts as a glucosyl donor for the synthesis of glycogen.
  • UDP-glucose is synthesised from UTP and Glucose 1-phosphate by the enzyme UDP-glucose pyrophosphorylase and pyrophosphate (PPi) is also produced. This reaction is readily reversible.

UTP+ Glu-1-PUDP-Glu+ PPi

  • The pathway is essentially irreversible due to the hydrolysis of PPi by a very active pyrophosphatase.
  • Many biosynthetic reactions are driven by the hydrolysis of PPi.
  • Glycogen Synthase catalyses the transfer of glucose from UDP-Glu to the non-reducing ends of the glycogen molecule.
  • Glucosyl unit is transferred to the C-4 in the terminal glucose residue to form an -1,4 glycosidic linkage.
  • Branching enzyme (a different protein to debranching enzyme) breaks an -1,4 glycosidic and transfers the resultant oligosaccharide which is then attached via an -1,6 glycosidic linkages at regular intervals in the glycogen.
  • Branches are created by transferring blocks of 7 glucosyl residues to the C6 hydroxyl of a glucose unit in an adjacent chain.
  • Each oligosaccharide block of 7 residues must come from a linear chain of at least 11 -1,4 glucosyl residues and the new branch point must be at least 4 residues away from another branch point
  • In plant starch (amylopectin) which has a comparable structure to glycogen, although with fewer branch points, ADP-glucose is the main high energy glucosyl donor.

Glycogenin

  • In a number of purification schemes for the isolation of glycogen synthase (86 kDa) from muscle it has proved very difficult to separate a tightly bound contaminating protein which forms a 1:1 mole/mole complex with GS
  • It turned out that this protein (Glycogenin) had an important function in the initiation of glycogen synthase
  • It has glycogen synthase –like activity and is capable of auto-glycosylation, the transfer of Glucose from UDP-Glu to a Tyr194 residue within the protein
  • Glycogenin then transfers a further 7 Glucosyl residues
  • The reactions are autocatalytic (ie catalysed by glycogenin itself) until the oligosaccharide grows to 8 units at which point Glycogen Synthase and Branching Enzyme take over
  • The glycogenin remains buried at the core of each glycogen molecule.
  • Glycogen Synthase is incapable of de novo glycogen synthesis
  • Muscle glycogenin can be distinguished from Glycogen Synthase because of the different MWt, a higher affinity for UDP-Glu,and the fact that it requires Mn2+ for activity
  • Now cloned and expressed in E.Coli and shown to be capable of autoglycosylation and the initiation of glycogen synthesis
  • Two forms of glycogenin have been found in mammalian systems
  • Glycogenin 1 (37 kDa form with a broad tissue distribution, inc. muscle)
  • Glycogenin 2 (50 – 55 kDa in liver, pancreas and heart)

BS2510 -2004