BIOCHEMISTRY OF GLYCOGEN


Glycogen (also called dextrin in older texts, which is not to be confused with the polysaccharide called dextran that is made by bacteria) is found principally in muscle and liver cells, where it serves as a readily accessible depot for the storage of glucose. Glycogen is broken down when ATP is needed by muscle cells, or when blood glucose levels drop too low.


GLYCOGEN IS A POLYMER OF GLUCOSE

Glycogen is composed of linked a-D-glucose residues.

 

The linkages between glucose residues are of two types, a-1,4 and a-1,6:



 



Glycogen is found in two forms, proglycogen (with a molecular weight of around 400 kDa) and macroglycogen (with a molecular weight in the millions).

 

GLYCOGEN SYNTHESIS

The starting point for synthesis of a molecule of glycogen is the protein glycogenin. This is a self-glucosylating enzyme that can create short chains of glucose attached to itself. Once the chains contain more than 10 glucose residues, then they can act as a primer for proglycogen synthase to elongate them.

Chain elongation

Once molecules of proglycogen are established in a cell, further synthesis is controlled by glycogen synthase. This enzyme elongates existing glucose chains by transferring a new glucose residue onto the free reducing end of the chain.

Action of glycogen synthase

 

The newly-attached glucose is derived from uridine diphosphate glucose (UDP-glucose):

 

 

UDP-glucose is made by UDP-glucose pyrophosphorylase:

 

By itself, this is a readily reversible reaction; however, the subsequent hydrolysis of pyrophosphate to two inorganic phosphates will readily occur, and this will drive the reaction over to the product side.

Regulation of the synthase

Glycogen synthase is inactivated by phosphorylation of a specific serine residue on the enzyme. The a form of the enzyme is the active one, the b form is inactive. The activation and de-activation of glycogen synthase is coordinated with that for the degradative enzyme, glycogen phosphorylase.

Regulation of glycogen synthase

 

Chain branching

The elongated chains of glycogen can have branches. Branches in the glycogen molecule help keep the polymer soluble. The branching also creates lots of ends for enzyme attack and provides for rapid release of glucose when it is needed, and for rapid re-synthesis of glycogen, for storage of available glucose.

Branching enzyme forms branched glucose chains by transferring oligomers of around seven glucose residues from one chain onto another glucose residue on a different chain. The attachment of the oligomer is onto position 6 of the receiving glucose, thus forming a 1,6 linkage.

Action of branching enzyme:


GLYCOGEN BREAKDOWN

Synthesis and breakdown of glycogen occur by different paths, catalyzed by different enzymes. For synthesis, the cell uses an activated intermediate, UDP-glucose. Conversely, breakdown produces glucose 1-phosphate.

Glycogen is broken down principally by glycogen phosphorylase. This enzyme (usually known simply as "phosphorylase") uses the cofactor pyridoxal 5'-phosphate (PLP) to cleave glycogen phosphorolytically. Notice that the reaction is not hydrolytic; no water is used in the cleavage reaction. Instead, inorganic phosphate combines with the nonreducing terminal glucose residue to give glucose 1-phosphate.

 

Regulation of phosphorylase

The pattern of activation/inhibition for glycogen phosphorylase is just the opposite of that for the synthase.

Regulation of glycogen phosphorylase

 

"Debranching" glycogen

Phosphorylase cannot cleave past a branch in glycogen; in fact, it stops at a point four residues away from the branch and leaves a short "stub". To resolve the branch into a linear chain, a transferase enzyme first moves the outer three residues of the stub onto an adjacent branch, leaving one residue (the one with the 1,6 linkage) at the branchpoint. Then a second enzyme, alpha-1,6-glucosidase, clips the alpha-1,6 bond, releasing the last residue of the stub and converting the chain into a linear polymer that phosphorylase can continue to act on.

Role of glucose 6-phosphatase

This enzyme is present in liver but absent in other tissues. Its role there is to de-phosphorylate glucose 6-phosphate, and so help to release glucose into the bloodstream. The phosphorylated (and ionic, highly charged) sugar cannot pass through the plasma membrane of the liver cells, while the de-phosphorylated (and neutral) sugar can. Thus liver cells help to regulate the blood glucose level by degrading liver glycogen stores.

In other tissues, however, once glucose is taken up from the bloodstream it is more desirable to keep the glucose inside the cell and not release it back into the bloodstream. To "trap" the incoming glucose these cells phosphorylate it, using various hexokinases. If these cells had active glucose 6-phosphatase, the newly-phosphorylated glucose would be rapidly de-phosphorylated and the glucose lost. As a part of the overall strategy of glucose metabolism, then, only the liver has appreciable amounts of glucose 6-phosphatase.

 

HORMONAL CONTROL OF GLYCOGEN METABOLISM

Control of glycogen synthesis and breakdown is under hormonal control. A rise in insulin levels in the blood indicates adequate levels of blood glucose (the "fed" state); consequently, insulin is used as a signalling agent to induce the synthesis of glycogen, storing glucose against future need.

 

 

 

Epinephrine and glucagon have the opposite effect from that of insulin. Binding of these hormones to receptors on the outside of the cell leads to glycogen breakdown and the release of glucose. Epinephrine acts more strongly on muscle cells and their stores of glycogen, while glucagon acts more strongly on liver cells.

 

 

Effect of insulin: Hormonal deactivation of glycogen phosphorylase kinase and activation of glycogen synthase

 

These are complex control systems that must "mesh" with other metabolic systems (e.g., lipid synthesis and breakdown); hence the use of a common set of intermediates in the signalling pathways.

Points to note

 

 

 

 

Brief review of Glycogen Storage Diseases

Clinical Cases: Glycogen Storage Diseases

References