8. Glycogen metabolism

8.2 Glycogen structure

• Why store glucose in polymeric form?
• Covalent structure of glycogen
• The size of glycogen particles is limited by crowding in the outer layers
• Glycogen is more loosely packed and more soluble than amylose

8.2.1 Why store glucose in polymeric form?

• The osmotic pressure is governed by the gas equation:

  $$ begin{aligned} pV = nRT : Longleftrightarrow : p = frac{n}{V}RT onumber end{aligned} $$

• Glycogen amounts to 10% of the liver’s wet weight, equivalent to 600 mM glucose
• When free, 600 mM glucose would triple the osmotic activity of the cytosol—liver cells would swell and burst
• Linking 2 (3, …) molecules of glucose divides the osmotic effect by 2 (3, …), permitting storage of large amounts of glucose at physiological osmolarity

The proportionality of concentration and osmotic activity does not strictly apply to large molecules, but the approximation is good enough for the present purpose.

8.2.2 Covalent structure of glycogen

Glycogen consists of linear stretches of glucose residues connected by ?-1?4-glycosidic bonds, with branches that are attached through ?-1?6-glycosidic bonds. The entire tree-shaped polymer, or dendrimer, is rooted in a single molecule of the protein glycogenin. Each linear stretch contains approximately 13 glucose residues and, except of course for the outermost layer of the molecule, carries two branches of the same length that are attached 3–4 residues apart.

The structure of glycogen is similar to that of amylopectin (see slide 1.6.11). However, in glycogen, the density of branches is greater, which means that a glycogen molecule has a greater number of free ends than an amylopectin molecule of the same molecular weight. The number of free ends determines the possible rates of synthesis and breakdown, and the greater number of free ends in glycogen than in amylopectin reflects a difference in metabolic rates, which are higher in animals, particularly warm-blooded ones, than in plants.

8.2.3 The size of glycogen particles is limited by crowding in the outer layers

According to the rules detailed in the preceding slide, the number of branches will double with each successive generational layer of the glycogen molecule. However, the amount of space available to those branches will only grow in proportion to the square of the particle radius or, approximately, the square of the number of generations. Taking into account the actual dimensions and architecture of the polymer, it has been calculated that in the 13th generation the required space would exceed the available space. Therefore, a glycogen molecule can contain no more than 12 generational layers. This implies that a single glycogen molecule can contain up to approximately 54,000 glucose residues; it will have a molecular weight of almost 107 Da and a diameter of approximately 25 nm [1]Author: Goldsmith, E;Sprang, S;Fletterick, R
Title: Structure of maltoheptaose by difference Fourier methods and a model for glycogen
Journal: J Mol Biol
Pages: 411-27
Volume: 156
Year: 1982
ISBN: 0022-2836.

Electron microscopy shows glycogen particles whose dimensions agree well with this theoretical maximum size of single molecules; these are referred to as ? particles. In many tissues, variable numbers of ? particles are found clustered into so-called ? particles. Interestingly, ? particles can be broken up with thiol-reducing agents, which implies that they are held together by disulfide bonds. Disulfides usually form between protein molecules. In addition to such scaffolding proteins, glycogen particles also contain a considerable number of enzymes and regulatory proteins [2]Author: Roach, Peter J;Depaoli-Roach, Anna A;Hurley, Thomas D;Tagliabracci, Vincent S
Title: Glycogen and its metabolism: some new developments and old themes
Journal: Biochem J
Pages: 763-87
Volume: 441
Year: 2012
ISBN: 1470-8728, some of which will be discussed below.

8.2.4 Glycogen is more loosely packed and more soluble than amylose

The above structural model of glycogen assumes a relatively loose packing of the glucose residues within the ?-1?4-linked linear stretches. However, perfectly linear polyglucose—that is, amylose—adopts a much more densely packed helical structure. In this structure, more hydroxyl groups are engaged in hydrogen bonds with other glucose residues rather than with water; amylose therefore has low aqueous solubility.*Cooking starch has the effect of breaking up hydrogen bonds within amylose and increase its degree of hydration. Amylose thereby becomes digestible by amylase. Cooking food ranks among mankind’s greatest inventions, almost comparable to Twitter and the iPad.

Unlike amylose, which mostly serves for long-term storage in plant bulbs and seeds, glycogen typically is degraded within hours of synthesis; this rapid turnover is facilitated by its loose structure. However, if branch formation breaks down, aberrant, condensed glycogen particles may arise that are no longer amenable to regular turnover. Various enzyme defects that interfere with branch formation cause the accumulation of such particles inside the cells; an example is the defect of the enzyme laforin in Lafora disease (see slide 8.6.4).

Aberrant glycogen particles also arise spontaneously in normal metabolism. The high density of polyglucose chains in the outermost layers of the glycogen molecule may interfere with the activity of branching enzyme and may promote tighter packing. Lysosomal glycogen degradation (see section 8.3.7) may have evolved as a pathway to dispose of such dysfunctional particles.*Undegraded insoluble glycogen particles may be seen inside the cells of aged individuals. Such particles are described as corpora amylacea in the brain and as cardiac colloid in heart muscle.

Lecture notes on human metabolism