Glucose in animals is not only the basic unit of monosaccharides and disaccharides, but sometimes tens of thousands of glucoses aggregate into huge polysaccharides. Glycogen was first isolated from the liver by French physiologist Claude Bernard in 1857. It is a polysaccharide found in animals and is similar to amylopectin, but it has more branches and a more complex structure, so it is also called animal starch. The molecular weight of glycogen isolated from different tissues of various organisms varies widely. Even in an individual, the dispersion of glycogen molecular weight can be 1000 times and higher, as glycogen granule is always in a cycle of degradation and replenishment.
Whelan Model: 3D Structure of Glycogen Granule
The straight chains, branches, and left-handed helices of glycogen represent its primary structure. Glucose is the basic unit of glycogen granule, forming straight chains through 1,4-glycosidic bonds and branches through 1,6-glycosidic bonds. The mathematical reasoning below reveals that these branches are not random but follow certain rules. These glucose chains also have a left-handed helix similar to starch.
The β-particle represents the 3D secondary structure of glycogen that is described in detail by Whelan model. The glycogen β-particle is spherical in this model. At its center is a protein called glycogenin that is attached by glucose chains. There are B chains with two branching point inside the sphere, and each chain is composed by 13 glucose residues. Branches connect to branches and expand outward to form 12 concentric tiers (the first tier surrounds the central protein, the second tier surrounds two glucose chains branching from the protein, the third tier surrounds four glucose chains branching from two chains in the second tier, and so forth). The unbranched A chains and some proteins for glycogen metabolism are on its surface. A complete β-particle has a diameter of about 44 nanometers, contains 55,000 glucose residues, and has a molecular weight of about 10 million daltons. However, complete glycogen β-particles are rare, as some outer tiers are involved in degradation.
The broccoli like glycogen α-particle is the tertiary structure. Glycogen α-particles are abundant in the liver and have been found sparingly in nerve cells and other tissues. In the liver, 20-40 β-particles aggregate to form an α-particle with a diameter about 200 nanometers. How they cluster together is currently unknown, but it is speculated that proteins on the surface may cause them to stick together. In other tissues, there are also a few glycogen granules consisting of only a few β-particles.
How did glycogen structure evolve to satisfy the rapid glucose mobilization?
The glycogen granules described by Whelan's model have some interesting properties. 1. All B chains are inside the ball, and all A chains are on the outermost tier. 2. The radius of the next tier is 1.9nm larger than the previous one. 3. Each time a tier is added, the number of chains doubles. 4. The number of outermost chains (A chains) is equal to half of the total chain, or equal to the sum of all inner chains (B chains). 5. In the A chains, only a portion is broken down by phosphorylase because the four glucose residues near branching points can't not be degraded due to the confined space. Therefore, the ratio of glucose involved in phosphorolysis each time is 50%x9/13≈34.6%
The value of chain length (13), branching degree (2) and max tiers(12) are not empirical, and they can be deduce from mathematical analysis. When they take on these values, the smallest volume can store the most glucose without being too dense for enzymes to work. It makes the glycogen store and release glucose as quickly as possible.
Next, let's explain how these values were calculated.
The distance between the tiers is about 1.9 nm. Surface area of the ball: S=4π x (1.9n)². The total number of chains: T=1+2+·······+2ⁿ⁻¹=2ⁿ. The exponential grows much faster than the square, so when n is large, the density of the glucose chain on surface will be too great for enzymes to work. This number is 12 in biology.
If the degree of branching is equal to 1, its structure is similar to a linear straight chain and cannot form a ball. If it is equal to 3 or greater, fewer tiers are required to achieve maximum density. The radius of glycogen granule and the amount of total glucose is smaller than the actual value. So the 2 is the most suitable value.
Phosphorylase and debranching enzymes play important roles in glycogenolysis. First, phosphorylase attacks the 1,4 glycosidic bond to release glucose 1-phosphate at the non-reducing end. It releases glucose one by one along the chain until it reaches the branching point (the 4 glucose residues near the branching point cannot be degraded). At this time, debranching enzyme is needed to destroy the 1,6 glycosidic bond, but this process is very slow, so it is the rate-limiting enzyme.
Now let's assume that two glycogen granules have the same number of glucose residues and degree of branching is 2, but their chain lengths are different. If the chain is short, the glycogen has more non-reducing ends that can be attacked by phosphorylase, and the glycogen is denser. However, when breaking down short chains, the enzyme is more likely to encounter branching points that can only be broken down by debranching enzyme. Chains that are too short can severely slow down the release of glucose from glycogen. The condition is opposite, if the chain is long. There are very few reducing ends that can be attacked by phosphorylase, and the glycogen density is low. The advantage is that it is not easy to meet branching points. Therefore, both long and short chains have disadvantages, and only medium-length chains are most suitable. This value is 13 in the Whelan model, which is very consistent with the real length of 9-14.
We have to admire that the delicate structure of glycogen seems to have been designed, and natural selection may be the designer behind the scenes. Only those structures that meet the best optimization can store and release energy in the shortest time. A slight deviation will reduce efficiency and be eliminated during evolution.