Glycogen metabolism

Definitions & Key takeaways

Glucagon is a hormone that helps your body to break down glycogen (a type of sugar) in the liver to release glucose into the bloodstream. This can help to raise blood sugar levels when they are too low, like during fasting. Glucagon is produced by alpha cells of the islets of Langerhans in the pancreas.

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Glucose is a 6-carbon molecule that’s used to make energy, in the form of adenosine triphosphate, or ATP. Glucose is such an important energy source, that our body stores excess glucose in skeletal muscle cells and liver cells in the form of glycogen.
Glycogen is basically an enormous molecule or polymer, that’s made up of glucose molecules linked together by glycosidic bonds.
You can think of glycogen having a main chain, and there being multiple branches sprouting off of it. These branches allow glycogen to be compact and capable of rapid addition and removal of glucoses.
It’s a bit like growing a plum tree in a tiny house with a short ceiling. The short ceiling limits the tree’s vertical growth, but the tree’s able to branch off, so that it can still grow and produce many plums in a tight space.
Now let’s say that you just wrapped up a delicious lunch - you had tacos! Glucose is absorbed from the intestine and our blood sugar goes up.
The pancreas responds to high blood sugar by secreting insulin. Insulin acts on glucose transporters on the cell membrane, which are called GLUTs - and makes them bring more glucose into all the cells in our body.
Inside the cell, an enzyme called hexokinase adds a phosphate group to it’s 6th carbon, creating glucose 6 phosphate. Then, glucose-6-phosphate is broken down during glycolysis, making ATP as a byproduct.
Over time, ATP levels start to rise and that inhibits certain enzymes in glycolysis. When that happens, the extra glucose-6 phosphate can be used to make glycogen.
And that usually takes place in the liver and muscle cells. There are four main steps in glycogen synthesis.
First is attaching a uridine diphosphate, or UDP molecule to glucose. Second, is attaching the glucose part of the UDP-glucose molecule to a glycogen primer called glycogenin, forming a short linear glycogen chain, which serves as a primer.
Third, is adding more glucose molecules to that primer - a bit like forming a conga line. And fourth, is adding branches to the glycogen molecule.
So starting with step one, to make UDP-glucose, an enzyme called phosphoglucomutase moves the phosphate from the 6th carbon of glucose-6-phosphate to the 1st carbon, creating glucose-1-phosphate.
Next, we’ll need energy - which, uniquely, comes in the form of uridine triphosphate, or UTP. In the presence of glucose-1-phosphate and UTP, an enzyme called UDP-glucose pyrophosphorylase cuts two phosphate molecules off of UTP, which give the energy necessary to complete this reaction.
So only one phosphate remains attached to uridine, and then glucose-1-phosphate is added to it. That makes two phosphates.
So the resulting molecule is called UDP-glucose. Once many glucose molecules are converted into UDP-glucose molecules, we’re ready to create glycogen.
An enzyme called glycogen synthase catalyzes the attachment of the glucose part of UDP-glucose to another glucose residue at the end of the glycogen branch, forming an alpha 1,4 glycosidic bond.
it’s almost as if the glucose molecules are holding hands! And in addition to prolonging the glycogen chain, another byproduct of this reaction is UDP.
But, it turns out that glycogen synthase can only elongate an already existing glycogen chain that’s at least 4 glucose molecules long.
So, if there aren’t at least four glucose molecules linked up together already, then glycogen synthesis requires a protein called glycogenin.
Glycogenin plays the role of fooling glycogen synthase by catalyzing the attachment of 4 glucoses to itself, creating a short chain connected with alpha 1,4 glycosidic bonds.
By doing that, it’s able to tell glycogen synthase “Hey, we have a chain here that kind of looks like an old glycogen molecule”.
Glycogen synthase falls for it, and elongates this short chain on glycogenin by attaching lots of glucose molecules to it through alpha 1,4 glycosidic bonds.
This elongates the chain and creates a new linear glycogen molecule. Next, an enzyme called the branching enzyme, goes to the ends of the chain and cuts off a chain of about 6 to 8 glucose residues in length.
The branching enzyme then attaches that chain to the side of the linear glycogen strand by creating an alpha 1,6 glycosidic bond - so there’s now a bond between the 1st carbon of the glucose on the small cleaved segment and the 6th carbon of a glucose that’s part of the linear chain.
And as soon as you’ve shortened the linear chain, glycogen synthase will elongate it once again. This happens over and over again, resulting in a branched glycogen tree to serve as stored energy.
Now let’s say it’s been couple of hours since those tacos, and you decide to go for a run. Because you’re fasting, your blood glucose levels take a dip.
In response, the pancreas secretes the hormone glucagon and the adrenal glands secrete epinephrine to increase your heart rate.
It turns out that glucagon tells the liver cells to break glycogen down into individual glucose molecules, and epinephrine tells skeletal muscle cells to do the same.
In both the liver and skeletal muscle cells, glycogen breakdown begins with the branches. First, an enzyme called glycogen phosphorylase cleaves the alpha 1,4 bonds between individual glucose residues and catalyzes the transfer of a phosphate group to the freed glucose.
The result is that the enzyme releases one glucose-1-phosphate molecule at a time. It keeps on doing this until exactly 4 glucose molecules remain on the branch.
Next, a debranching enzyme literally cuts off glycogen branches. It has a component called 4-alpha-glucanotransferase, which transfers 3 out of the 4 glucose molecules off of the branch and reattaches them to the linear glycogen chain instead, extending it as a result.
The same debranching enzyme has another component known as alpha 1,6 glucosidase, which cleaves off the alpha 1, 6 glycosidic bond and releases a free glucose.
So for each glucose that’s removed via phosphorolysis, there’s a glucose-1-phosphate that gets liberated, and it’s converted to glucose-6-phosphate by phosphoglucomutase.
The difference between glycogen breakdown in the liver and what goes on in the muscles results from the different enzymes in those two tissues.
In liver cells, glucose-6-phosphatase removes the phosphate off of the 6th carbon, releasing free glucose into the bloodstream, for other organs and tissues to use.
Skeletal muscle doesn’t have this enzyme, so they simply use the glucose-6-phosphate by sending it into the glycolysis pathway to make energy that can help you with that run.
Glycogen metabolism is primarily regulated the two pancreatic hormones - insulin and glucagon. Now a general rule of thumb is, glycogen synthase is active when it doesn’t have a phosphate, whereas glycogen phosphorylase is active when it does have a phosphate attached to it.
So in liver and skeletal muscle cells, insulin binds to a tyrosine kinase receptor on the cell surface, and that ultimately activates a protein phosphatase which goes around removing phosphates from glycogen synthase, making it active, and from glycogen phosphorylase, making it inactive.
This promotes glycogen synthesis and decreases its’ breakdown. On the other hand, glucagon in the liver cells binds to a G-protein coupled receptor on the cell surface, which activates adenylyl cyclase, which converts ATP to cyclic AMP, or cAMP.
cAMP then activates protein kinase A which adds a phosphate to glycogen phosphorylase kinase, activating it. Glycogen phosphorylase kinase adds a phosphate to glycogen phosphorylase increasing its’ activity and promoting glycogen breakdown.
It also adds a phosphate to glycogen synthase, decreasing its activity and therefore decreasing glycogen synthesis. Alright, a quick recap.
Glycogen is a multi branched, compact structure that’s made of alpha 1,4 glycosidic bonds between the glucose molecules, and alpha 1,6 bonds at the branching points.
Glycogen is considered the major form of glucose storage in the body. It’s primarily stored in the liver cells and skeletal muscles cells.
After a meal, high insulin levels promote glycogen synthesis, whereas during fasting, high glucagon and epinephrine levels promote glycogen break down.