Hello and welcome to the review of chapter 11 of Lippincott's biochemistry textbook and in this video we're going to go over glycogen metabolism. If you enjoy the video please don't forget to give it a like and subscribe to the channel and if you'd like to support the channel you can do so in the patreon link within the description where you can get downloadable audio files of every single chapter. So we're going to talk about glycogen because it's a nice store of glucose.
Now glucose is an absolute requirement for human life. Your brain needs it. Certain cells in your body can only use it for energy.
Your muscles use it as a quick source of ATP. Glucose is essential. If you don't have blood glucose levels, or if you have low blood glucose levels that are too low, then you're going to die.
So glucose needs to be sustained within the body. We have three primary sources. Obviously our diet, which can be irregular, may not have carbohydrates within your diet.
You may fast for a period of time. Glycogen. degradation is the second source which provides a rapidly mobilizable form of glucose so it's able to easily maintain blood glucose levels at a normal state when you start fasting and then gluconeogenesis which we covered in the last chapter remember gluconeogenesis is able to provide sustained synthesis of glucose but it's a longer course so it's a slower production of glucose it takes its time so Really primarily you get glucose from your food, if food's not available you break down glycogen and then once glycogen has either run out or we have a sustained fasting period you're going to start to produce glucose via gluconeogenesis. So we're obviously going to cover glycogen today and that really covers this one little reaction down here which is a part of the overall metabolic process.
So you can see we have glycogen at the top here which just basically comes from glucose. Now remember glucose enters the cell, gets converted into glucose 6-phosphate, which kind of stores it in the cell. That then gets converted into glucose 1-phosphate, which in order to create glycogen, you have to create this UDP glucose, which we'll go over.
So you can see the process of forming glycogen is different to the process of breaking glycogen down. So those are the two parts we're going to go over in this chapter. So the main stores of our glycogen, although every cell has glycogen. The main stores is your skeletal muscle because it uses glycogen when you're exercising to provide a very easy source of glucose for energy.
And then our liver, because our liver has the primary role of maintaining normal blood glucose levels when you are fasting. So when it comes to actually the structure of glycogen, it has this branch-like structure. So it's almost like a branching tree or a twig, which has a row of glucose, each little circle is a glucose that branches off at certain points.
So the main linkages are these alpha 1,4 linkages. So that creates the linear structure. And then at each branch, it's an alpha 1,6 linkage. So mainly alpha 1,4s with the occasional 1,6 to branch it off. And it's all made out of alpha D glucose.
So you're going to store glycogen in your liver when you are well fed, you've just eaten, you've had a lot of glucose. and you're going to deplete it in the liver when you are fasting. In your muscle, however, your glycogen is going to be used when you're exercising, and then it's going to be stored when you're finished exercising. So two slightly different processes there, and reasons for when we're synthesizing and degrading glycogen. So let's get into glycogenesis, or the synthesis of glycogen.
It involves uridine triphosphate. and also energy supplied by ATP. So it's an energy requiring process and we need this other molecule of UTP.
So as you can see in this figure 11.5 here, the first step is turning glucose 6-phosphate down into glucose 1-phosphate and then combining this glucose 1-phosphate with UTP and in doing so you lose two inorganic phosphate molecules. So it's catalyzed by this enzyme UDP glucose phosphorylase that turns glucose one phosphate, takes off that phosphate, and also one phosphate from UTP to create UDP glucose. And that's represented by this little symbol UDP with a little red circle.
The red circle means one little glucose molecule. Now in order for the glucoses to now form an alpha-1,4 linkage with one another, they need an enzyme called glycogen synthase. Now there is a little trick with this glycogen synthase. and that it can't just join two together. It needs at least four glucoses in a row before it can actually work to add additional glucoses onto this chain.
So that's where this other molecule called glycogenin comes in, which acts as a primer. So glycogenin comes in and catalyzes this reaction so it's also an enzyme by actually forming the alpha 1,4 linkages with four glucose molecules getting rid of the UDP molecule. So now that we have four glucoses in a row glycogen synthase can now add additional glucoses onto this linkage while removing that UDP. So you can see now that we've got this four glycogen synthase works and now we can build out our chain here.
Now the end that the glucose molecule is getting added to is called the non-reducing end. So this is where glycogen synthase works to keep adding on glucose molecules. Now if we didn't have any branches to this chain then we would create amylose which happens in plants.
But we obviously produce glycogen and that's because of the branching enzyme that's able to... create an alpha 1,6 bond. And it does it in a slightly odd way.
So it first cuts off the last six to eight glucose molecules. So in this example, it's cutting it off right at this link between the I and the J. So it actually breaks an alpha 1,4 bond. Then it actually moves it to the non-reducing end. So in this example, it's moving it up to the G molecule here.
So it moves it a couple down. And then it creates the... alpha 1,6 bond and that creates two non-reducing ends. So now at I and now also at O.
So glycogen synthase can now work at both of these regions to create more branches and more bonds. So this branching enzyme is called a 4,6-transferase because it basically converts it into this different bond. We break this 1,4 bond to create a 1,6 bond. So that is the branching enzyme. which has a much more complicated name.
So bear with me here, it's amylo-alpha-1,4-alpha-1,6-transglycosylase which is able just to shuttle that one branch over and by actually creating this branching molecule it actually increases the solubility of this polymer or this polysaccharide. So then we're able to have a soluble molecule within our cell rather than forming these big insoluble aggregates. When it comes to actually breaking down glycogen or glycogenolysis, then we actually convert these molecules or these little glucose molecules into glucose 1-phosphate, primarily when the 1,4 chain is broken, and also some free glucose when the 1,6 bond is broken. So it's a slightly different pathway.
We don't use UTP here or UDP glucose. it's purely converting straight into glucose 1-phosphate or the occasional free glucose. So we have two separate enzymes here or two separate activities.
The first is that we have glycogen phosphorylase that is able just to add a phosphate group and break off a glucose to the non-reducing end. So it just starts chopping these little bonds off and adding a phosphate. Now the trick is once we get down to four total glucose residues, as you can see here, the glycogen phosphorylase actually stops working.
So once we've chopped these down, right down to four glucose residues on the branch, then it no longer works. So we need to do something about that. And that occurs by these two different deep branching enzymes.
So we got the four to four transferase, which basically cuts the one-four bond between the second and the third residue. So between... C and what would be D over here and then actually moves these three glucose molecules all the way to the other end or Onto another non reducing chain so you can see that that has happened from this Diagram down to this bottom one down here where this ABC has been added to the DEF On this diagram, so we are moving the branch or the three glucoses from one branch onto the non reducing end somewhere else and and then that creates a longer chain for our glycogen phosphorylase to start chopping it off again. And then we're left with just these one little glucose residues, which are actually broken down by a different enzyme called amylo-alpha-1,6-glucosidase, which is able to just break it off into a free glucose. So that's how you're able to break down glycogen, by first chopping down the non-reducing ends with glycogen phosphorylase, adding a phosphate group, creating glucose 1-phosphate.
Once we end up with four residues, we chop off the three residues, add them to a non-reducing end so glycogen phosphorylase can continue, and then we are able to chop off that one extra little glucose or glucose residue using the other deep branching enzyme that's able to convert it straight into a free glucose. So that's how you break down glycogen. Now once you have glucose 1-phosphate, that then gets converted into glucose 6-phosphate. They're phosphoglucomutase. Now, glucose 6-phosphate, what happens here depends on the tissue.
So in the liver, the cells actually contain an enzyme called glucose 6-phosphatase. So it's able to just chop off that phosphate and create glucose. But in other cells, we don't have this glucose 6-phosphatase.
So for example, in your muscles, you actually lack glucose 6-phosphatase. But that doesn't really matter because glucose 6-phosphate just goes straight into... glycolysis and starts to create energy which is the whole reason you have glycogen in your muscle cells you're not trying to release glucose into your bloodstream from your muscle you're trying to actually use it for atp so there's no need to break glucose 6 phosphate down even more whereas the liver is actually trying to increase your blood glucose levels so that's why it needs this glucose 6 phosphatase enzyme to now chop off that phosphate in provide glucose that can now leave the cell.
So next we're going to talk about the regulation of glycogenesis and glycogenolysis. So the building and the breakdown of glycogen. And it all comes down to this very, very simple little diagram here down the bottom, which clearly is quite complicated.
So it really depends on the receptor or the hormone that is present. So to try to simplify this as much as possible, glucagon. And epinephrine wants to break down glycogen and release glucose. Insulin wants to store glucose as glycogen because insulin is produced when you have an abundance of energy or an abundance of nutrients. So insulin creates glycogen and reduces degradation.
Glucagon and epinephrine breaks down glycogen. So we're going to talk about how glucagon and epinephrine break down glycogen. It does it via the adenyl cyclase system.
Remember that's a G protein that creates C-A-M-P that then activates a protein kinase. Now protein kinases are then able to phosphorylate various molecules. Now it's quite confusing here because we have two pathways here where two different molecules get phosphorylated in a sequential manner.
Basically, glucagon... results in the end phosphorylation of various enzymes which then actually activates glycogen phosphorylase which gets activated by getting phosphorylated so glycogen phosphorylase can then obviously break down our glycogen as we talked about before so glycogen gets broken down through the phosphorylation of various enzymes mainly glycogen phosphorylase kinase and also glycogen phosphorylase itself. Insulin on the other hand does the opposite. It activates the phosphatases. So it takes off those phosphate groups and inactivates glycogen synthase.
So it prevents glycogen from being degraded. Now that is one main way that glycogen or glycogenolysis actually gets regulated. The other way is that the enzymes are allosterically regulated. And that just means that when you have an abundance of nutrients and a abundance of ATP, then you do not need to break down glycogen. So then the abundance of those nutrients basically inactivates the enzymes that's going to break down glycogen, which is glycogen phosphorylase.
And then the opposite is true. When you have high AMP, low glucose, then they actually get allosterically activated to break down glycogen. So we are able to regulate our glycogen breakdown by either hormones or the presence of our nutrients and energy supply.
which is allosteric regulation so that is a real summary of glycogen regulation it does obviously have a little bit more detail with every single tiny little enzyme or kinase that gets activated that can become overwhelming if I just talk about protein kinases phosphorylases synthases and just start listing them off so I just tried to keep it as simple as possible and then the last thing to mention is that glycogenolysis or the breakdown of your glycogen and your muscles can also be activated by calcium because remember calcium is a huge component in muscle contraction so it's nice that calcium also stimulates the breakdown of glycogen by binding to calmodulin which is then able to actually activate phosphorylase kinase b that is able to go on and phosphorylate our glycogen system days. So that is a summary of how glycogen is regulated. There are glycogen storage diseases, which is genetic diseases, where either you can't break down your glycogen or you can't form it.
Usually you can't break it down, so then they actually form excessive glycogen within their cells. So within your liver, excessive glycogen in your liver results in hypoglycemia because you can't release it anymore. Or in your muscles, it causes muscle weakness because you can't release your glucose for energy to then actually use your muscles.
If it's more generalized, then you result in some other issues in your heart and kidneys. So clearly the severity of this condition just depends on how widely affected it is. So you may be fatal in early childhood or you just might have mild signs that it's not life-threatening.
And then that really summarizes glycogen metabolism for us today. There is the summary flowchart down the bottom here. And as always, we have the questions on the side and then the answers. So feel free to pause at each section. I hope you enjoyed this video.
Feel free to drop a comment. Otherwise, we'll see you in the next video.