Glycogen: Biosynthesis and Degradation

Bello, everyone! I hope you’ve had a nice hour or so! Hopefully you’ve had fun doing things like watching 50% Off!, eating proper meals, or not drinking all of your calories in Dr. Pepper while studying biochemistry.

(I complain, I know, but I love every minute of it.)

This’ll be the last in my sequence of biochemistry posts until I can detox after tomorrow’s test. Still, I’ve got a little bit of ground to cover, so I guess it’s best to cut all this small talk and get to it.

Humans take in about 2000 Calories per day. That’s something we’re all pretty familiar with. If you’re a smol girl like me, you’re probably supposed to eat less than that, but less be honest, it’s a little hard to watch your calories when most of your meals come out of plastic wrap as you’re running from Point A to Point B. Still, even a 1500 Cal diet contains a lot of energy. Where the heck does all of it go?

Well, some of it goes in your blood. Your body keeps your blood glucose levels at 1 g/L, in fact. Assuming that you have 5 L of blood, that’s 5 grams of glucose. Assuming 4 Cal/gram of glucose, that’s 20 Cal of the 2000 Cal you took in in your blood at any given time. That means 1% of your calories are in your blood.

This is where the liver starts looking more impressive; when you’re sleeping, you burn a calorie a minute. If you were to take a twenty minute nap without your liver’s help, you’d be dead. Like, super dead.

Okay, okay. So, then, some of that energy goes into fat. We know that. That’s why a lot of us get so self-conscious about taking in calories in the first place. (Yes, I’m looking at you, Finn… I kid, I kid.)

However, there’s another very important form of energy storage that’s present in our muscles and liver. We keep about 200 grams of it around at any given time (120 g in muscle, 70 g in liver), and it’s called glycogen.

Glycogen is a highly branched polymer of activated glucose. Tens of thousands of D-Glucose molecules are strung together using alpha(1—>4) glycosidic bonds (along the chain) and alpha(1—>6) glycosidic bonds (at branch points, which occur every four residues or so). It’s pretty similar to plant starch (amylopectin), so it’s sometimes called “animal starch.”

In muscles, the glycogen storage is used to generate ATP when muscles need it (which they very often do). Glycogen branches are pruned down, producing glucose-6-Pi, which then is converted to 3 ATP (circumventing the first ATP consuming step!) using glycolysis. After that pyruvate is made, it can either be used to undergo aerobic respiration, or it’s subjected to fermentation (anaerobic respiration), producing the lactic acid that makes your muscles hurt when they’re overworked.

In liver cells, on the other hand, glycogen is busted apart into glucose when blood glucose levels are low. This is triggered by glucagon, that pancreatic hormone that tells the liver to enter a catabolic state. When glucagon levels are high, the liver converts its glycogen into glucose, then exports it, upping serum glucose levels.

Both glycogen degradation and biosynthesis are important in our bodies, then. The net reaction for degradation looks like this:

Glycogen (n) + Pi —> Glycogen (n – 1) + Glucose-6-Pi

Here, a phosphate group is used to cleave a glucose molecule from the end of one of the branches of glycogen. This reaction has a free energy change close to zero, but under cellular conditions, it’s spontaneous in the forward direction, since catabolism reduces the amount of glucose in the environment and drives the reaction toward products.

If, on the other hand, we want to make glycogen, we have to do this:

Glycogen (n) + Glucose-6-Pi + UTP —> Glycogen (n + 1) + UDP + 2 Pi

Here, UTP is used to activate the anomeric carbon of glucose-6-Pi. This makes it susceptible to nucleophilic attack, and the glucose residue on the end of a branch of glycogen reacts with it, forming an alpha(1—>4) glycosidic bond and ejecting the two phosphate groups in the process. The cleavage of two phosphoanhydride bonds (equivalent to using two of the bonds in ATP) is what drives this formation of a glycosidic bond, and the reaction is irreversible.

Now, let’s look at both of these mechanisms in a bit more detail. First, we’ll look at degradation, which occurs in two steps.

In step one of glycogen degradation, an enzyme called glycogen phosphorylase mediates the transfer of a phosphate group to the anomeric carbon (carbon 1) of a terminal glucose residue. This requires a cofactor called Pyridoxal-L-phosphate (PLP), which is a vitamin B6.

First, the oxygen in the terminal glycosidic bond pulls a proton off of a protonated phosphate, breaking the glycosidic bond and generating a carbocation on the last glucose. PLP gives phosphate its proton back, and the carbocation on the terminal glucose reacts with the phosphate to produce glucose-1-phosphate.

After that, the enzyme phosphoglucomutase, which contains magnesium, is used to make glucose-6-phosphate out of glucose-1-phosphate. The way it does this is actually pretty simple. The enzyme contains a phosphate group bonded to a serine residue (-OH). The magnesium in the enzyme polarizes the phosphate group, making it easy for the OH group at carbon 6 of glucose-1-phosphate to attack. Glucose-1,6-Bisphosphate is formed, and the serine residue takes the phosphate group from carbon 1, regenerating the original enzyme and forming glucose-6-phosphate.

So, wait, why are we making glucose-6-phosphate again? Don’t we get energy from glucose? Couldn’t we just hydrolyze a glucose off of glycogen? That would be a lot easier.

Well, that’s true, dearest reader, but the reason behind the more complicated phosphorolysis reaction that produces glucose-6-phosphate is quite simple: muscles cells are freakin’ greedy. Keep in mind that the first step of glycolysis involves transferring a phosphate group from ATP to glucose to make glucose-6-phosphate. If our lazy and hungry muscle cells can bypass that step and save the ATP, they will. Not only that, but phosphorylating glucose prevents it from leaving the cell—as if muscle cells would share their energy with the rest of the body! That’s what the liver is for, right?

Right you are. That leads to my next point: different cells do different things with glucose-6-phosphate. In the muscles, glucose-6-phosphate is shoved through glycolysis, and 3 ATP are made per molecule of glucose-6-Pi. On the other hand, in the liver, glucose-6-phosphatase uses water to take off the phosphate group, and glucose is exported into the blood.

Now, let’s talk for a minute about what happens when you take in something besides straight-up glucose. If you’re like me, you probably do—in the form of lovely carbs such as potatoes, for example~ ❤

Well, turns out there’s a whole set of hydrolase enzymes that live just to cut up complex carbohydrates into smaller bits. The first one of these that your food encounters is alpha-amylase, which is in your saliva and stomach. When I was in biology, they pointed out that, because this enzyme is in your mouth, if you hold a bit of bread in your mouth, it will start to taste sweet after a little while.

(This led to many instances of frustration where I swore that amylase was just a myth meant to keep the lesser-minded of us busy and that it was somehow tied to the Illuminati.)

Anyway, alpha-amylase hydrolyzes alpha(1-4) glycosidic bonds in complex carbohydrates, producing four varieties of “smaller bits:” glucose, maltose (a disaccharide of glucose), maltotriose (a trisaccharide of glucose), and alpha-limited dextrin (a tetrose with a central alpha(1-6) glycosidic bond).

Once those pieces are floating around, three other enzymes finish the job. Alpha-glucosidase and maltase, which are each bound to intestinal walls, hydrolyze maltotriose and maltose, respectively. Alpha-dextrinase hydrolyzes alpha-limited dextrin.

Okay, now that we’ve talked about breaking things to a sufficient degree, it’s time to be productive. Yepperino, we’re going to talk about glycogen synthesis.

Now that we’ve got glucose floating around in our blood, we need to suck it up and make it into glycogen. Our cells do just that when glucose concentrations are high. Once they get it, it’s immediately converted into glucose-6-phosphate using hexokinase. (Cells are greedy, remember?) Phosphoglucomutase isomerizes this to glucose-1-Pi, and UTP is used to activate it to UDP-glucose. (The enzyme that does this is UDP-glucose pyrophosphorylase.) Pyrophosphate (PPi) is ejected from the UTP, and a phosphoanhydride bond is formed between the UMP and the glucose-1-Pi.

Just based on the energy of those bonds, this reaction has a free energy change close to zero. However, PPi is hydrolyzed to to 2 Pi very irreversibly by an enzyme called pyrophosphatase. This pushes the whole equilibrium toward products, and makes the conversion irreversible.

Once that’s done, another enzyme, called glycogen synthase, mediates the transfer of UDP-glucose to a nonreducing end of a branch of glycogen. UDP is eliminated as a leaving group. Although the free energy change for this reaction is negative, we should note that no ATP (or UTP, etc.) was used in this part of the reaction.

UDP is a really good leaving group for the same reason that pyrophosphate was; it’s quickly transformed into UTP in cells. That pushes equilibrium toward products, making this reaction more favorable.

(And, in case you were wondering, the branch points in glycogen come from an enzyme called Branching Enzyme, which takes glucose residues from the nonreducing ends of branches and makes them into branches using alpha(1-6) glycosidic bonds.)

Phew. Okay, now we know how the actual reactions work, but we still have a huge question unanswered. We know that glycogen and insulin affect this whole setup, but how, exactly? Don’t worry, I shall show you!

When blood glucose is low, glucagon is released by the pancreas. Glucagon binds to receptor sites on cell membranes, triggering the synthesis of cAMP. cAMP triggers kinases that phosphorylate both glycogen phosphorylase and glycogen synthase. Phosphorylation activates glycogen phosphorylase, but it inhibits glycogen synthase. Phosphorylation of residues in glycogen occurs, and glucose is produced.

If, on the other hand, blood glucose levels get too high, insulin is released by the pancreas. It also binds to receptors on cell membranes, but, rather than triggering the formation of cAMP, it triggers its degradation. This activates protein phosphatases, which hydrolyze the phosphates from glycogen phosphorylase and glycogen synthase. Glycogen synthase becomes activated (while glycogen phosphorylase becomes deactivated), and glycogen synthesis occurs.

So, what affects your blood glucose levels? Well, what you eat, naturally! Foods have a glycemic index, which tells you how quickly glucose appears in the blood after it’s consumed. It’s recommended by nutritionists to eat foods with low glycemic indices, since lower glycemic indices will cause a slower, steadier release of glucose that won’t trigger a large spike in insulin release. Usually, the less processed the food, the better it is for you. Fibers especially up glycemic indices.

So, what’s the take-home message? You liver is awesome, your muscles are greedy, and eating a chocolate bar for lunch is not, in fact, a good way to ensure you don’t pass out halfway through lab. Who said that science wasn’t useful? (Nobody I know, I hope.)

All right, everyone! It’s been nice hanging! Until my next test (or until I resurface from a day-long hibernation), I’ll see you around!

I just spent thirty minutes talking to Sapphire about this stuff while I was eating a milkshake and she was eating mozzarella sticks.  Well, you know how it goes. Do as I say, not as I do.


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