Gluconeogenesis - Online Tutor, Practice Problems & Exam Prep

Gluconeogenesis is a metabolic pathway that synthesizes glucose from pyruvate, primarily when glucose stores are low. This process requires significant energy, utilizing 4 ATP and 2 GTP per glucose molecule. Key regulatory enzymes include phosphofructokinase, which promotes glycolysis based on ATP levels, and fructose 2,6-bisphosphate, which activates phosphofructokinase-1 while inhibiting gluconeogenesis. Additionally, fats and polysaccharides can be broken down for energy, with fatty acids generating Acetyl CoA and activated carriers like NADH and FADH₂, yielding more ATP than glucose metabolism.

Gluconeogenesis

Hi. In this video, we're going to be talking about gluconeogenesis and metabolic regulation. So first, let's talk about gluconeogenesis. This is a fancy word, it's kind of complicated, but essentially, it's just a metabolic pathway that is responsible for synthesizing glucose from pyruvate. Remember, pyruvate is the end product of glycolysis. Gluconeogenesis uses pyruvate to sort of go backwards from glycolysis and create glucose. So when is this used by the body? This is used when glucose stores are depleted. There's not enough glucose, none is coming in; therefore, your body needs to synthesize it so that it has the energy, and can use it for energy and other processes. But it's not the easiest thing to do because the synthesis of gluconeogenesis requires energy. Every time you create a glucose molecule it's actually going to use 4 ATP and 2 GTP. That's kind of a lot of energy, but it ends up being worth it because, if glucose can eventually turn into 36 ATP if it's processed in the presence of oxygen. So, eventually, you do get that energy back, but it does require a lot of energy to create it.

Now, like I said, this runs almost, and the keyword here is almost in reverse of glycolysis. Glycolysis has 10 steps, there are 10 steps in gluconeogenesis, but it's not the exact reverse. The reason is that 3 steps in gluconeogenesis have to be different, compared to glycolysis. These 3 steps, which are steps 1, 3, and 10 of glycolysis, are just so exergonic, which means that when they're running in glycolysis, they release so much energy, they actually can't be reversed. The cell cannot overcome the amount of energy it would need to run those reactions in reverse. So instead, it sort of bypasses them.

I'm going to go over the 3 steps that are different between gluconeogenesis and glycolysis. The first is going to be step 10 of glycolysis. So this would be step 1 of gluconeogenesis. What happens here is CO₂ gets added, and phosphate gets added to pyruvate. So, the important thing here is because this is step 10 of glycolysis, we're starting with pyruvate and it uses ATP, uses CO₂, and uses GTP to create this molecule. That's the first step of gluconeogenesis, which is the 10^th of glycolysis. Then, step 7 of gluconeogenesis is the same as step 3 of glycolysis. What happens is the removal of a phosphate. So you have 2 phosphates here, one gets removed, you're left with just 1, and this happens again in step 10, where there's 1 phosphate, it gets removed and you end up with the byproduct here of glucose. The rest of the steps are exactly the same as glycolysis just running in reverse. So if you're, you won't need to necessarily know all the steps of gluconeogenesis in order, just know that there are 3 that differ because they can't overcome the energy and what they do is they just sort of bypass that through the use of different enzymes. So with that, let's now move on.

Feedback Regulation

So this video is going to focus on the two main ways that the cell determines whether or not it needs to use gluconeogenesis or glycolysis. How cells decide this is actually through 2 main enzymes. The first one is phosphofructokinase, and this enzyme promotes glycolysis, but it's controlled through ATP regulation. When ATP is low, the site that ATP binds on phosphofructokinase is unbound because there's not a lot of ATP there so why would it bind? And so, the enzyme then remains turned on and can then promote glycolysis. But, if ATP is high, then it can bind to phosphofructokinase, which turns off the enzyme and stops glycolysis. That's the first enzyme that's important. The second one is fructose 2,6-bisphosphate, and this enzyme is responsible for activating phosphofructokinase 1. And so when it activates it, it actually inhibits gluconeogenesis. This ends by inhibiting this enzyme called Fbpase. This works very similarly as the ATP did before. Fructose 2,6-bisphosphate is an activator of phosphofructokinase 1. So, when it binds to phosphofructokinase 1, it activates it, but if it binds to this gluconeogenesis enzyme called FBPase, then it will inhibit gluconeogenesis. Fructose 2,6-bisphosphate can also promote glycolysis by activating the glycolysis enzyme phosphofructokinase and inhibiting this FBPase that is important for gluconeogenesis. These are 2 main enzymes, the ones that you may hear about in your textbook or in your lecture, but there are other enzymes that are regulated in this way. They can be regulated via binding, allosteric modifications, phosphorylation, or various feedback inhibition and all of these enzymes control what reaction the cell is actually going to do. Here's an example of allosteric regulation of phosphofructokinase: You have phosphofructokinase here, and you can see it has 2 sites, an active site and an allosteric site. Remember, it's an enzyme so the active site is going to be a binding site. If there are high ATP levels, then ATP is going to take up both, and this is actually going to inactivate glycolysis. It was going to inactivate the enzyme and stop glycolysis, but if there are low levels of ATP then only one of the sites is bound and so glycolysis can continue because the enzyme remains active.

So that is how phosphofructokinase 1 works to regulate glycolysis or gluconeogenesis. So with that, let's now move on.

Energy Storage in Other Macromolecules

So in this video, we're going to talk about how other molecules, such as fats or larger polysaccharides or carbohydrates, can be broken down and used by the sulfur energy. Fats and larger polysaccharides, like glucose, can be broken down for energy. For fats, they're generally broken down into glycerol and free fatty acids. Fatty acids can actually be used to create Acetyl CoA, NADH, FADH₂, these chemicals and activated carriers that we've been seeing in other steps like glycolysis. Just to give you an example, you don't need to know these numbers, but as an example, a 16 Carbon fatty acid will create 7 NADH, 7 FADH₂, and 8 Acetyl CoA's, which will eventually lead to the formation of 131 ATPs. To compare that with what we're used to with glycolysis, one glucose molecule will only end up making 38 ATPs, which is significantly less. So, you don't need to know these numbers, but you can get an idea that they store this very large amount of energy that the cell can use to create ATP.

Also, glycogen and starch can store monomers of glucose as large branched polysaccharides. These polysaccharides can then be broken down using glycolysis. For instance, glycogen is broken down by an enzyme called glycogen phosphorylase. You don't necessarily need to know that enzyme, but it converts glycogen into glucose 6-phosphate, which, if you remember from our glycolysis video, is actually created in the first step of glycolysis. In glycolysis, glucose is turned into this, but this special enzyme can actually just turn glycogen straight into that instead of going through the glucose step. Another term you need to know is phosphorolysis. When you break apart molecules, typically we refer to breaking apart molecules as hydrolysis, right? Because water is added, and it splits the molecules. But in phosphorolysis, instead of water, an inorganic phosphate is used to split apart molecules, and that’s called phosphorolysis.

If we look here at just an example of the breakdown of fatty acids, you don’t need to know all these terms or these steps, but you can see here that you start out with some kind of fat, but eventually, it's turned into free fatty acids, which go on to create Acetyl CoA, use ATP, and can create FADH₂ and NADH. So all of these things, even though you don’t need to know the steps, just know that fatty acids can also be broken down and used to create energy in the form of activated carriers or ATP. So with that, let's now move on.

Which of the following is not true regarding gluconeogenesis?

• A. It requires energy from ATP
• B. It generates glucose
• C. It is the exact reverse of glycolysis
• D. It requires energy from GTP

True or False:Gluconeogenesis occurs in the exact reverse as glycolysis.

• A. True
• B. False

What happens to the glycolysis and gluconeogenesis when ATP levels are high and glucose is low?

• A. Glycolysis and gluconeogenesis are activated
• B. Glycolysis is activated and gluconeogenesis is suppressed
• C. Glycolysis is suppressed and gluconeogenesis is activated
• D. Nothing, the rates of glycolysis and gluconeogenesis stay the same

When phosphofructokinase-1 is active, what happens to gluconeogenesis?

• A. It is also activated
• B. It is repressed
• C. Nothing

Here’s what students ask on this topic:

What is gluconeogenesis and when does the body use it?

Gluconeogenesis is a metabolic pathway that synthesizes glucose from pyruvate, which is the end product of glycolysis. The body primarily uses gluconeogenesis when glucose stores are depleted, such as during fasting or intense exercise. This process is crucial for maintaining blood glucose levels and providing energy to tissues that rely on glucose, like the brain and red blood cells. However, gluconeogenesis is energy-intensive, requiring 4 ATP and 2 GTP per glucose molecule synthesized.

How does gluconeogenesis differ from glycolysis?

While gluconeogenesis and glycolysis are related, they are not exact reverses of each other. Glycolysis converts glucose to pyruvate, whereas gluconeogenesis synthesizes glucose from pyruvate. Three steps in gluconeogenesis differ from glycolysis due to the high energy barriers of the corresponding glycolytic steps. Specifically, steps 1, 3, and 10 of glycolysis are bypassed in gluconeogenesis using different enzymes to overcome these energy barriers.

What are the key regulatory enzymes in gluconeogenesis and glycolysis?

The key regulatory enzymes include phosphofructokinase (PFK) and fructose 2,6-bisphosphate (F2,6BP). PFK promotes glycolysis and is regulated by ATP levels; high ATP inhibits PFK, while low ATP activates it. F2,6BP activates PFK-1, promoting glycolysis, and inhibits fructose 1,6-bisphosphatase (FBPase), thereby inhibiting gluconeogenesis. These enzymes ensure that glycolysis and gluconeogenesis do not occur simultaneously, maintaining metabolic balance.

How are fats and polysaccharides used for energy in the cell?

Fats are broken down into glycerol and free fatty acids. Fatty acids are further converted into Acetyl CoA, NADH, and FADH2, which enter the citric acid cycle and oxidative phosphorylation to produce ATP. For example, a 16-carbon fatty acid can yield 131 ATPs. Polysaccharides like glycogen are broken down into glucose-6-phosphate by glycogen phosphorylase, which then enters glycolysis to produce ATP. This process is known as phosphorolysis, where an inorganic phosphate splits the molecule instead of water.

Why does gluconeogenesis require more energy than glycolysis?

Gluconeogenesis requires more energy than glycolysis because it involves synthesizing glucose from smaller molecules, which is an energetically uphill process. Specifically, it uses 4 ATP and 2 GTP per glucose molecule. This energy investment is necessary to drive the reactions that are not energetically favorable. In contrast, glycolysis releases energy by breaking down glucose into pyruvate, making it an exergonic process.