Gluconeogenesis - Video Tutorials & Practice Problems
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Gluconeogenesis 1
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Gluco neogenesis is often thought of as simply the reverse of glycolysis and this is mostly true. As you probably realize, many of the reactions are readily reversible. So, many of the same enzymes used in glycolysis are actually used in gluconeogenesis. They're simply doing the reverse reaction that they do in glycolysis meaning, that again, they're readily reversible. However, remember, there are those 3 reactions favorable. They're too they have 2 negative favorable. They're too they have 2 negative delta G. And so new enzymes are going to be required to undo the actions of those particular reactions. And we'll get to that on the next page. For now, let's take more of a a top down look at gluconeogenesis. So just like glycolysis, has many different molecules that can enter the pathway at different points. Gluconeogenesis has a variety of feeder molecules that it can use to make glucose. In terms of fats, only glycerol can enter gluconeogenesis. Only glycerol. No fatty acids, sterile, anything like that. For amino acids, only lysine and leucine are unable unable to be gluconeogenic. Those cannot be used for gluconeogenesis. However, all of the other amino acids are able to be used for gluconeogenesis. It's worth noting though that some of these are only able to contribute specific carbons. For example, the ketogenic amino acids are only able to contribute certain carbons to gluconeogenesis and others are going to wind up as ketone bodies. Lastly, lactate, the molecule we were just talking about in the context of fermentation can be converted back into pyruvate and used as again starting material for gluconeogenesis. And here you sort of have the overview of gluconeogenesis and you can see that many of the same enzymes are being used. However, there are a few 4 to be exact new enzymes that we're going to talk about on the next page. But for now, let's just talk about, the overview of what is required for gluconeogenesis. And it's basically, it's very similar to glycolysis but opposite of course. So, for glycolysis, you start off with 1 glucose molecule and from that Well, sorry. 1 glucose molecule and 2 ATP, right? You need to burn 2 ATP in the preparatory or energy investment phase. And then from that, you yield 4 ATP. So that's going to be a net of 2 2 NADH and to hyruvate. And I should for completion sake, say that you need 2 NAD plus to carry out glycolysis because of course, as we saw, NAD plus is a very important ingredient to glycolysis as, you know, there's this whole, fermentation process solely dedicated to regenerating NAD+ from NADH. So, this is glycolysis right here and you can see that gluconeogenesis is almost the opposite, right? We need to take To make one molecule of glucose, we need to take 2 pyruvate, 4 ATP, 2 GTP, and 2 NADH. So you can see here that actually we're using more energy to build the glucose than we, than we get from actually, catabolizing a glucose. So gluconeogenesis is more energy intensive than glycolysis provides energy. But but this is okay. This is okay. And, you know, for one thing, when we get to cellular respiration, you'll see that even though you might not be yielding, all your ATP back from the glycolytic part, once you get over to oxidative phosphorylation, your ATP yield is just bonkers. So, this slightly extra amount of energy that our cells need to use to generate gluconeogenesis, we'll they'll get a return on that investment from cellular respiration. However, gluconeogenesis is also sometimes used just to provide glucose for cells to continue glycolysis in periods of intense energy demand. Glycolysis and gluconeogenesis also both occur in the cytosol, which should make sense. That's where all the enzymes for glycolysis are. So of course, gluconeogenesis is also going to occur there. And really important part to think about is that the 2 pathways are very tightly regulated. And this is because we don't want a futile cycle. So, let's let's think about this for a second. If we have looking at this figure, if we have glycolysis and gluconeogenesis running simultaneously, what's happening? Are we really generating anything? Every action taken by the glycolytic enzymes will will be undone by the gluconeogenic enzymes. So, it's almost like we're you know, spinning our wheels, right? We're running in place. We're expending energy but we're not really getting anywhere for that. That's what we call a futile a futile cycle and the Our cells just can't afford to waste energy like that. So, these two processes are regulated, They're they're very tightly regulated and they're regulated in such a way that when one pathway is running, the other is shut off. And this is also important from a enzymatic standpoint. If you think about the fact that many of these enzymes are being shared, well, these enzymes, it's very easy for them to reverse their reactions. So they they need some sort of oversight telling them sort of which way they should be pushing those reactions. And again, you know, for glycolysis, we have those, 3 particular reactions that drive the whole pathway. So, you know, the regulation of those particular enzymes is going to play a big role in actually controlling glycolysis and gluconeogenesis. You'll see that when those glycolytic, those specifically glycolytic enzymes are active, the specifically gluconeogenic enzymes be inactive and vice versa when the specifically gluconeogenic enzymes are active, those enzymes specific to glycolysis will become inactivated and of course again those are the enzymes from reactions 1, 3, 10. Alright, let's flip the page and actually talk about those reactions specific to gluconeogenesis.
2
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Gluconeogenesis 2
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7m
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Video transcript
Let's cover the reactions specific to gluconeogenesis in the order that they appear in the gluconeogenic pathway, that means that the first reactions we're going to talk about are actually undoing the reaction from the very very end of glycolysis. So these first two reactions we're going to talk about are reversing the action of pyruvate kinase or reaction number 10 of glycolysis. And the reason that this actually has to be done in 2 steps rather than just 1 is pyruvate kinase, the action of pyruvate kinase is so favorable, right? It cannot be simply undone in just one step. Pyruvate kinase takes PEP, turns it into pyruvate, generates an ATP ATP in the process. These two steps that undo the action of pyruvate kinase and convert pyruvate back into hep both require energy input in the form of a nucleoside triphosphate. Pyruvate Kinase generates an ATP. These two reactions are going to burn 2, nucleotide triphosphates to get back to that point, of having PEP. So, the first reaction is carried out by pyruvate carboxylase. So this is like our first enzyme of the gluconeogenic pathway and it's going to take pyruvate and it's turn it into oxaloacetate and it's going to use an ATP to do that. And so we're going to be left with an ADP. And this actually, this reaction adds a CO2 to pyruvate. So you'll see, here we have our pyruvate and we're actually going going to add CO2 onto our pyruvate. The next reaction is carried out by Pep carboxykinase and this is going to take that oxaloacetate and that's a name to remember. Oxaloacetate is a name to remember because it's going to become a very important molecule, later in the next unit when we talk about the citric acid cycle. So PEP carboxykinase is going to take oxaloacetate and it's going to turn it into PEP and it's going to burn or it's going to use a GTP in the process. I always use the phrase burn because I like to think of it as like using up the energy from the molecule. But I really just mean, you know, break that phosphate bond to, harness that the energy released. So this this reaction, actually removes the CO two that was just put on in the previous reaction. So we add the CO 2 and then we get rid of it. But in the process, we add on a phosphate group to our or well, our oxaloacetate. And that leaves us with pep. So we are now back at reaction the well, sort of the end of reaction 9 of glycolysis. But, this is actually going to be the beginning of reaction 3 of gluconeogenesis. Moving on to in 2 steps rather than 1. Okay. Moving on to what is reaction 3 of glycolysis which is carried out by phosphofructokinase or PFK1 as I'm abbreviating it here. So phosphofructokinase you might recall is going to is going to take fructose 6 phosphate and add another phosphate group onto it. It's going to be phosphorylated. So, the enzyme that's to reverse the action of PFK 1 is fructose 16 bisphosphatase, right? Phosphofructokinase using a phosphatase to remove a phosphate group. So we're going to take fructose 16 bisphosphate, remove phosphate group, and we are left with fructose 6 phosphate. And of course, this is undoing step 3 from glycolysis. And lastly, undoing the very first reaction of glycolysis, that task is left up to the enzyme Glucose 6 Phosphatase. So, remember, hexokinase, that's the first, enzyme of the glycolytic pathway and and it's going to act on glucose as soon as it enters the cell and phosphorylate it. Again, we're undoing the action of a kinase with a phosphatase here and going to remove that phosphate group from glucose 6 phosphate and turn it back into glucose. And it's worth noting that, this enzyme, glucose-six phosphatase is actually only present in liver cells. And that's, very important because, gluconeogenesis is one of the big functions of the liver actually. And, you know, if you get more into anatomy and physiology, you'll see that the liver plays a huge role in maintaining blood sugar levels. So it makes sense that gluconeogenesis is one of, the main jobs of liver cells and so it should also make sense that the enzyme needed to sort of complete this process and, and turn our glucose 6 phosphate into actual glucose, ready to hit the bloodstream and be delivered to the cells, the tissues that need more glucose, that that enzyme would only be present in the liver where this process is being carried out. Alright. So, just to recap, we are reversing reactions 10, 3, and 1 of glycolysis with the 4 enzymes presented on this page. And reaction 10 of glycolysis takes 2 enzymes to actually undo that step. All right. Let's flip the page.