Metabolic Regulation 2 - Video Tutorials & Practice Problems
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Metabolic Regulation 2
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So after hexokinase, phosphofructokinase 1 is like our 2nd most influential enzyme on glycolysis. And it, you might remember, catalyzes like that commitment step to glycolysis when you burn your second ATP to phosphorylate the molecule a second time, right? So just to, you know, be crystal clear here. I'm sorry if this is review but you know, as soon as glucose enters the cell, it's turned into glucose 6 phosphate regardless of what it's going to go on to do. But if you're going to commit to glycolysis, that's where phosphofructokinase comes in, right? That's that commitment step to glycolysis. Glucose 6 Phosphate can do other things but once PFK is done, it's glycolysis time. Anyways, so this, you know, it should make sense then that phosphofructokinase is like the 2nd most influential enzyme on glycolysis, on the rate of glycolysis. It actually has allosteric regulatory sites that, bind ATP and hopefully, you know, you just guess that well, ATP is the product, right, the downstream product so I bet ATP is going to have an inhibitory effect and you betcha. High ATP concentrations lower enzyme activity. Citrate actually will also inhibit PFK 1. Citrate, you might recall the first, molecule formed in the citric acid cycle. It is actually an important molecule for biosynthesis and it will be transported out into the cytoplasm, right? Citrate is going to be produced in the mitochondrial matrix but it's transported out into the cytoplasm to undergo biosynthesis And, if it is in excess concentrations, it'll inhibit PFK1 and and you know, let's think about this logically. If citric acid cycle is going gangbusters, right? It's overproducing. It's going to filter off some citrate to do biosynthesis with. It's like we don't need all these, right? We're doing we're making too much so let's filter some off back in the cytosol, do biosynthesis but if you're filtering off a lot, you're going to really build up a lot of citrate in the cytosol then you're going to inhibit PFK1, right? So it's it's just another negative feedback mechanism. And, you know, hopefully comes as no surprise that ADP and AMP, those energy poor molecules actually stimulate this enzyme's activity. Now, fructose 26 bisphosphate is an allosteric activator of PFK1 and it's actually the most important regulator of the molecule without, fructose 26 bisphosphate, attached or bound to the allosteric site, PFK 1 is you know, has very very low activity. It's barely moving. It needs fructose 26 bisphosphate to to really do its job. And what's even crazier is fructose 26 bisphosphate is effective. Like it can stimulate PFK 1 very effectively at super small concentrations. Tiny concentrations like 1 micromolar concentrations. It can it can get to higher concentrations. I'm saying that, you know, this is sort of like the lower limit like at at about 1 micromolar, it's effective at at getting p f k one to do its job. Fructose 2 26 bisphosphate also inhibits fructose 16 bisphosphatase which you might recall is PFK1's kind of gluconeogenic counterpart. Fructose 16 bisphosphatase undoes the step that PFK1 carries out. And if you need a refresher of what's going on in glycolysis versus gluconeogenesis, flip a couple pages, you'll see there's a nice chart. We're not actually going to go through it. It's just there as a reference to help you keep track all these enzymes, because I know that was like the last unit. Maybe it's a little rusty. Hopefully not but it's just there so you can look this stuff up if you need. Lastly, AMP is also going to inhibit fructose 16 bisphosphate, and therefore inhibits gluconeogenesis. So just to kind of sum this up, AMP stimulates PFK1 and inhibits Fructose, 16 bisphosphatase. So it has that one molecule has dual opposite effects on those 2 metabolic pathways to turn one on and turn the other off, right? That's the idea for the regulation of these two processes is to to have, this sort of dual regulation system like that. Okay. Let's move on. So, fructose 26 bisphosphate. Spend a lot of time talking about it. Where the heck does it come from? Well, turns out there's this molecule called phosphofructokinase 2 PFK 2 that generates fructose 26 bisphosphate, to regulate the action of PFK 1. That's like its job. So insulin insulin, stimulates the removal of sorry, the removal of phosphate group that's attached to PFK2. It's going to activate PFK2. That's the long and the short of it. Insulin is going to activate PFK 2 and you can see in this figure, we have 2 states. What's going on when insulin is present? What's going on when glucagon is present? And hopefully you remember, insulin is secreted in response to high blood sugar and glucagon with insulin, we are going to remove with insulin, we are going to remove that phosphate group that was inactivating PFK 2 and that's going to activate PFK 2. And glucagon does the opposite. Glucagon is going to cause PFK 2 to be phosphorylated and inactivated again. And it's going to spend an ATP to phosphorylate PFK2. What's so basically, fructose 26 bisphosphate is produced by PFK 2 and it's broken down by this other enzyme called fructose 26 bisphosphatase, right? Name, not very creative but very clear what this enzyme does. All right. What's cool so let's try and get it. What's cool is PFK 2 and fructose bisphosphatase 2 are part of the same enzyme and you probably notice that from the figure, right? They're connected. Or I shouldn't say they're they're part of the same enzyme but they're they're linked. They are linked together. So, when one is active, the other is inactive. And when one gets inactivated, the other will become activated. So protein, protein phosphatase is responsible for dephosphorylating PFK2. So this reaction right here is carried out by protein phosphatase. And that happens to be stimulated by xylulose-five phosphate. Now hopefully that molecule sounds familiar. I'm just going to abbreviate it as X5P. Hopefully that molecule sounds familiar because it comes from the pentose phosphate pathway, right? And hopefully you recall the purpose of the pentose phosphate pathway, right? Biosynthesis. If you have some extra stuff lying around so let's think about this. What does PFK do? PFK produces the thing that activates PFK 1, right? So if you have too much xylose 5 phosphate making too much bio to stimulate protein phosphatase to activate PFK2 which will cause PFK1 to be activated which will ultimately lead to glycolysis. So hopefully you can kind of see. You know, it's like a lot of points on the map. You gotta try to connect all these dots in your mind. Alright. With that, let's move on, talk about some other enzymes from glycolysis and gluconeogenesis. So pyruvate kinase, that's gonna be our last like really important enzyme from glycolysis. And pyruvate, kinase has some special properties basically. In the liver and basically only in the liver will only in the liver, will glucagon cause protein kinase A to phosphorylate and inactivate protein kinase. So remember, when our blood sugar is low, that's when glucagon is present. Right? So our blood sugar is low. And in the liver we're going to inactivate pyruvate Kinase. So we're going to block glycolysis, right? Why do you think this is important? What's the liver's job? The liver's job is to deliver sugar to the body. So if we're getting glucagon, that means our blood sugar is low. That means our liver needs to deliver sugar to the body which means it needs to stop burning all that sugar and start producing some, right? This is just a way of, you know, responding to low blood sugar and switching over these metabolic cycles or metabolic pathways rather. Pyruvate Kinase is stimulated by Fructose 16 bisphosphate, right? That upstream subs upstream glycolytic substrate. And, and you know, hopefully that makes sense like you are producing that molecule. It's going to kind of feed forward. Get the end of the cycle ready and activated. Get it ready to accept all that all the substrate that's going to be coming its way. And it's also inhibited by ATP, right? Pyruvate kinase glycolytic enzyme, ATP, kind of product of glycolysis. So it's going to shut off glycolysis if there's too much. Same with Acetyl CoA except Acetyl CoA is obviously comes a little after glycolysis. It's a downstream product but it's also going to have this negative feedback effect and also long chain fatty acids. Also, this is a side note, but alanine will actually also inhibit pyruvate kinase and that's because alanine is derived from pyruvate. So if you're overproducing pyruvate, you're probably gonna make some alanine. And if you're making too much alanine, it's going to say, yo yo pyruvate kinase. Chill out. Chill out. You don't need to make You don't need to work so hard. So last thing I wanna note, pyruvate carboxylase, right, the first gluconeogenic enzyme. The enzyme that's going to partially undo what pyruvate kinase does, right? Remember, pyruvate kinase is action has to be undone 2 steps. So pyruvate carboxylase is the first step and it's going to, be activated by Acetyl CoA. So again, think about this. Acetyl CoA is a downstream product of glycolysis, right? Comes after pyruvate oxidation. If you make too much of it, this is gonna feed back to the first enzyme of gluconeogenesis and say, hey, maybe we're breaking down too much glucose. Maybe it's a good idea to, you know, like make some glucose with, with us. Alright. With that, let's turn the page.