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Regulation of pyruvate dehydrogenase

Dive into the regulation of the citric acid cycle, exploring how Acetyl-CoA enters the cycle and gets oxidized into carbon dioxide. Uncover the irreversible reaction from pyruvate to Acetyl-CoA, and how it's a prime target for cellular regulation. Learn about the major roles of Acetyl-CoA and the allosteric regulation of the pyruvate dehydrogenase enzyme. Created by Jasmine Rana.

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  • blobby green style avatar for user CHD
    The video talks about how fatty acids cannot contribute to gluconeogenesis, which is true. However, I think the reasoning is incorrect. The video claims that acetyl-coa from fatty acid oxidation cannot contribute to gluconeogenesis because the pyruvate dehydrogenase step is irreversible. Hypothetically acetyl coa could enter the TCA and become OAA. That OAA can be converted to phosphoenolpyruvate (PEP) by PEP carboxylase. The PEP can be converted to glucose via gluconeogenesis! I think the real reason fatty acids cannot contribute to gluconeogenesis has something to do with the number of carbons required as input, but I can't remember the exact reasoning from my biochem class, can somebody help me out?
    (8 votes)
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    • male robot hal style avatar for user Okilus
      It's awesome that you're thinking that far, but the OAA from the Krebs cycle does not come from fatty acids. The OAA is made from pyruvate (by pyruvate carboxylase) or directly from amino acids. FAs contribute the two carbon Acetyl in from of acetyl-coA that makes citric acid when reacted with OAA. So again the premise that acetyl coA can enter TCA to become OAA is wrong. When acetyl coA enters TCA it becomes citric acid. The acetyl group is then carbon-for-carbon used and you end up with OAA again.
      (16 votes)
  • blobby green style avatar for user S Beckett
    Does the creation of acetyl-CoA occur in the cytoplasm, or is pyruvate transported into the matrix first?
    (4 votes)
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  • blobby green style avatar for user Mrose85
    At , NAD+ is stated as a cofactor, but other videos describe NAD+ as a coenzyme. Could you please clarify?
    (5 votes)
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    • leaf green style avatar for user Kevin James Tokoph
      Cofactors are typically metal ions or other NON-GROUP-TRANSFERRING molecules required for catalysis. For example cytochrome c oxidase contains copper ions. Glucokinase, phophoglucoisomerase, and ATP-specific PFK contain Mg 2+. Certain hemes would also be cofactors, as in cytochrome P450's. These would be cofactors. Coenzymes are organic molecules derived from vitamins or other organic metabolites that TRANSFER groups, and therefore are usually in enzymes classified as transferases (class 2 enzymes) or oxidoreductases (class 1). PDH (pyruvate dehydrogenase (DH)) contains 5 coenzymes: NAD+ (niacin, B3), FAD (riboflavin, B2), Coenzyme-A (pantothenate, B5), thimaine pyrophosphate (amino-imidizole ribonucleotide and 1-deoxy-xylulose-5-phosphate), and lipoate. It is not critical to differentiate between cofactors and coenzymes usually, as even biochemists use the terms interchangably. But, technically, the video is incorrect.
      (7 votes)
  • marcimus pink style avatar for user kteschenbach
    What are the exact inputs, numbers included, of the Krebs Cycle?
    (3 votes)
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  • blobby green style avatar for user gjesusmo
    Is ADP an activator or inhibitor?
    (2 votes)
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  • female robot grace style avatar for user Anna
    couldn't you take the glycerol from fats, turn glycerol into glyceraldehyde, and then bond together 2 glyceraldehydes to form C6H12O6 or glucose from fats in case you have 0 glycogen and low blood glucose levels?
    (3 votes)
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  • leaf blue style avatar for user Anand
    If the reaction is irreversible, isn't it supposed to have a very highly positive delta G instead of a very negative one ?
    (1 vote)
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    • piceratops ultimate style avatar for user Darmon
      A reaction that has a very large negative delta G value in one direction will proceed spontaneously in that direction to form the products. The reason such a reaction is irREVERSIBLE is that the REVERSE reaction has a very large positive delta G value, meaning that a large input of energy would be required to cause the reaction to proceed in this reverse direction. :)
      (5 votes)
  • leafers ultimate style avatar for user ff142
    If pyruvate is both a substrate and an allosteric activator of an enzyme, does that mean it can bind either an active site or an allosteric site of the enzyme?
    (3 votes)
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  • blobby green style avatar for user Grandwizard
    Wait, why can't a fatty acid contribute to the formation of glucose in the following way:
    Fatty acid is broken down into acetyl CoAs, which enters the TCA cycle and ultimately becomes OAA, which can enter gluconeogenesis and then be converted to phosphoenolpyruvate (PEP) through PEPCK.
    I am speculating here but this process makes sense to me
    After watching more videos, I realized that the acetyl CoA carbons are oxidized fully to CO2. The flux of other metabolites into the TCA cycle is ultimately what contributes to the formation of Oxaloacetate––not acetyl CoA, per se. Thanks, KA!
    (2 votes)
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  • blobby green style avatar for user parsaasartipi6
    "this enzyme has a cofactor called NADH"
    shouldn't it be coenzyme? because its a carrier molecule, it carries electrons.
    (2 votes)
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Video transcript

- [Instructor] Before talking about the regulation that occurs inside the citric acid cycle, let's take a moment and step back and talk about what regulates the entry into the citric acid cycle. So remember that a molecule called Acetyl-CoA is what really enters the citric acid cycle and is oxidized into the carbon dioxide molecules as it kind of goes around in a citric acid cycle. And instead of writing out the entire chemical formula I just want to abbreviate this as a two carbon molecule with the coenzyme A functional group. Which is actually a thiol group, a sulfur group. So I'll just write, two carbons with a sulfur coenzyme group for short. Now I want to remind you what produces Acetyl-CoA. So remember we have glycolysis and from glycolysis which begins the breakdown of glucose, we produce pyrate. And so it's the pyrate that travels from the cytosol into the mitochondria that's converted into Acetyl-CoA by a very special enzyme called pyruvate dehydrogenase. And remember dehydrogenase means we're dehydrogenating or oxidizing our molecule. And so if we're oxidizing it shouldn't surprise you then that this enzyme has a co factor indeed. It requires NAD+ , which is converted into NADH, or I should say reduced into NADH as pyruvate is being oxidized into Acetyl-CoA. And I want to remind you that pyruvate is a three carbon molecule. So it's losing a carbon molecule. You can see here because Acetyl-CoA is two carbons but pyruvate is three so a carbon must be lost during this reaction. And indeed, part of the oxidation process releases a carbon dioxide molecule. And finally, I also want to note as well that of course, in order to get this coenzyme A here we need to have that as a substrate as well. Now one important point about this step, this entry point into the citric acid cycle, is that this reaction, in going from pyruvate to Acetyl-CoA, is irreversible. Which is why I'm kind of bolding this unidirectional arrow here to tell you that while we can take pyruvate into Acetyl-CoA, it's not possible to take Acetyl-CoA and turn it into pyruvate. And remember, that when we say a reaction is irreversible that's just another way to say that we have a pretty large negative Delta G value. Now the big point I want to make is that because this reaction is irreversible it makes it a nice target for the cell and for lots of regulation. And remember that regulation often occurs on irreversible steps because these are the steps that if you open basically, then the ball will keep rolling down the pathway. So we want to make sure that these irreversible steps are tightly regulated. But just as a quick side note before we talk about the actual regulation, it's also kind of nice to recognize that fatty acids can also contribute to the production of Acetyl-CoA when they're broken down. But because this reaction is irreversible, this Acetyl-CoA produced by fatty acids cannot contribute to the production of pyruvate and therefor, cannot contribute to the production of gluconeogenesis. Which remember, if you recall, occurs by using pyruvate as one of the substrates. And so that's why you might hear some text books kind of quote this fact that fatty acids, or at least most of them, cannot contribute to the production of glucose. All right, so let's leave that tangent for a moment and let's return to our question which is, how is the production of Acetyl-CoA regulated? And to answer this question I'd first like to kind of just start off with the big picture. Which is, what is the purpose of Acetyl-CoA? And the two major purposes are one, which most people are familiar with which is entry into the citric acid cycle. And of course, the entry into the citric acid cycle allows Acetyl-CoA to be oxidized into carbon dioxide and produce the electron carrier molecules NADH and FADH two which then enter the electron transfer chain to produce ATP. All right, so that's one purpose. But another purpose is also, remember how I mentioned that fatty acids can be broken down to Acetyl-CoA? Well Acetyl-CoA can also be used to produce fatty acids when ATP levels are high. And so this is kind of this second major use of Acetyl-CoA in the body. And so keep these kind of two major pathways for Acetyl-CoA in mind as we talk about how this step is regulated. Now I should say at this point that the major form of regulation, in this case, is allosteric regulation of the pyruvate dehydrogenase enzyme. So remember, that's just a fancy way for saying that there are molecules that can essentially bind to a part of the enzyme to make it work better. In which case it's an allosteric activator or to make it not work as good, in which case it would be an allosteric inhibitor. And, I kind of remember that this is the main form of regulation in this step because it really allows this step to kind of assess the energy state of the body by looking at, kind of, what molecules it has floating around. And in fact, let's go ahead and write out what some of the allosteric activators and inhibitors are off this pyruvate dehydrogenase enzyme and you'll kind of see what I mean when I talk about the energy state of the cell. Now one important principle that I use to kind of remind myself what activates and inhibits this enzyme is to remember what products and substrates are for this reaction. And I kind of, essentially, I think back to Le Chatelier's principle and justify to myself that if we have an accumulation of substrates these are going to want to be allosteric activators. Essentially they want to push this kind of reaction forward. And if we have an accumulation of the products these are going to probably most likely be allosteric inhibitors, because they're going to, you know, assign that too much is being produced and we can put a break on the reaction. And so indeed, the allosteric activators include the substrates CoA as well as NAD+ and even pyruvate. And then the inhibitors include Acetyl-CoA of course, as well as NADH. Now a couple more allosteric activators and inhibitors that might not be immediately obvious, but will make sense once we discuss them, are ATP is also a negative allosteric inhibitor. On the flip side, AMP is a allosteric activator. And additionally, fatty acids can also be an additional allosteric inhibitor and calcium can be an additional allosteric activator. All right, so how can we reason out these final allosteric activators and inhibitors? Well first simply realize that the levels of ATP and AMP again are getting at this energy state as the cell. It's a way for the body to assess if it needs to shuttle more Acetyl-CoA through the citric acid cycle and then, you know, channel all of these electron carrier molecules to the electron transfer chain or whether it has enough ATP and it can slow down the flux of Acetyl-CoA through the citric acid cycle. And so it should make sense to you that having a low-energy state in the cell, indicated by lots of AMP, should activate this, should alert the body to produce more Acetyl-CoA. But if we have enough, if we have enough ATP lying around, then the, you know, this reaction can essentially slow down. Now this calcium here may not be immediately obvious but I'll remind you that, remember that exercising skeletal muscle involves the influx of a lot of calcium. So when you're exercising of course your energy needs to go up and so in skeletal muscle this free calcium in the cell is kind of a nice alert to say, you know what, we're gonna need more energy. Let's start producing more Acetyl-CoA. And finally, these fatty acids, why do these fatty acids inhibit the production of Acetyl-CoA? Well of course I remind you here of the second purpose of Acetyl-CoA which is to produce the synthesis of fatty acids. And so if we have enough fatty acids in the body again it can be a signal to the cell to say, you know what, we don't need any more Acetyl-CoA. We can slow this process down. So at the end of the day there might be a lot of these allosteric regulators to keep track of but just go back to the basics and remind yourself what is a substrate, what is a product, and what the energy state of the cell is. And I think you'll be able to reason out most of these.