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Krebs / citric acid cycle

Overview of the Krebs or citric acid cycle, which is a series of reactions that takes in acetyl CoA and  produces carbon dioxide, NADH, FADH2, and ATP or GTP.  Created by Sal Khan.

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  • blobby green style avatar for user crystaljganatra
    Near the end of the video, it says at the end of cellular respiration you end up with the promised 38 ATPs. My textbook says "The complete breakdown of glucose through cellular respiration, including glycolysis, results in the production of 36 molecules of ATP. Where did the extra 2 ATPs go?
    (21 votes)
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  • female robot grace style avatar for user Aditi
    What is the tricarboxylic acid cycle? Is it the same as the Krebs/citric acid cycle?
    (14 votes)
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  • male robot hal style avatar for user samuelhbird
    are there any other sugars other than glucose, fructose and lactose
    (12 votes)
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  • blobby green style avatar for user philtrum
    When explaining the citric acid cycle (circle diagram), he says FAD gets oxidized to FADH2. But isnt that wrong? I believe it should be FAD gets reduced to FADH2, correct??
    (21 votes)
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  • duskpin ultimate style avatar for user MatthewDMcIntyre
    How do the pyruvate get into the matrix?
    (5 votes)
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    • mr pants teal style avatar for user Matthew Belliveau
      Great question. I had to do a bit of research, because I've taught cellular respiration many times, but never looked in detail at exactly how pyruvate gets into the matrix. This is what I found:

      Getting across the outer mitochondrial membrane is relatively easy. Pyruvate carries a negative charge, and there are anion channels that allow pyruvate to penetrate the intermembrane space by simple passive diffusion! No energy is required. Getting across the inner membrane and into the matrix, however, is a different story.

      Entry into the matrix is much more restrictive, and rightfully so. This is an important site in the large-scale energy production process and we don't want all kinds of molecules contaminating this space. Pyruvate transport into the matrix is accomplished therefore by active transport by a class of recently discovered transport proteins called mitochondrial pyruvate carriers (MPC). They are embedded in the inner membrane and use ATP to transport pyruvate into the matrix. It uses ATP, which it is able to recuperate by the vast amounts of ATP that are created by each molecule of pyruvate through oxidative phosphorylation.

      This is the journal where I got this information from if you'd like to have a look yourself. I focused on reading the abstract/introduction, as the experimental processes used to identify and describe the MPC were a bit technical for my Sunday brain :)


      The first picture on this website shows a picture of MPC 1/2 (different types of the MPC protein) on the inner membrane, transporting pyruvate into the matrix. It's at the top of the first picture:

      (18 votes)
  • blobby green style avatar for user Suzie Johnson
    How long does the Kreb's cycle take? Is it different for different cells and is it different for people who exercise than couch potatoes? Animals? Plants? Bacteria?
    (9 votes)
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    • leaf blue style avatar for user Chris
      The speed of cellular respiration is nearly impossible to determine. For animals, plants, and couch potatoes, the Kreb's cycle happens at a 'normal rate'. For people who exercise, they need more immediate energy which is why glycolysis and the Kreb's cycle runs faster to produce more ATP. When there is a lack of oxygen (such as exercise), glycolysis can go directly to lactic acid fermentation to operate anaerobically while recycling NAD+.
      For bacteria (in which they either use cellular respiration with oxygen, are faculative anaerobes, or obligate anaerobes), they may not need oxygen/may not be able to use oxygen in cellular respiration. In bypassing the Kreb's cycle due to unnecessarity of oxygen, the bacteria would use lactic acid fermentation.
      (6 votes)
  • duskpin ultimate style avatar for user Tzirliya
    Where does Oxaloacetic Acid come from and what is it?
    (6 votes)
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  • blobby green style avatar for user Cara Roberts
    Just curious. Where does the oxaloacetic acid come from?
    (4 votes)
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    • mr pants teal style avatar for user Eric Fausto
      Oxaloacetate forms in several ways in nature. A principal route is upon oxidation of L-malate, catalysed by malate dehydrogenase. It arises from the condensation of pyruvate with carbonic acid, driven by the hydrolysis of ATP:
      CH3C(O)CO2- + HCO3- + ATP → -O2CCH2C(O)CO2- + ADP + Pi
      Occurring in the mesophyll of plants, this process proceeds via phosphoenolpyruvate, catalysed by pyruvate carboxylase. Oxaloacetate can also arise from degradation of aspartic acid.
      (2 votes)
  • blobby green style avatar for user rachel
    My model in respiration shows that each glucose produces 38 ATP's, my teacher says, that's not true because there are other things going on. Can you tell me what those other things are? Why are exactly 38 ATP's not accurate?
    (3 votes)
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    • duskpin ultimate style avatar for user FalconVIII
      The process of Cellular respiration does 'involve' 38 ATP, however there is only a 'Net Gain' of 36 ATP... which it probably the number your teacher was referring to...? :), This is, as in the Glycolysis 'phase' of respiration, 2 ATP are needed/used to 'kick things off'/ help start the process, which results in the formation of 4 ATP, so 2(used) - 4 (produced) = 2 Net Gain of ATP, and then add the 34 from the other processes of respiration, so 36 ATP are produced total, so it is more 'accurate' to say 36 ATP, over 38... Hope that explains! :)
      (2 votes)
  • male robot donald style avatar for user Austin Alexander
    And they learn all this under a microscope? :o
    (2 votes)
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Video transcript

So we already know that if we start off with a glucose molecule, which is a 6-carbon molecule, that this essentially gets split in half by glycolysis and we end up 2 pyruvic acids or two pyruvate molecules. So glycolysis literally splits this in half. It lyses the glucose. We end up with two pyruvates or pyruvic acids. ruby And these are 3-carbon molecules. There's obviously a lot of other stuff going on in the carbons. You saw it in the past. And you could look up their chemical structures on the internet or on Wikipedia and see them in detail. But this is kind of the important thing. Is that it was lysed, it was cut in half. And this is what happened in glycolysis. And this happened in the absence of oxygen. Or not necessarily. It can happen in the presence or in the absence of oxygen. It doesn't need oxygen. And we got a net payoff of two ATPs. And I always say the net there, because remember, it used two ATPs in that investment stage, and then it generated four. So on a net basis, it generated four, used two, it gave us two ATPs. And it also produced two NADHs. That's what we got out of glycolysis. And just so you can visualize this a little bit better, let me draw a cell right here. Maybe I'll draw it down here. Let's say I have a cell. That's its outer membrane. Maybe its nucleus, we're dealing with a eukaryotic cell. That doesn't have to be the case. It has its DNA and its chromatin form all spread around like that. And then you have mitochondria. And there's a reason why people call it the power centers of the cell. We'll look at that in a second. So there's a mitochondria. It has an outer membrane and an inner membrane just like that. I'll do more detail on the structure of a mitochondria, maybe later in this video or maybe I'll do a whole video on them. That's another mitochondria right there. And then all of this fluid, this space out here that's between the organelles-- and the organelles, you kind of view them as parts of the cell that do specific things. Kind of like organs do specific things within our own bodies. So this-- so between all of the organelles you have this fluidic space. This is just fluid of the cell. And that's called the cytoplasm. And that's where glycolysis occurs. So glycolysis occurs in the cytoplasm. Now we all know-- in the overview video-- we know what the next step is. The Krebs cycle, or the citric acid cycle. And that actually takes place in the inner membrane, or I should say the inner space of these mitochondria. Let me draw it a little bit bigger. Let me draw a mitochondria here. So this is a mitochondria. It has an outer membrane. It has an inner membrane. If I have just one inner membrane we call it a crista. If we have many, we call them cristae. This little convoluted inner membrane, let me give it a label. So they are cristae, plural. And then it has two compartments. Because it's divided by these two membranes. This compartment right here is called the outer compartment. This whole thing right there, that's the outer compartment. And then this inner compartment in here, is called the matrix. Now you have these pyruvates, they're not quite just ready for the Krebs cycle, but I guess-- well that's a good intro into how do you make them ready for the Krebs cycle? They actually get oxidized. And I'll just focus on one of these pyruvates. We just have to remember that the pyruvate, that this happens twice for every molecule of glucose. So we have this kind of preparation step for the Krebs Cycle. We call that pyruvate oxidation. And essentially what it does is it cleaves one of these carbons off of the pyruvate. And so you end up with a 2-carbon compound. You don't have just two carbons, but its backbone of carbons is just two carbons. Called acetyl-CoA. And if these names are confusing, because what is acetyl coenzyme A? These are very bizarre. You could do a web search on them But I'm just going to use the words right now, because it will keep things simple and we'llget the big picture. So it generates acetyl-CoA, which is this 2-carbon compound. And it also reduces some NAD plus to NADH. And this process right here is often given credit-- or the Krebs cycle or the citric acid cycle gets credit for this step. But it's really a preparation step for the Krebs cycle. Now once you have this 2-carbon chain, acetyl-Co-A right here. you are ready to jump into the Krebs cycle. This long talked-about Krebs cycle. And you'll see in a second why it's called a cycle. Acetyl-CoA, and all of this is catalyzed by enzymes. And enzymes are just proteins that bring together the constituent things that need to react in the right way so that they do react. So catalyzed by enzymes. This acetyl-CoA merges with some oxaloacetic acid. A very fancy word. But this is a 4-carbon molecule. These two guys are kind of reacted together, or merged together, depending on how you want to view it. I'll draw it like that. It's all catalyzed by enzymes. And this is important. Some texts will say, is this an enzyme catalyzed reaction? Yes. Everything in the Krebs cycle is an enzyme catalyzed reaction. And they form citrate, or citric acid. Which is the same stuff in your lemonade or your orange juice. And this is a 6-carbon molecule. Which makes sense. You have a 2-carbon and a 4-carbon. You get a 6-carbon molecule. And then the citric acid is then oxidized over a bunch of steps. And this is a huge simplification here. But it's just oxidized over a bunch of steps. Again, the carbons are cleaved off. Both 2-carbons are cleaved off of it to get back to oxaloacetic acid. And you might be saying, when these carbons are cleaved off, like when this carbon is cleaved off, what happens to it? It becomes CO2. It gets put onto some oxygen and leaves the system. So this is where the oxygen or the carbons, or the carbon dioxide actually gets formed. And similarly, when these carbons get cleaved off, it forms CO2. And actually, for every molecule of glucose you have six carbons. When you do this whole process once, you are generating three molecules of carbon dioxide. But you're going to do it twice. You're going to have six carbon dioxides produced. Which accounts for all of the carbons. You get rid of three carbons for every turn of this. Well, two for every turn. But really, for the steps after glycolysis you get rid of three carbons. But you're going to do it for each of the pyruvates. You're going to get rid of all six carbons, which will have to exhale eventually. But this cycle, it doesn't just generate carbons. The whole idea is to generate NADHs and FADH2s and ATPs. So we'll write that here. And this is a huge simplification. I'll show you the detailed picture in a second. We'll reduce some NAD plus into NADH. We'll do it again. And of course, these are in separate steps. There's intermediate compounds. I'll show you those in a second. Another NAD plus molecule will be reduced to NADH. It will produce some ATP. Some ADP will turn into ATP. Maybe we have some-- and not maybe, this is what happens-- some FAD gets-- let me write it this way-- some FAD gets oxidized into FADH2. And the whole reason why we even pay attention to these, you might think, hey cellular respiration is all about ATP. Why do we even pay attention to these NADHs and these FADH2s that get produced as part of the process? The reason why we care is that these are the inputs into the electron transport chain. These get oxidized, or they lose their hydrogens in the electron transport chain, and that's where the bulk of the ATP is actually produced. And then maybe we'll have another NAD get reduced, or gain in hydrogen. Reduction is gaining an electron. Or gaining a hydrogen whose electron you can hog. NADH. And then we end up back at oxaloacetic acid. And we can perform the whole citric acid cycle over again. So now that we've written it all out, let's account for what we have. So depending on-- let me draw some dividing lines so we know what's what. So this right here, everything to the left of that line right there is glycolysis. We learned that already. And then most-- especially introductory-- textbooks will give the Krebs cycle credit for this pyruvate oxidation, but that's really a preparatory stage. The Krebs cycle is really formally this part where you start with acetyl-CoA, you merge it with oxaloacetic acid. And then you go and you form citric acid, which essentially gets oxidized and produces all of these things that will need to either directly produce ATP or will do it indirectly in the electron transport chain. But let's account for everything that we have. Let's account for everything that we have so far. We already accounted for the glycolysis right there. Two net ATPs, two NADHs. Now, in the citric acid cycle, or in the Krebs cycle, well first we have our pyruvate oxidation. That produced one NADH. But remember, if we want to say, what are we producing for every glucose? This is what we produced for each of the pyruvates. This NADH was from just this pyruvate. But glycolysis produced two pyruvates. So everything after this, we're going to multiply by two for every molecule of glucose. So I'll say, for the pyruvate oxidation times two means that we got two NADHs. And then when we look at this side, the formal Krebs cycle, what do we get? We have, how many NADHs? One, two, three NADHs. So three NADHs times two, because we're going to perform this cycle for each of the pyruvates produced from glycolysis. So that gives us six NADHs. We have one ATP per turn of the cycle. That's going to happen twice. Once for each pyruvic acid. So we get two ATPs. And then we have one FADH2. But it's good, we're going to do this cycle twice. This is per cycle. So times two. We have two FADHs. Now, sometimes in a lot of books these two NADHs, or per turn of the Krebs cycle, or per pyruvate this one NADH, they'll give credit to the Krebs cycle for that. So sometimes instead of having this intermediate step, they'll just write four NADHs right here. And you'll do it twice. Once for each puruvate. So they'll say eight NADHs get produced from the Krebs cycle. But the reality is, six from the Krebs cycle two from the preparatory stage. Now the interesting thing is we can account whether we get to the 38 ATPs promised by cellular respiration. We've directly already produced, for every molecule of glucose, two ATPs and then two more ATPs. So we have four ATPs. Four ATPs. How many NADHs do we have? 2, 4, and then 4 plus 6 10. We have 10 NADHs. And then we have 2 FADH2s. I think in the first video on cellular respiration I said FADH. It should be FADH2, just to be particular about things. And these, so you might say, hey, where are our 38 ATPs? We only have four ATPs right now. But these are actually the inputs in the electron transport chain. These molecules right here get oxidized in the electron transport chain. Every NADH in the electron transport chain produces three ATPs. So these 10 NADHs are going to produce 30 ATPs in the electron transport chain. And each FADH2, when it gets oxidized and gets turned back into FAD in the electron transport chain, will produce two ATPs. So two of them are going to produce four ATPs in the electron transport chain. So we now see, we get four from just what we've done so far. Glycolysis, the preparatory stage and the Krebs or citric acid cycle. And then eventually, these outputs from glycolysis and the citric acid cycle, when they get into the electron transport chain, are going to produce another 34. So 34 plus 4, it does get us to the promised 38 ATP that you would expect in a super-efficient cell. This is kind of your theoretical maximum. In most cells they really don't get quite there. But this is a good number to know if you're going to take the AP bio test or in most introductory biology courses. There's one other point I want to make here. Everything we've talked about so far, this is carbohydrate metabolism. Or sugar catabolism, we could call it. We're breaking down sugars to produce ATP. Glucose was our starting point. But animals, including us, we can catabolize other things. We can catabolize proteins. We can catabolize fats. If you have any fat on your body, you have energy. In theory, your body should be able to take that fat and you should be able to do things with that. You should be able to generate ATP. And the interesting thing, the reason why I bring it up here, is obviously glycolysis is of no use to these things. Although fats can be turned into glucose in the liver. But the interesting thing is that the Krebs cycle is the entry point for these other catabolic mechanisms. Proteins can be broken down into amino acids, which can be broken down into acetyl-CoA. Fats can be turned into glucose, which actually could then go the whole cellular respiration. But the big picture here is acetyl-CoA is the general catabolic intermediary that can then enter the Krebs cycle and generate ATP regardless of whether our fuel is carbohydrates, sugars, proteins or fats. Now, we have a good sense of how everything works out right now, I think. Now I'm going to show you a diagram that you might see in your biology textbook. Or I'll actually show you the actual diagram from Wikipedia. I just want to show you, this looks very daunting and very confusing. And I think that's why many of us have trouble with cellular respiration initially. Because there's just so much information. It's hard to process what's important. But I want to just highlight the important steps here. Just so you see it's the same thing that we talked about. From glycolysis you produce two pyruvates. That's the pyruvate right there. They actually show its molecular structure. This is the pyruvate oxidation step that I talked about. The preparatory step. And you see we produce a carbon dioxide. And we reduce NAD plus into NADH. Then we're ready to enter the Krebs cycle. The acetyl-CoA and the oxaloacetate or oxaloacetic acid, they are reacted together to create citric acid. They've actually drawn the molecule there. And then the citric acid is oxidized through the Krebs cycle right there. All of these steps, each of these steps are facilitated by enzymes. And it gets oxidized. But I want to highlight the interesting parts. Here we have an NAD get reduced to NADH. We have another NAD get reduced to NADH. And then over here, another NAD gets reduced to NADH. So, so far, if you include the preparatory step, we've had four NADHs formed, three directly from the Krebs cycle. That's just what I told you. Now we have, in this diagram they say GDP. GTP gets formed from GDP. The GTP is just guanosine triphosphate. It's another purine that can be a source of energy. But then that later can be used to form an ATP. So this is just the way they happen to draw it. But this is the actual ATP that I drew in the diagram on the top. And then they have this Q group. And I won't go into it. And then it gets reduced over here. It gets those two hydrogens. But that essentially ends up reducing the FADH2s. So this is where the FADH2 gets produced. So as promised, we produced, for each pyruvate that inputted-- remember, so we're going to do it twice-- for each pyruvate we produced one, two, three, four NADHs. We produced one ATP and one FADH2. That's exactly what we saw up here. I'll see you in the next video.