All right, reactions 7 and 8, the final two reactions of the citric acid cycle. First, we have fumarase with ΔG close to 0, and it is going to take fumarate and make malate. Malate can have an L or a D form. We're going to make L-malate. So important to note, here is L-malate. And, it's going to add in water basically. So here I've just shown, you know, water being added in as one whole thing, kind of simplifying the whole reaction a bit. But if we were to look at the mechanism, you would see that water is added in 2 parts. First as OH-, then as H+. We are basically going to reduce this double bond and put a little alcohol group right there.
And then finally, malate dehydrogenase. Look at that ΔG. Right? 30. That's big. Right? A big positive ΔG. Well, it turns out in biological conditions — remember, this is the ΔG, not ΔG′. In biological conditions, this ΔG is actually close to 0. So this reaction is also one of those easily reversible ones. It produces NADH and it takes malate and turns it into oxaloacetate, and we are ready to start the cycle again.
So, let's finish up our discussion of the citric acid cycle with a little bit of accounting, right? Let's talk numbers. So NADH will ultimately produce 2.5 ATP in oxidative phosphorylation. Don't worry about the specifics of that. That's going to be what we cover in the next unit. For now, just know that an NADH makes 2.5 ATP and FADH2 makes 1.5 ATP. We'll talk about why there's a difference there in the next unit, and it'll make tons of sense. It's not one of those arbitrary things. There's a reason, and it'll make sense once we go through it.
One important note is that the NADH that's generated in glycolysis, right? By glyceraldehyde 3-phosphate dehydrogenase, that can actually generate 1.5 or 2.5 ATP, and it depends on where it enters in metabolism, you know, downstream. Where it enters in metabolism—again, don't need to worry about specifics. But basically, depending on the path that it takes, it will either produce 1.5 or 2.5 ATP. So a bit of a toss-up there, and that is why we say that one glucose yields 30 to 32 ATP because it's because of this discrepancy, right? For every NADH, that's a difference of 1 ATP and remember that for glucose, you're going to generate 2 of these NADH because the sky is going to do the reaction twice for each glucose molecule, right? There's going to be 2, 3-carbon molecules going through. Anyways, so that would ultimately turn into a difference of 2 ATP depending on what happens to those NADHs.
Now, you don't really need to worry too much about that. Let's focus on the important stuff: Where is all of this ATP coming from? So, again, you're going to get 5 to 7 from glycolysis, right? And there's a 2 ATP difference here because of these NADHs. So, let's say that from glycolysis, but you use up 2. So there's a net 2 ATP. So that's where our ATP from glycolysis is coming from. From pyruvate oxidation, you make 5 ATP, right? Because pyruvate oxidation for 1 glucose will generate 2 NADH, and that will make 5 ATP ultimately, and then you're actually going to produce 20 from the citric acid cycle. Big money, right? That's why citric acid cycle and aerobic respiration is so important when you think about it in terms of ATP yield versus glycolysis. Glycolysis is so much less energy efficient. It's just phenomenal. Your cells literally wouldn't be able to provide enough energy for your body if it weren't for aerobic respiration. I mean, really, not to harp on it, but just to put it in perspective, your body basically cycles 50 kilograms of ATP a day. That means that you generate and burn about 50 kilograms of ATP a day. Go check out how much that is of your actual body weight. It will astonish you.
Moving on, citric acid cycle: For 1 glucose, right, we're going to have 2 acetyl CoA's going through the cycle. So we're going to generate 6 NADH, 2 FADH2, and either 2 ATP or 2 GTP. And that's going to yield a total of 20 ATP. So that is where we get our 30 to 32 ATP total from these processes.
Now, let's talk a little bit about regulation of the citric acid cycle. Generally speaking, the citric acid cycle is regulated by the energy-poor and energy-rich molecules involved in respiration. So energy-rich molecules, as we've mentioned before, stuff like ATP and NADH, right? And energy-poor molecules, stuff like AMP, ADP, and NAD&apos+. So let's look at our big player enzymes, right? Pyruvate dehydrogenase and then the enzymes for reactions 1, 3, and 4 from the citric acid cycle are drivers, right? Pyruvate dehydrogenase is inhibited by ATP—duh—acetyl CoA, no surprises there, and NADH. All very logical, right? The stuff that it produces is going to inhibit it so it doesn't overproduce. Likewise, the stuff that it uses to carry out its reaction stimulates it because, you know, if it needs to start carrying out its reaction, kick its button into gear, it's going to get the signal from the buildup of all this stuff. Meaning, that these molecules have been consumed and now we're left with this. So we need to make more.
Moving on, citrate synthase is inhibited by NADH, succinyl CoA, citrate—its direct product. Right? Citrate synthase makes citrate. Its direct product inhibits it. Succinyl CoA comes downstream in the citric acid cycle, but it still will feedback to the first step of the cycle. Pretty smart, right? Have a later reaction give feedback on the first one. You have multiple feedback points in your citric acid cycle. It's also inhibited by ATP and is stimulated by ADP. Isocitrate dehydrogenase is inhibited by ATP, stimulated by ADP. Hopefully, no surprises here. Alpha-ketoglutarate dehydrogenase complex is inhibited by NADPH—NADH rather—and succinyl CoA.
So hopefully, this regulation stuff just seems, very like it's kind of common sense type stuff. You know, I don't think you need to really know all the specifics, memorize all the specifics. I think it's more important that you just kind of understand the general idea that the products, both the direct products and the downstream products, tend to inhibit, and the reactants tend to stimulate.
Last thing I want to talk about: these anaplerotic reactions. These reactions are used to generate oxaloacetate to replace the loss of acceptor molecules from the citric acid cycle. So the molecules of the citric acid cycle like alpha-ketoglutarate, succinate, you know, oxaloacetate, for example. These can all be used as biosynthetic precursors and they'll make many amino acids. Some can actually be used to make other things, and what's important is that if they're pulled away from the citric acid cycle, it's, you know, very likely that they'll need to be replaced at some point if the cycle needs to output higher production. So these anaplerotic reactions are basically just reactions used to generate oxaloacetate. And remember, oxaloacetate is made in step 8 of the cycle but steps 8, 7, 6, and 5 can be reversed, right? We can go backwards. So we can produce up to, you know, succinyl CoA. We can produce up to succinyl CoA to regenerate whatever molecule of the cycle we need. You know, so any of these guys, for example, or, you know, if we Yeah. I mean just the basic idea that you can reverse these reactions so that you can produce like, you know, malate, fumarate, succinate, succinyl CoA, whatever it is. You can't reverse the reaction that produces succinyl CoA because it's one of the drivers.
With that, let's flip the page.
