01.05 Krebs Cycle

Hey there. What we’re going to talk about today is the Kreb's cycle. We’re going to look at energetic aspects of it, some of the key players, and also a particular reaction that I’d like to tell you a bit about. The Kreb's cycle is pretty complicated, and there is a lot to know. So I’m going to just try and touch on what I think are the most important parts. The Kreb's cycle is also known as the citric acid cycle. It occurs in the mitochondria and the basic gist of what happens is that two carbons from a molecule called acetylCoA are going to enter the Krebs cycle and they exit as to CO2 molecules. Just a reminder, what CO2 looks like...that’s the structure of it. In addition to those two CO2 molecules, the Krebs cycle is going to make a GTP, an FADH2, and three NADH molecules. Lastly, we’re going to touch on dehydrogenation reactions; that’s a very common type of reaction that you see in the Kreb's cycle. Basically what we’re looking at here is sort of the "where", the "what", the "why" and the "how". Where...meaning it happens in the mitochondria. What...happens is that two carbons of acetylCoA go in and two CO2s come out. Why...it’s because we want to create these high energy molecules. And then how...that’s really the realm of electron pushing, like understanding exactly how the electrons move during a reaction. Here’s a cell and this would be a eukaryotic cell because it’s got a cytoplasm and it has a nucleus. And in addition, it’s got lots of these little bean shaped structures and those are mitochondria. In reality, you’d have like 1000 or 2000 of these little mitochondria in your cells. What happens here is that--let’s say you’ve got glycolysis taking place out in the cytoplasm--the end product of glycolysis is pyruvate which is going to enter into the mitochondria. That’s where it’s going to go through the citric acid cycle in a circle. Here's the cycle taking place inside the mitochondria. AcetylCoA is a super important molecule. It is at the center of metabolism, so I’d like it to have a little in depth view of what it looks like before we look at the actual Kreb's cycle. I like to call it a "two carbon chunk". (We’ll put that in quotes because it’s not a super sciency term.) The two carbons are this carbon here and this carbon here. Now in reality, this SCO part is actually quite massive. So let’s go take a look at that. This is all that extra stuff that’s on there. You may notice that here that’s an adenine. Here’s ribose, and we got phosphate phosphate phosphate. So it’s almost like an ADP with an extra phosphate down here. And then there’s some things kind of maybe a little amino-acid-looking through here. Eventually make your way over to this sulfur...these carbons, this one here and this one here, those are the two carbons that are the "two carbon chunk". So that’s the business end. That’s all that really matters about the acetylCoA. Here is the top half of the citric acid cycle. Now we’re going to look at here’s the pyrivate that would come from glycolysis. The first step that happens outside of the cycle is the conversion of the pyruvate to the acetylCoA. You’ll notice that this is three carbons here. That’s because you split that six carbon glucose into two, three carbon molecules. This step actually takes one of those carbons off. So that’s the generation of the first CO2. I also want to point out that acetylCoA (pronounced in different ways) can also come from fats through fatty acid breakdown. That’s a way that you also can get some acetylCoA and so together they’re going to then enter into the cycle. The first step of the cycle is taking this two carbon chunk and then adding it to this four carbon molecule oxaloacetate...you can see those four carbons...plus these two carbons creates this six carbon molecule, citrate. If you remember the, the conjugate base of an acid, you could say citric acid, and then for its conjugate base, you would say citrate. So that’s where "Citric Acid" cycle is coming from because you’ve got citrate as this first molecule that’s getting made. When you start into the cycle...in terms of energy, notice that we’ve got NADH getting made at this pre-step over here. You’ve got another NADH getting made over here and you’ve got another NADH getting made there. So keep track. That’s actually three NADH's here. If we go into the bottom half, you’re going to see that there’s another NADH getting made there. And then we have an FADH2. So that gets made. So how many NADH is, was that total? We had three on the other slide. This is four. So if you think about the entry plus the whole cycle: That’s going to be four NADH and that’s because one of those was made from that entry part here, three of them are getting made from just inside of the cycle. Sometimes you hear three. Sometimes you hear four. I want to make sure that that’s clear to you. FADH2 also gets made. Those guys--NADH and FADH2--are going to go to the electron transport chain and deliver electrons there. The cycle also makes the GTP...this guy can deliver its third phosphate to an ADP molecule and create ATP that way. This is essentially like making an ATP. So we’re generating energy by going through the citric acid cycle. The last thing I want to touch on here--and if you go back to the previous slide, you’ll notice that there’s this word dehydrogenase again and again. There are lots of dehydrogenases in the citric acid cycle. So let’s do a little in-depth look at what happens in a dehydrogenation reaction. This is malate going to oxaloacetate. Remember, this is that four carbon molecule that combines with the two carbon acetylCoA to make the citric acid, or the citrate. So this is like the last step of the whole cycle. Now let’s look at these two molecules. They’ve got a lot of similarities. If you look back and forth, you’re going to see some similarities. But you’re gonna notice right here, you’ve got a hydroxyl here that is getting turned into a carbonyl. That’s a hallmark of a redox reaction. Sometimes in regular chemistry, we would assign oxidation numbers in order to show it's a redox reaction. You can do that in this case--though it’s a little bit time consuming to do it like that. But if you see a functional group change like this, it's a good indication that it’s redox. In addition, see how you’ve got this NAD turning into NADH? That’s another indication of it being redox. I’ll talk about that a bit more in a moment.Let’s redraw this structure just a little bit. I’m going to fill that bond in just a little bit. I’m showing the electrons between the oxygen and this hydrogen right here. What’s going to happen is that there’s going to be a base, and that base is going to be part of the amino acid chain, like the peptide/protein chain of the dehydrogenase active site. This is going to be stuck inside. This is your enzyme right here. This base is going to have an affinity for this proton sitting right here. It’s going to grab onto that H, leaving behind these electrons. It just wants the H+; it doesn’t want the electron. So those electrons are going to move down over here and that’s what’s going to create this double bond that we have. You now have too many bonds around this carbon, right? If you have a double bond here. If you noticed, I put this little H in here...remember, we often don’t show the H’s on these organic molecules, but you know it is there. So now we see it there. It's going to be the leaving group. That guy leaves, and it’s the H plus those two electrons. So it’s like a proton plus two electrons leaves and comes over to the NAD+. And that’s what makes the NADH. A reminder, LEO says GER...that’s what happens in redox reactions. Loss of electrons is the oxidation, and if we look back here, the malate is losing those electrons. The NAD+ is gaining those electrons...so gain of electrons reduction. So you’d say that the malate is oxidized and the NADH is being reduced. We often say that, if we see these Hs (in a way that we know that it just wasn’t a proton...remember if you have a plus here and you were to add an H plus to it, you would now be at a two plus). Clearly some electrons were added on to the NAD+ in order to make it neutral now. Hopefully that was clear about how to look at a dehydrogenation reaction. Let’s do a little summary. We’ve got pyruvate coming from glycolysis. That’s going to enter the mitochondria. And that’s where it gets converted to acetylCoA prior to the Kreb's cycle, those special carbons of acetylCoA...there’s two of them. Those are going to get turned into two carbon dioxide molecules. In addition, there’s going to be four NADH in total because we’re now including the entry. Plus those three that were made in the cycle and FADH2 and the one GTP are going to be created. And then lastly, we took this in-depth view of what happens during an oxidation-reduction reaction known as a dehydrogenation.

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