Transcription
All engineers, in this video, we're going to talk about fatty acid oxidation. So if you guys have already watched our video on the mobilization of fat, that's going to really help you understand where we're going from here. So we said in the mobilization of, uh, specifically the fats, where we were breaking down the triglyceride into its components, glycerol and fatty acids; we were taking those fatty acids into different tissue cells. What can those tissue cells be that we're taking it to? Again, we said three really important ones were going to be heart muscle. So the heart muscle was going to be a big one—the myocardium of the heart, the skeletal muscles, and even the liver. Okay, so even the liver; many, many different tissues will utilize these fatty acids for energy, but the big ones are going to be your muscle and some of even the liver. And you're going to see why the liver is really important because it can generate these structures called ketone bodies, but we'll talk about that. Okay.
So now we brought the fatty acids into this actual cell. Now, let's just say that this is some general cell, and we're going to bring fatty acids into it. All right, so let's show here our fatty acids; let's show these in blue. Okay, here's our fatty acids. We bring these fatty acids from out here. So again, here's going to be our free fatty acids. What's going to happen is, let's take, for example, these free fatty acids and say that they're specifically long-chain fatty acids. So these are specifically long-chain fatty acids, so approximately about 16 carbons long. Okay. So let's say we bring in a specific type of one, and one of the more specific 16-carbon fatty acids is called palmitic acid. So it's a 16-carbon chain. What I'm going to do is, is I'm going to zoom on, on some of those carbons. I'm not going to look at all 16 carbons. So what I'm going to do is I'm going to put an R Group here, and then I'm going to have a couple special carbons. So let's say here is my fatty acid portion. So here's my carboxy, and right next to that I'm going to have another carbon, and that's going to be my alpha carbon, and then I'll have one more carbon next to that one, which is going to be my beta carbon, and then next to that I'll have many, many other carbons. So in this case, this would be one, two, three; the rest of them would be how many? 13 carbons long. So if I wanted to, I could continue to put all the way down 13 carbon long, but I'm just going to make it an R Group.
Now, the first thing that's going to happen with these free fatty acids is we have to prevent this fatty acid from getting out of the cell. So in order to do that, we're going to utilize a special enzyme. So what's going to happen is this free fatty acid is going to be acted on by a special enzyme. This enzyme is called fatty acyl-CoA synthetase, and what this enzyme is going to do is, is it's going to trigger the conversion of this fatty acid—because this is a fatty acid; okay, we need to make sure that we know that this is specifically a fatty acid, nothing on this guy—but then this fatty acyl-CoA synthetase enzyme is going to stimulate this reaction, and in order for this reaction to occur, we have to utilize energy. This is going to cost energy to add that CoA on. So I'm going to add a coenzyme A into this reaction, but in order for me to do that, it's going to cost energy. What is that? In the form of ATP. So I'm going to break down ATP into ADP and inorganic phosphate, and by doing that, I release energy from the breaking of those bonds, which adds the CoA onto this fatty acid. As a result, then what am I going to have over here then? So now let's draw the resulting product. So I'm going to have my R Group here. So here's my R Group. I'm going to have my CH2 CH2, and then right next to this I'm going to have my carboxy group, but specifically bound to that carboxy group is going to be a, uh, coenzyme A. So right next to this, I'm going to have a coenzyme A right there, and usually this is having some type of thiol group. Okay. Now, this new molecule that we just synthesized in this first step of this reaction is called a fatty acyl-CoA, so a fatty acyl-CoA.
Now, here's the next problem. So the first thing that we had to do is we had to put a CoA on this guy, and let's make this a different color, uh, for the sake of it; let's make this one green since we had green there for CoA, let's stay consistent there. So here's our coenzyme A, and again, it has some specialized thiol group on it, not necessarily important in this, but if you remember, we couldn't get this guy; we couldn't keep it in the cell unless we put a CoA on it. Okay, well, now we put a CoA on it; now we got another problem. We can't get this molecule into the mitochondria because of the CoA. Now I got to do something specific that can actually transport it in. Okay, there's another molecule; this molecule is coming from this specific transporter. This guy right here is adding on a special molecule to this guy. Okay, what is this molecule that he's adding on to him? He's adding on a molecule which is called carnitine. Okay, so carnitine is going to combine with this fatty acyl-CoA, and look what happens here. So I'm going to bring this fatty acyl-CoA down through, and then what happens is this fatty acyl-CoA is going to combine with what? The carnitine. When it combines with the carnitine, it gets rid of the CoA. So now that CoA is going to be lost. Okay, so we did that reaction just to get rid of the CoA. Hm, that's weird; we'll see why. So now we release the coenzyme A and we add in the carnitine. As a result, I'm going to form a molecule called fatty acyl—it's no longer CoA; it has a carnitine onto it—carnitine. So it's called fatty acyl carnitine. That fatty acyl carnitine can be transported through this structure, this translocase. And again, what's going to come out on this side? The molecule that we have on this side is going to be specifically—specifically look, I'm going to have my carbon here. And now what's going to be bound to it? Carnitine. Carnitine will be bound to this. What is this molecule here called? This molecule here is called fatty acyl carnitine. But here's the next problem: having this fatty acyl carnitine, it can easily go back out through that translocase because this is a bidirectional translocase. So to prevent him from getting back out, guess what I have to do? I have to rip that carnitine off and then add another coenzyme A back onto it. Okay, so how do I do that? You see this guy right here, this enzyme; this enzyme is going to take a CoA, so let's say he takes this CoA here; he takes that CoA, coenzyme A, and he adds that coenzyme A onto this fatty acyl carnitine. So he adds this coenzyme A onto this fatty acyl carnitine, but at the same time, he rips off that carnitine. So look what he does: this enzyme is going to break this bond here and rip off that carnitine, and then he's going to add on this CoA, and look what we get as a result of this reaction. Let's do this in pink here because this is an important step here. As a result, what are we going to get then? Now the result is going to be again a fatty acyl group with a coenzyme A. So now let's draw that. So we're going to have our R group, CH2 CH2, carbon double bond oxygen, and then again it's going to be bound to a coenzyme A over here. Now let's put our A there.
Now, next thing, what happens to that carnitine that we ripped off the fatty acyl carnitine? It's going to get pushed back out. So this fatty acyl carnitine, guess what's going to happen? He can get pushed back out here and recycled. Now the question at hand is: what the heck are these molecules that are doing this process? This one right here; they has two names. This one right here on the outer membrane, because you know this is the mitochondrial matrix, so we call this the mitochondrial matrix, and then out here, this is the outer membrane of the mitochondria. Out here is the cytosol. On the cytosolic side of the mitochondria, you have this transporter. This transporter here is called carnitine acyltransferase type one. Okay, so again, what is this molecule here called? This molecule here is called carnitine acyltransferase type 1. You know, they also have another name for it, since we're dealing with 16-carbon fatty acids; they can call it carnitine palmitoyltransferase, specifically carnitine palmitoyltransferase type one. So you can see it as CAT I or CPT I, just in case you see it in the literature; it can be referenced as carnitine acyltransferase, um, type one or carnitine palmitoyltransferase type one, just in case you see it in different literatures, and that way, right. Okay. So what is he doing? He's adding carnitine onto the fatty acyl-CoA, getting rid of the CoA, and then this fatty acyl carnitine structure is getting transported through this translocase into the mitochondrial matrix. Once in the mitochondrial matrix, to prevent him from getting back out, he has to be acted on by this enzyme who rips the carnitine off and pushes that carnitine back out into the, the cytosol via this translocase, and then he, this enzyme or transporter, adds on a coenzyme A. What is this transporter called? This is called carnitine acyltransferase type two, or again, carnitine palmitoyltransferase type two.
Now that we've done that, what have we formed? We're not even close to done, and it's crazy. We formed this fatty acyl-CoA. So from this step, we formed a fatty acyl-CoA that now we're going to undergo this next step. So what was this first step that we just performed? The first step was getting the fatty acid into the cells. The next thing was activating it. So this step right here is called activation. So again, what is this step right here called? Let's denote this; this step right here, holy crap, this step right here is called activation. So you're activating the fatty acid by adding a coenzyme A and converting ATP into ADP and inorganic phosphate, and this reaction is catalyzed by fatty acyl-CoA synthetase. The second step is going to be the transport, so how we're actually getting this specific fatty acyl-CoA into the mitochondria so that we can undergo this next step. This next step, where we'll spend most of the time, is going to be called beta-oxidation. Okay.
So now we're going to take this fatty acyl-CoA through a series of reactions. The first thing that we're going to do, we need to denote the nomenclature of this molecule. So you see this carbon right here; this is our number one carbon, this is our number two carbon, but sometimes we refer to the number two carbon as the alpha carbon, and this is our number three carbon, but sometimes we refer to the third carbon as the beta carbon, and then you'll go on and on and on and on. Now, here's what's going to happen in the first step of this reaction. I'm going to remove a hydrogen from this guy and a hydrogen from this guy and an extra electron. What do you call that whenever you have a hydrogen, a proton plus two electrons? It's called a hydride. So I'm going to pull hydrides off of this molecule. Who's going to do that? FAD. So let's show this reaction here. So look what's going to happen here in this step right here. I'm going to have FAD come in. So FAD is going to come in and pick up a hydride from this guy and a hydride from this guy, and then that's going to turn into FADH2. What enzyme is catalyzing this step? This is a fatty acyl-CoA, so they call this acyl-CoA, and you know how you're having a specifically some type of coenzyme involved that are picking up hydrides; usually that's a dehydrogenase. So this is an acyl-CoA dehydrogenase. Okay. When this happens, you're going to rip that hydrogen off, that hydrogen off, and you're going to form a double bond to stabilize that molecule. So now what am I going to have here? I'm going to have a double bond between my alpha and my beta carbon. So let's show that. As a result, this is the first step, so this is step one. Then, as a result, I'm going to have a CH here, double bond here; let's make that double bond a different color so that we very, very are particular with distinguishing the difference here. So now let's go ahead and put this in this color here; this is our double bond there. Okay. Okay, then on the other side, I'm going to have a CH and then a carbon doubly bonded to an oxygen, who's still bound to a coenzyme A. Okay, that was the first step; not too bad.
In the second step, I'm going to do something weird; I'm going to take and I'm going to add water across that double bond, but in order for me to add water across that double bond, I'm going to need an enzyme who can help me do that. In other words, I'm going to need an enzyme who can hydrate this. So how do you do that? So let's do this next step. The next step of beta-oxidation, step two, is I'm going to hydrate this guy. How am I going to do that? I'm going to add water into this reaction. So I'm going to take water, and I'm going to add water into this reaction, but in order for me to do that, I need an enzyme who can facilitate that reaction. Just like acyl-CoA dehydrogenase stimulated this step, I need an enzyme who can stimulate this step. That enzyme is called enoyl-CoA hydratase. Now you're probably wondering where the heck did this enoyl-CoA come from? That's what this molecule here is called; this molecule is called enoyl-CoA. But we have, have to be even more specific; this hydrogen here really should be poking upwards; this hydrogen here should really be poking downwards. So now this double bond is having the hydrogens on opposite sides; that's trans. So technically, and this is on, between what? This is the first carbon, this is the second carbon, that's the third carbon. So we denote double bonds whenever we're doing nomenclature according to, like, IUPAC, that that's going to be where I put my double bond; I name it like that way. So they call this trans because the hydrogens on opposite side, delta 2 to signify that there a double bond between the second and the third carbon. So they call this molecule technically trans-delta2-enoyl-CoA. Then, once we have this trans-delta2-enoyl-CoA, what's going to happen? He's going to get acted on by this enoyl-CoA hydratase. This enoyl-CoA hydratase is going to add water across this double bond, and then you're going to have an O here and you'll have an H there; that's all that's going to happen because when you add water, you add an O to one side and an H to the other side. So now let's draw the resulting molecule. As a result, here I'm going to have R; let's actually bring this up a little bit; let's actually bring this reaction up a little bit here; let's bring this arrow this way, guys, and that's a little better. Okay, this is again the second step; now we're getting ready to enter into the third step. So now we're going to have the again R group, carbon, hydrogen, and then we're going to have that double bond; I'll put that double bond in just a second, carbon, hydrogen, and you're again, you have the carbonyl group, and again, what is bound to that carbonyl group? Coenzyme A with a thiol. What is going to happen in this step here? Okay. So since we added the water, now what should be the result? I should get rid of that double bond; that double bond should go away because I added water across it. When I add water across it, let's actually make this double bond like that now. Now let's put different colors on this; that water, I'm going to add an OH to this side, to the beta carbon, and I'm going to add a hydrogen to the alpha carbon. So again, what is this carbon right here? This is number one carbon, alpha, beta carbon. Because the hydroxy group is on the beta carbon of this fatty acyl-CoA, we call it beta carbon. So the beta carbon of the third carbon, beta-hydroxyacyl-CoA; that's all you call it. So it's not a hard molecule to name, right? So again, what do you call this molecule? Beta-hydroxyacyl-CoA molecule, and that is formed by this enoyl-CoA hydratase adding water across this double bond. Now we have another step; we're going into the third, third step; there's three, there's four steps total, and I'll give you a mnemonic that helps you to remember it very easily. Okay.
Then, in this third step of the reaction, I'm going to bring in an enzyme who's going to help to have NAD+ turn into NADH, and what that's going to do is, you see this O here and you see this H here; what this enzyme is going to do is it's going to do something very, very cool. This hydrogen right here, I'm going to circle this one; he's going to take that one and he's going to take, take this one, that NAD+. So the NAD+ is going to come over here; let's say here we have an NAD+; he's going to get converted into NADH, and he's going to pick up some hydrides. When he picks up those hydride ions, this carbon has no choice but to form a double bond between that oxygen right there because I'm going to lose that hydrogen and that hydrogen. As a result, what am I going to have then? As a result, let's, let's draw it here; this guy is going to have to have a double bond carbon to, I mean double bond oxygen; we'll show that in a second; this guy's still going to have his hydrogens; we're still going to have the carbonyl, and that carbonyl is still going to be bound to a coenzyme A with the thiol group, but what's the difference now? Now we're going to have a double bond between this oxygen here, double bond between that oxygen, and this hydrogen is left alone. What do you call this molecule? Okay, well, now there's a ketone because there's a carbon here, a carbon here, so that's a ketone on the beta carbon because again, this is one, alpha, beta. So if the ketone group is on the beta carbon and this is a fatty acyl group with a CoA, they would call this beta-ketoacyl-CoA. Okay, this molecule is called beta-ketoacyl-CoA, and the enzyme that's driving this step, a very cool enzyme; what did I tell you guys? If you ever see NAD going to NADH, you always know that there's a dehydrogenase present. So just say the name of this molecule and then put dehydrogenase after that; that's it. This enzyme is called beta-ketoacyl-CoA, specifically beta-ketoacyl-CoA dehydrogenase. Okay, so we have a beta-ketoacyl-CoA dehydrogenase who is stimulating this step and doing what? Converting this alcohol group, this beta-hydroxyacyl-CoA into a beta-ketoacyl-CoA. Now we go into the fourth and final step. Okay, what's going to happen here is I'm going to take something, a special enzyme; this enzyme is very, very special; this enzyme is called thiolase, and what this thiolase enzyme is doing is it's doing two things in this reaction. Okay, one carbon, alpha carbon, beta carbon, right? If I were to come over here for a second and I were to just expand on that R group for just a little bit, I could technically draw another CH2 and another CH2, and then I'll just put an R group here for a second. Now this is one, alpha, beta carbon. You know what I can technically call these afterwards, after what I'm going to do in this step here is I'm going to cleave this bond between the alpha and the beta; that's my, my goal in this step; I'm going to break this bond, the bond between the alpha and the beta carbon. When I break the bond between the alpha and the beta carbon, I'm going to release out what? Acetyl-CoA. But then the problem is I have this whole fatty acid group that is going to be, you know, what am I going to do with him? I'm going to add in a CoA. So what happens in this step here is thiolase is going to cut this bond right here between the alpha and the beta carbon, and at the same time, he's going to add a coenzyme A, but to who? To the beta carbon.
After this bond is broken, so now look what two products we get out of this. So I'm going to show one product going up and one product coming over here. So, as a result, I'm going to get two products. One product I'm going to show is going to be this side, okay.
So now, if I show this side of that broken bond, I'm going to have an R group, CH2, CH2, and then this is going to be a carbon with a double bond oxygen, because all I'm going to do is just draw a double bond oxygen there. And then what did I say? This thylas is adding that co-enzyme A onto the beta carbon after this bond is broken. So what am I going to see right here? Co-enzyme A with a th group. This is a new fatty acyl CoA. Where is this fatty acyl CoA gonna go, guys? Let me show you. This fatty acyl CoA is going to go back over here and get recycled, and it's just going to go through another round of beta oxidation.
Now, the question at hand is why do they call it beta oxidation? Because what I was doing is I was breaking the bond between the alpha and the beta carbon. I'm breaking that bond and I'm releasing out a fatty acyl CoA. So this is a regenerated fatty acyl CoA; it's just two carbons short. So this is a fatty acyl CoA, and all it is is just two carbons short, but it'll go and get broken down again, and it'll go from 16, now it's going to be 14. So this is a 14-carbon fatty; it'll go through it again and make 12, go through it again, make 10. You guys get the point? What's the other product of this reaction? Because I said there were two products. Okay, the other product. Now I'm going to show this side; what's going to happen is this carbon is going to pick up a hydrogen; it'll pick up a hydrogen, and you're going to get a CH3 group. So that's going to be this carbon; this is our alpha, and then right next to it, I'm going to have the carbonyl group, and what's bound to that carbonyl group? Co-enzyme A with a th component. What is this molecule here called? This molecule you guys have seen many, many times; this is called acetyl CoA. You might not have seen him like this in this form, but you've heard of him, and he is a two-carbon molecule. What can happen with this acetyl CoA? You guys already know what can happen; he can do what? He can go and enter into a specific cycle. What is that cycle, guys? The Krebs cycle. Out of the Krebs cycle, what can I generate from the Krebs cycle? So from this guy right here, this acetyl CoA, what can I do with him? I can bring him into the Krebs cycle; he can be reacted in the Krebs cycle, and then what happens? You produce what? NADHs, FADH2s, and a little bit of ATP. What can happen with these NADHs, these FADH2s? They can take it to the electron transport chain and lead to oxidative phosphorylation, to where the overall result is going to be what? ATP formation. Because remember what I told you guys, what was the original problem of why we were doing this whole beta oxidative process? The whole reason we were doing this beta oxidative process because our blood glucose levels in the blood were low. If our blood glucose levels are low, it means we're fasting; that means that we don't—we're either not taking in enough carbohydrates into our diet, maybe due to doing a ketogenic diet or like some type of Atkins diet, or maybe you're having uncontrolled diabetes mellitus, and you haven't taken your insulin, whatever it might be. Your body needs another fuel source. So your primary fuel source is carbohydrates, but when that is not available, your body reverts to the secondary fuel source, which is fats, and so it starts breaking down fats to make what? Acetyl CoA. I can't stress how important this whole process is because the whole overall result depends upon this right here—that the whole significant purpose of beta oxidation is is to produce two-carbon fragments at a time, which is going to be called acetyl CoA.
Now, the last question is: if we take a 16-carbon fatty acid, so let's say I take that 16-carbon fatty acid and I run it through beta oxidation—16-carbon fatty acid, and I run this 16-carbon fatty acid through beta oxidation—the question is how many acetyl CoAs will this produce? Well, I told you it chops it into two-carbon fragments at a time. If it chops it into two-carbon fragments at a time, how many acetyl CoAs am I going to produce? Then I can produce up to eight acetyl CoAs. Wow! And then with that, imagine how many NADHs and FADH2s we can produce. We're going to do that in another video where we calculate the total energy yield of how much a 16-carbon fatty acid—how much ATP can actually produce. It's insane.
Now, the next question is: this sometimes gets people—how many rounds of beta oxidation actually occurred? This is a tricky one. Some people will be like, "Oh, well, you make eight acetyl CoA; you start with 16; you do it eight times." No, it's seven rounds of beta oxidation. The reason why is think about it like this, guys. Let's come over here for a second. Let's say I draw this for a second. So one, two, three. So we got one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen. If I start right here and I cut each one of these pieces here, so this is—we're going to call this the number one carbon, and this is going to be this 16th carbon, all right, and I'm chopping them into two-carbon fragments. So this is one and two, so I'm going to chop here; then I'm going to go one, two, chop here; one, two, chop here; one, two, chop here. You guys get the point? I'm going to chop here. How many cuts did I make? I made one, two, three, four, five, six, seven cuts on this molecule, because when I cut this thing the seventh time—let me actually do this one in a different color—when I cut this thing the seventh time, what am I doing? I'm breaking this four-carbon fragment into two two-carbon fragments. So that's why sometimes certain professors will say, "How many rounds of beta oxidation did you do for an 18-carbon fatty acid?" Just put the number of acetyl CoAs minus one; that's how you figure it out. So if they ask you—they say they take a 26-carbon fatty acid, undergo beta oxidation, how many acetyl CoAs will it produce? You just figure out, okay, if it's 26, I'm going to divide that by two, so I get 13 acetyl CoAs minus one; that's going to give me 12 rounds of beta oxidation.
Okay, guys, in the next video, we're going to talk about the energy yield, and we're going to talk about certain other types of fatty acids, that being odd-chain fatty acids, and also there is another process of beta oxidation that can occur in peroxisomes. So in the next video, we're going to talk about odd-chain fatty acids being broken down; we're going to talk about the beta oxidation that can occur in peroxisomes, and the energy yield that can come from all of this oxidative process.