Fatty Acid Oxidation - Part I

- [Instructor] What I've drawn out here are three compartments found inside of a cell. And what I want to go ahead and do now is kind of label what I've drawn out here because these three compartments are going to be very important when discussing the three kind of major phases involved in oxidizing and extracting ATP from fatty acids inside of the cell. So starting up here, this compartment I'm going to label as the cell's cytoplasm. And these two lines down here are both representing the two membranes around the mitochondria. If you remember the mitochondria has two membranes. It has the outer mitochondrial membrane facing the cytoplasm, and then below it, it has the inner mitochondrial membrane. And I'm abbreviating these as OMM and IMM. And so, of course, the space between these is the inter-membrane space. Now if you remember this is where the proton gradient was built up for the electron transport chain. And then finally, down here, this is going to be the inside of the mitochondria, which is something that we also commonly refer to as the mitochondrial matrix. Now you might recall that fatty acid synthesis takes place inside of the cytoplasm, where the enzymes required for that process are located. Now in the other hand it turns out that the enzymes required for the oxidation of fatty acids, to obtain all of that ATP from that molecule, are located inside of the mitochondria. But remember that cells take up fatty acids into their cytoplasm from the bloodstream. So we need some way to be able to transport these fatty acids from the cytoplasm into the mitochondrial matrix. And this might look familiar to you. It might kind of ring a bell from fatty acid synthesis because, remember in fatty acid synthesis, we were also having to transport something across the cytoplasm. Of course you were going the opposite direction in fatty acid synthesis, where we wanted to transport Acetyl CoA into the cytoplasm. But I actually want to come back at the end of the video to touch on kind of the seemingly rounded out way to have to transport things across this mitochondrial membrane because it turns out it has a very interesting implication for how our body is able to regulate fatty acid synthesis and oxidation. And so I'll come back again and touch on that. But just going back to this transport process, it turns out that in order to be able to transport these fatty acids across this mitochondrial membrane, there's a specific pathway that requires us to actually activate, so to say, a fatty acid molecule with another molecule in order for this transport machinery to work. And so all together, there are kind of three major phases involved in being able to ultimately extract ATP from a fatty acid. So let's go ahead and cover these three phases in turn. Alright, so starting ofF with the activation step, let me go ahead and draw out the chemical structure of a fatty acid, starting off with its carboxylate head group, and of course it also long chain of carbons and hydrogens that comprise its fatty acid tail, which we usually refer to it as. But instead of drawing this tail out every single time or drawing or writing out all the carbons or hydrogens, I'm just going to abbreviate that using the letter R to keep things in our diagram simple. Now as I mentioned before, the goal here is to activate this molecule, quote unquote, with another molecule so that we're able to transport it into the mitochondria. So how does the body do that? Well the body does that by reacting this fatty acid with one of the most versatile metabolites in our body, which is coenzyme A. Because the structure of this molecule is quite large, we end up just abbreviating it as CoA, and usually at most textbooks will highlight this one functional group, this sulfur hydrogen group, this thial group because it's involved in forming a bond with this carbon here. So let's kind of see what that looks like, what the product of this reaction is. So we end up preserving this acyl group, and the acyl group just refers to this kind of part of the molecule here. We end up forming a bond with the coenzyme A through this sulfur atom as such. And the name of this molecule is acyl-CoA. And I remember when I was first learning about this, I confused this often with acetyl-CoA, which, remember just has a methyl group instead of this long fatty acid chain. So just keep those two things in mind, making sure not to confuse this acyl-CoA with acetyl-CoA. Now as a quick disclaimer, I want to apologize in advance for any stoichiometry calculations that don't seem to be right. Perhaps like this oxygen atom here. Where is this oxygen atom going? And that's due in part because I'm abbreviating some things in these molecules and so the oxygen atoms might be hidden somewhere. But mostly it's due to the fact that I'm not going over the entire mechanistic pathway by which this reaction occurs. It ends up that there are a couple steps involved in this reaction. And so I encourage you, if there's something that doesn't make sense, in terms of the stoichiometry, to just do a quick google search and the entire mechanism will be illuminated. But I'm just trying to give you the big picture and keep our diagram a little bit neater here by just kind of giving you the big picture here. And so going back to this particular reaction, it turns out that like any reaction where we have to activate something, with a higher energy functional group perhaps, so to say, we need some input of chemical energy. And indeed this reaction is coupled to the hydrolysis of ATP. And in fact, ATP, we normally think of about it as ATP going to ADP in a free phosphate group, but in this case, we actually go all the way to a monophosphate group and produce what we call a pyrophosphate group, which is just two phosphate groups stacked together. And what really makes this reaction thermodynamically favorable just kind of as a fun fact here, is that it turns out that when this reacts with the water, it splits up into two individual phosphate groups. And this hydrolysis reaction right here ends up being having very negative delta G value. And so that's kind of what drives this overall reaction forward. So just to summarize here, we've successfully transformed our fatty acid into an acyl-CoA group, which is what we refer to as an activated fatty acid for the transport process that we'll talk about next. But before we do that, I do want to mention that the enzyme that catalyzes the reaction is actually located on this outer mitochondrial membrane here and it's called acyl synthetase. So I kind of just think that we're synthesizing essentially another acyl group, an acyl-CoA, acyl synthetase. That's kind of how I try and remember it by. Alright. So what happens to our acyl-CoA molecule next? Well it turns out that there is another molecule inside of the cell by the name of carnitine, and at this usually has a kind of bolty chemical structure to draw out. So I won't draw it out completely but what I will draw out is the fact that it has hydroxyl group here. And I'm drawing this hydroxyl group, this oxygen bound to hydrogen because if I put on my organic chemistry hat for a moment, I remind myself that this oxygen can serve as a nucelophile, and form a bond with the carbon on this acyl-CoA molecule like such. And the coenzyme A group that we added can serve as a leaving group, and the sulfur essentially can take back its electrons. And so ultimately, what we've done is we've to this carnitine molecule, which I'll abbreviate here, as just C now, for simplicity, we've attached via this oxygen right here, our fatty acid. And so we have a structure that looks something like this. Now just as a quick aside, one way that I kind of remember the name of this molecule and its function in fatty acid, oxidation is that I kind of think about it as being carnivorous. Carnitine being carnivorous for the fatty acid, so it kind of essentially takes a bite into this acyl-CoA through its oxygen group and is able to attach it to itself like this. So just a quick aside in case that helps you remember anything. But going back to this particular reaction, this reaction also has an enzyme that carries this out, and it's called carnitine acyl transferase. And it's located on, again, the outer mitochondrial membrane. And so I'll go ahead and write that out. So carnitine acyl transferase. So pretty logical name, right? It's transferring the acyl group onto the carnitine molecule. And it's actually denoted as carnitine acyl transferase one because you will meet another one of these enzymes on the inside of the mitochondrial matrix in just a bit. So keep that at the back of your mind.