Hi Nisioners, in this video we're going to talk about fatty acid synthesis. Okay, so let's start it off. First off, why is this fatty acid synthesis occurring?
And it can occur in various different tissues. Now, we're going to talk about it preferentially in the liver, but it can happen in other tissues as well. So, let's start it off.
So, let's start it off. tissues just so you know but we're going to start this process off basically explaining that this is occurring whenever the blood glucose levels are high so again this is occurring whenever you're in what's called a A fed state, so a fed state, so you're eating, you're taking in food, you're in the absorptive state, you're eating the food, you're absorbing the food. It could be whenever your blood glucose levels are high, so you have high blood glucose levels. What happens is...
There's going to be a specific hormone that's going to be regulating this step and we'll talk about them very very much in this process but there also is other hormones that are negatively regulating this process. But the main hormone is trying to directly stimulate this process to try to be able to help to synthesize. fatty acids is primarily going to be that of insulin.
Okay, and it's because insulin is released whenever your blood glucose levels are high. Okay, so we know it's occurring when we're in the fed state, so we're eating food or we're having high blood glucose levels. glucose levels or there just could be a lot of other situations too. Maybe there's a situation in which there is actually high amounts of cellular ATP.
So high amounts of ATP being produced. Whenever there is so much ATP being produced, our body just doesn't want to continue to keep breaking down molecules. Instead, they want to store those molecules as something else that we can utilize later when we need it. So there could be a couple reasons.
We could be in the fed state, high blood glucose levels, or we could be producing excess. excessively too much, too much amounts of cellular ATP that our body says, okay, too much ATP, let's stop breaking down molecules, start building them up and storing them and we'll use them later when we need it. How does that occur?
Okay, so we have to start here with glucose. So say we bring the glucose in, obviously through some type of glut transporter. So let's say we bring the glucose in here through some type of transporter. And then you know that glucose actually gets converted into pyruvate, right? So it gets converted into pyruvate.
and then you remember that the pyruvate was doing what it was getting pushed into the mitochondria and it was actually being converted into acetyl CoA and then what was happening without acetyl CoA if you guys remember you remember that acetyl CoA was combining with a special molecule which was called oxaloacetate and if you remember oxaloacetate and acetyl CoA were fusing together right so they were reacting together to form what molecule they were forming a new molecule molecule called citrate. And if you remember, citrate is actually going to be a six carbon structure. Now, if you remember, citrate can then be acted on by another enzyme called a conitase, right?
And a conitase can do what? It can convert citrate into isocitrate. Okay.
And then if you remember after that, isocitrate can be converted into another molecule, which is called alpha keto glutarate. The whole point of this is, is that this can go throughout the Krebs cycle and it can actually produce ATP right eventually. They're making NADHs and FADH2s.
We're not going to do all the rest of these, but here you get the point. It can go through this process. What happens is though, as we start producing too much cellular ATP, right?
There was too much ATP. If there's too much ATP being produced, our body has a way of being able to regulate these processes. One of the things that happens is you remember this enzyme that converts isocitrate into alpha-ketoglutarate. When isocitrate is being converted into alpha-ketoglutarate it's through a special type of enzyme and that enzyme is called isocitrate dehydrogenase enzyme. If you guys remember ATP was actually responsible for allosterically inhibiting this enzyme.
If ATP is allosterically inhibiting this enzyme. Can you convert isocitrate into alpha-ketoglutarate? No.
So then what happens? Your isocitrate starts building up. And if you can remember, this citrate to isocitrate is reversible.
So that means that I... isocitrate can actually get converted back into citrate. What happens is, is we start actually developing significant amounts of citrate. Now, citrate is extremely interesting because what he can do is he can pass right through the mitochondrial membrane.
And when he passes through the mitochondria and comes out here, there's a special enzyme waiting for him. What is that? enzyme called. This enzyme is going to stimulate this step right here, the citrate.
He's going to break him down into two components. What are these two components that he'll break him down into? So two things will come out of this citrate reaction. He'll get broken down into one molecule will be specifically called oxaloacetate.
Just think about what he was eventually originally made of. Citrate is made up of acetyl-CoA and oxaloacetate. But you guys have to remember when acetyl-CoA and OAA combine, what is it? lose?
It loses a coenzyme A. This enzyme right here is going to take the citrate and what is it going to do? It's going to take the citrate and cut the citrate up and turn it back into oxaloacetate. You know oxaloacetate can be converted back into malate. You know there's a special enzyme right here I need to make this this reaction special because this malate is going to pyruvate.
When malate is going to pyruvate There's a very special enzyme involved in this process. This enzyme is called the malic. enzyme. Why is this important?
Because this step is one of the few steps in the body where we actually take NADP positive and convert him into NADPH. And this is super important for fatty acid synthesis. You also make this from another pathway in your body called the pentose phosphate pathway or the hexose monophosphate shunt. But we'll talk about that in another video. For right now, just realize that you can generate NADPH when you're converting malate into pyruvate via the malic enzyme which is stimulating this step here.
But then look, citrate is being converted into oxaloacetate and then he's also going to get broken down into acetyl CoA. But you know acetyl CoA, it has to have the CoA on it or it's just acetate. So what has to happen is this enzyme also has to add in a what? It has to add in a coenzyme A.
So this enzyme is doing two things. One thing is he's cutting the citrate and converting them into OAA, the other one is actually going to be adding a coenzyme A onto this molecule and convert this other molecule into what? Acetyl coenzyme A.
Okay, so acetyl CoA. Now, what is this enzyme? This enzyme is called citrate citrate.
So the citrate lyase is actually doing what? It's cutting up the citrate into oxaloacetate into acetyl-CoA. This acetyl-CoA is going to go through a special pathway. Okay, now what's going to happen to the acetyl-CoA? The acetyl-CoA...
is actually going to go through a special, special enzyme. We need to make this enzyme special because it's the most important part of all of this fatty acid synthesis. Okay, so let's make this enzyme here because he is extremely important in this pathway. We can't forget this one.
This enzyme is called acetyl. CoA carboxylase. Okay ACC and what does that stand for again? Acetyl-CoA carboxylase enzyme. So this acetyl-CoA carboxylase enzyme is going to be very special because he's very highly regulated within this step.
Okay, so now what is this acetyl-CoA carboxylase going to do? You know he has an important molecule in him that we need in order for this process to occur. You know what that molecule is that's actually combined onto him?
It's called biotin. So we need biotin. Okay, so he's a carboxylase.
So what this acetyl-CoA carboxylase enzyme is going to do is, this acetyl-CoA carboxylase is taking this acetyl-CoA, and look what's happening here. it's driving this reaction here. So this acetyl-CoA carboxylase contains biotin, which is really, really important because biotin is going to act as a specific type of coenzyme within this molecule. And what this acetyl-CoA carboxylase is going to do is it's going to add in another carbon and usually you do that within the form of CO2 or bicarbonate, right?
So it's going to add in a carbon onto this acetyl CoA. So acetyl CoA is normally two carbon molecule. But what I'm going to do is I'm going to take and add in another carbon in the form of carbon dioxide or maybe bicarb and what's going to happen as a result of this reaction? I'm going to get what's called malonyl malonyl CoA.
And to be consistent, let's let's put that CoA in orange. So to be consistent with it, let's put that CoA in orange. So now we did what? We took a two-carbon molecule. Acetyl-CoA converted into how many carbons now?
Malonyl-CoA is now a three carbon molecule. So now we have a three carbon molecule. And we did that by doing what?
We did a carboxylation reaction. We added CO2 into this reaction. Now I told you that this enzyme is very heavily regulated. Let's talk about the... there's two types of regulation like you guys know.
One type of regulation is going to be allosteric. The other type of regulation is going to be hormonal. So now the two types of allosterics. One is going to be citrate.
That's going to be an allosteric regulator. And specifically, he's going to stimulate. And we'll explain that in a second. The other allosteric regulator is actually going to be called long chain fatty acids with a coenzyme A on it. So any type of long chain fatty acids with a coenzyme A on it.
These can also control this, but specifically these guys are going to inhibit the acetyl-CoA carboxylase. And we'll explain how. And then there's going to be hormonal. So then you can think about hormonal, there's going to be insulin and insulin is going to want to stimulate this process.
And then you're going to have the opposite of insulin, which is going to be cortisol or glucagon. epinephrine, norepinephrine. They're going to try to oppose this process.
Now let's go ahead and explain this. Now what we have to do is we have to realize that acetyl-CoA carboxylase can exist in two forms, an active form and an inactive form. Okay so now acetyl-CoA carboxylase can exist in two forms. Look at this. So let's say you know originally he exists in dimers.
He's actually in inactive. He's in dimers. So let's say here's a dimer and here's a dimer.
Let's say I have a couple of these dimers. Obviously there's going to be tons of these to make up this whole enzyme. But in the dimer form, so these are the dimers, these are the dimer form of acetyl-CoA carboxylase.
So this is the dimeric form of ACC, acetyl-CoA carboxylase. And what did I tell you? In this form he is inactive, he's inactive in this form, these dimeric forms.
But then what I can do is when he is stimulated by certain types of processes like citrate or insulin so he said see stimulated if he is stimulated and again what were those things that stimulated it citrate okay let's go ahead and explain that really quick why would citrate be a stimulus okay come back over here what was the reason why we even did this process because we had too much citrate and if we're building up so much citrate okay we need to tell the citrate lies okay Okay, cut me open and give me OAA and acetyl-CoA so that I can start this process. I have too much of me. So start shuffling it in and shunting it into making fat.
So citrate is going to stimulate it. But then what did I tell you? These long chain fatty acetyl-CoAs. What are those the product of? Fatty acid oxidation, right?
Or they're beginning to go into fatty acid oxidation. If we have so much fatty acids that we're going to want to try to oxidize, wouldn't you want that to basically say, okay, inhibit this enzyme because now I want to start. breaking them down instead of building them up.
So in the contrast, what would inhibit this process? Long chain fatty acids with the CoA on them, but we'll come back to that in a second. Now citrate can stimulate this and we'll talk about how insulin does it in a second. But if citrate and insulin activate this enzyme, what it's going to do is it's going to cause these dimers to come together and fuse.
If you fuse these guys together, look what happens. I take all of these dimers. have here, it's six right, one, two, three, four, five, six.
All of these dimers are going to be together and whenever they're actually polymerized together this is the active form of acetyl-CoA carboxylase, right? This is the active form and this is the polymerized form. So this is the polymerized form.
of acetyl CoA carboxylase. So now we know exactly what's happening then. Citrate is allosterically stimulating this enzyme. So let's show that over here.
So look, if I come over here and I have citrate, citrate is stimulating this enzyme to drive this reaction. But in a condition in which I don't want to drive this reaction, I don't want to be able to convert my dimeric form into the inactive form. Let's say I want to do the opposite reaction. So if I wanted to do the opposite reaction, I wanted to go from the polymerized form into the dimeric form the inactive form what's going to be stimulating this we already said it would be long chain fatty acids with the Co a right which is a sign that there's that you want to do beta oxidation so if you want to do beta oxidation you don't want to build up fats you want to break them down so that'll stimulate this step going to the inactive form and already we told you that insulin and glucagon can also regulate these guys and we'll talk about that in just a second okay Now, this malonyl-CoA and this NADPH, they're very important.
And again, I told you that you can get this NADPH from the malic enzyme, but where's another place that I can get that NADPH? That's very important, and we'll talk about that in another video, but it's from the pentose phosphate pathway. Extremely important pathway.
It's responsible for generating a lot of different things that's important for our body, but it's making NADHs, NADPHs I'm sorry. So this is making tons of NADPHs through the oxidative phase. When you're making a lot of NADPHs here, and then what else are you making over here?
A lot of NADPHs here. These are important because these are going to be the reducing agents. So again, what are these molecules here for? These are your reducing agents.
You need these as the precursors to start up because you know Malonyl-CoA? Malonyl-CoA, and we'll see this in the next video, he is a precursor for fatty acids. He's going to what we're gonna build on for these fatty acids and you'll see exactly how in the next video. But NADPH is needed in order for this process to occur and you'll see why. Now let's come back to this thing that we were going to talk about with NADPH.
and glucagon. Okay, so let's say that I have insulin working on this receptor here. So let's say here I have insulin. So insulin comes over here and it binds on to this receptor.
When it binds onto this receptor, it leads to the activation of these molecules which are called phosphoprotein phosphatases. These phosphoprotein phosphatases are very, very, very important. Before we talk about what they do, let me explain what glucagon and epinephrine does because it's going to make more sense. Now, let's say over here, binding to this G-protein coupled receptor, I have glucagon. I have epinephrine.
I have norepinephrine. These guys are binding to this G protein coupled receptor and activating it. And the eventual end product of this reaction is protein kinase A. So now I'm gonna have protein kinase A and phosphoprotein phosphatases that I'm going to explain. But let's bring this over here so it's not too cluttered.
Okay. So let's say we draw again over here. I have the inactive form of ACC, acetyl-CoA carboxylase.
And again, what was that form? We're just going to write it down. It was the dimer form, right?
So it was in its dimeric form. So it was in the dimer form. And then you have the form of acetyl CoA carboxylase active form of acetyl CoA carboxylase and this is when it's in the polymer form when you've you know taken all those dimers and put them together so now If I want to take my dimer and put my dimer into the active form, what do I need to do?
I need to polymerize them. So that means I want them to be active. I want to synthesize fats. What did we say would stimulate that? One thing we said...
was citrate we said citrate would stimulate that the other thing is going to be insulin okay before I explain this we need to I'll show you something okay let's say we come down here and I want to go from my active form to the inactive form. And we already said that what's going to stimulate this process. We said it would be the long chain fatty acids with the coenzyme A on them.
This would stimulate this pathway. But we also said it could be glucagon. Okay, now that's where that protein kinase A comes from. That protein kinase A is going to phosphorylate this active form of the acetyl-CoA carboxylate.
So it's going to put phosphates on it. When he puts phosphates onto this guy, he puts them into the inactive form of acetylchoyocarboxylase. So again, whenever there is the protein kinase A, which is coming from who?
Coming from glucagon. Coming from... epinephrine or from norepinephrine this is stimulating the formation of protein kinase a which phosphorylates the active form of acetyl-CoA carboxylase and turns them into the inactive dimeric form so now imagine that this guy has phosphates on him and he's inactive If we want to activate him, then we have to bring in those other molecules. And those other molecules were called phosphoprotein phosphatases. So what were they called?
This marker sucks. We'll do phosphoprotein phosphatases. Phosphoprotein. Phospho. So you can imagine what these enzymes are going to be doing.
There's tons of phosphates on this dimeric form which is keeping it inactive. If I rip off what? If I pull off those phosphates, what will it do? It'll turn it back into the active form. Who is stimulating this process?
Phosphoprotein phosphatases. They're ripping off the phosphates off the dimeric form of it, the inactive form of it, and turning it back into the active form of it. okay so now we understand we should understand how this whole process is occurring so whenever you have acetyl-CoA carboxylase and it's being phosphorylated it's inactive if you have it specifically having the it's removed it's no longer in the inactive form it's in the active form in the active form it's going to want to make malonyl Co a in the inactive form it will not want to make malonyl Co a and malonyl Co a is important for fatty acid synthesis which we will discuss in the next video alright in this video we got the basic outline that we're gonna need for fatty acid synthesis I hope it all made sense I hope you guys enjoyed it in the next video we'll talk about how we're building those fatty acids up