Dirty Med - Fatty Acid Synthesis

Welcome back to Dirty Medicine's Biochemistry series, also known as Dirty Biochemistry. In this video, we're going to be discussing fatty acid synthesis. Now, before we get into fatty acid synthesis in terms of the actual biochemical pathway that you need to know for medical school and all of your exams, we first should give an overview of what fatty acids are and how we differentiate different types of fatty acids. So when we talk about fatty acids, there are a few types that you'll probably see. come up not only in scientific textbooks and primary literature, but also in just the layperson's conversations. You've probably heard of things like saturated fats, unsaturated fats, and polyunsaturated fats. Now, there's a lot of confusion regarding what makes a fatty acid saturated versus unsaturated. And for the purposes of this discussion, it's really appropriate to just keep it simple. Saturated fatty acids have no double bonds. Unsaturated fatty acids do have double bonds. Now you can see clearly in this picture that these are carbon chains and there's no double bond between carbons. That is what makes something a saturated fatty acid. But in the unsaturated fatty acid you can clearly see, depicted for your convenience in the middle of this molecule, that there is a double bond between the carbon molecules. Now I would like to pause for a second and state that biochemically speaking when you look at a molecule it's very important to realize that the double bond that we're talking about must be between carbon molecules. There, of course, is going to be a double bond between a carbon molecule and an oxygen molecule all the way on the left side of these molecules. But that does not count. That double bond absolutely does not count because the only way that a fatty acid will qualify to be at least monounsaturated will be to have a double bond between carbon molecules. So once you make the distinction of whether or not it has double bonds, that's how you know is it saturated or is it unsaturated. Once you're in the unsaturated category, you can then further categorize fatty acids based on how many double bonds there are. So if there's only one double bond, as you see here in this example, that would be called a monounsaturated fatty acid. And if there were more than one double bond, you would have a polyunsaturated fatty acid. Poly meaning multiple and mono meaning So the prefix tells you exactly how many double bonds we're talking about between carbon molecules. Mono is just one and poly is two or more. Now the polyunsaturated fatty acids also have another distinction that we need to categorize. And these are referred to as essential fatty acids. Now just like in the previous lesson, if something is essential, it means the body cannot make it. Therefore, it has to be included in the diet. in order to get it into the body. So essential fatty acids are polyunsaturated fatty acids, which again, just to quickly summarize, means that they have two or more double bonds between carbon molecules. They are not synthesized by the body, hence the name essential fatty acids, because it's essential to get them in the diet since the body cannot make them. And they decrease the risk of cardiovascular disease. And this is probably why you've already heard this term before. In all of the different documentaries on Netflix and on HBO and on Hulu and in the news and on Oprah and Dr. Oz and any mainstream media outlet that you're familiar with, you've probably heard a lot of hype about unsaturated fats. And when people use that term, what they're referring to is polyunsaturated fatty acids. But of course, Joe Schmo down the street who's not in medicine is not going to refer to it as a polyunsaturated fatty acid. He's just going to call it the good fat, in quotes. So these decrease the risk of cardiovascular disease. And the other way that lay people refer to these and the way that medical professionals also refer to these are omega-6 and omega-3 fats. Now, there's a distinction between omega-6 fatty acids and omega-3 fatty acids. The omega-6 fatty acid is known as linoleic acid. There are a few omega-3 fatty acids and they include alpha-linolenic acid, also known as ALA, icosapenta. tenoic acid, also known as EPA, and docosehexanoic acid, also known as DHA. So there are three different types of omega-3s, but only one omega-6. And the truth is, is that really the ratio between the omega-3s to the omega-6s is what determines how much of a decrease there is in the cardiovascular disease risk modification. So it's not just, you can't just shove your mouth with omega-6s and omega-3s and expect that. to have your arteries not have plaques in them. It's really about the ratio between omega-3s and omega-6s. What you should remember for the purposes of medical school exams and board examinations, such as USMLE and COMLEX, is that ALA has to come first, and EPA and DHA both come. from ALA as a derivative. So you start with alpha-linolenic acid, and then you can derive from that EPA and DHA. So because again, these are all essential, none of this stuff is made by the body. So you have to ingest linoleic acid, alpha-linolenic acid, and then from the alpha-linolenic acid, the body can produce EPA and DHA, but you still need to ingest it in the diet first in the form of ALA. So the question is... is how do you remember these different molecules for the purposes of exams? How do you know which ones are omega-3s and how do you know which one is the omega-6? Well the omega-6 is easy to remember because it's only one, right? It's linoleic acid. It has the shortest name, it's the omega-6. But the three that you need to remember as omega-3s are ALA, EPA, and DHA. So the way that I always remember this is very stupid but very simple, is that these all have three letters and therefore these are your omega-3s. Now that all of that categorization is out of the way, and you have a basic working knowledge of double bonds between carbon molecules, and I apologize if I cause any of you to have post-traumatic stress disorder thinking about organic chemistry from undergraduate school. But now that you've got all of that up, let's talk about fatty acid synthesis. So this is the meat and potatoes of this lesson, right? This is the biochemical pathway in which fatty acids are synthesized. So just as an overview, fatty acid synthesis... is a process by which the saturated fatty acid palmitate is formed. Now, in order for fatty acid synthesis to take place, there has to be some signal from the body telling it to make fatty acids. And if you're thinking to yourself, why the hell would the body want to make fat when all I hear about in the news is that fat causes heart disease and plaque and everything like that, well, then your thinking is pretty rational. But the reason is that excess carbohydrates get converted to fatty acids, which are really a way for the body to store energy so that it can be broken down for future energy use. So if you think about it, if you're sitting down and you eat a massive meal with a ton of carbohydrates, you're going to exceed your body's ability in terms of what it needs for glucose. So let's say that you eat a soft pretzel, a hamburger, and a slice of pizza. That's a ton of carbohydrates, right? It's a ton of glucose. Now glycolysis can only work so hard to break that glucose down. But at some point, it's used up all of the glucose that it could possibly use. And it doesn't need any more glucose to make any more ATP because it's hit its maximum. That is when fatty acid synthesis starts because you can take that excess glucose and convert it into fat and store that fat in the body to later be broken down for future energy use. And if you think about this, imagine somebody who gets stranded on an island. They have no food and all of a sudden they get skinnier and skinnier over time. The reason that that happens is because they have fat stores that were built up over time converting glucose into fatty acids, and now in a period of starvation, or a period of low intake of different macronutrients, they're breaking down those pre-stored fats to be harnessed as energy. So that's the big sort of if you take a step back approach to fatty acid synthesis. Now let's go to our summary slide and go through what we've already talked about up to this point in the Dirty Biochemistry series. Glucose goes to pyruvate, shown there in red. going through glycolysis. Pyruvate can be converted to acetyl-CoA, shown there in blue, through pyruvate metabolism. Acetyl-CoA can enter the TCA cycle, shown in purple, and one of the products of the TCA cycle is citrate. Now, normally, everything that you see here in this dotted box is occurring in the mitochondria. And under normal circumstances, we could simply convert acetyl-CoA into fatty acids. But the problem is that acetyl-CoA is in the mitochondria because that's where it's occurring in the TCA cycle, but fatty acids actually get produced in the cytoplasm. And this is a problem because you can't shuttle acetyl-CoA out of the mitochondria into the cytoplasm. You simply cannot do it. It's one of the rules of the body. I'm not sure exactly what the evolutionary mechanism behind that is, but just memorize that you cannot shuttle acetyl-CoA out of the mitochondria. into the cytoplasm to be converted to fatty acids. So because of that, we need some way to go from glucose to fatty acids. Remember again that the big picture idea here is that there's excess glucose and we want to convert it to fatty acids to be stored for future energy utilization. So how do we go from glucose to fatty acids if acetyl-CoA is stuck in the mitochondria? Well, unlike acetyl-CoA, citrate can be shuttled out of the mitochondria. And it does that through something called the citrate shuttle. Pretty easy to memorize because it tells you exactly what's happening. Citrate is being shuttled out of the mitochondria into the cytoplasm. That is shown here in green. Citrate can then be converted back to acetyl-CoA, and once we've reformed acetyl-CoA, we can go through a series of reactions to convert that acetyl-CoA into the fatty acids, since now acetyl-CoA is in the cytoplasm. That whole reaction that I just described is what's going to take place in fatty acid synthesis with a few intermediary steps. Now, let's go through fatty acid synthesis step by step to help you understand how this pathway works. So again, we start with citrate which is stuck in the mitochondria. But citrate, unlike acetyl-CoA, can leave the mitochondria through the citrate shuttle. So citrate gets on a bus, leaves the mitochondria, and is now in the cytoplasm. At this point, the body wants to convert the citrate back into acetyl-CoA, and it does that through ATP citrate lyase. Again, remember this slide. We couldn't move acetyl-CoA out of the mitochondria into the cytoplasm. So we had to move citrate out first to convert it back into acetyl-CoA. Once we've reformed acetyl-CoA, we're in good shape. But the other thing that you need to know is that citrate, in addition to becoming acetyl-CoA, also gets split into oxaloacetate, which is going to keep feeding the TCA cycle. Remember, oxaloacetate is one of the inputs in the TCA cycle. And the fact that citrate can become both acetyl-CoA and oxaloacetate means that you have this cycle going in circles. where citrate can go to oxaloacetate to stimulate the TCA cycle, which means more citrate can jump out of the mitochondria to become acetyl-CoA for ultimate conversion into fatty acids. So it's a very important feedback mechanism. Now, acetyl-CoA will then be converted into something called melanocoy. And the enzyme that does this conversion is acetyl-CoA carboxylase. Once you have melanocoy, there's one final step where melanocoy is turned into palmitate. which is a 16 carbon fatty acid, and the enzyme that does this is fatty acid synthase. So pretty easy to remember because the enzyme is synthasing or synthesizing fatty acids. So this is the final step of fatty acid synthesis. Now let's pause for a second. Everything that you see on this slide is what is referred to as fatty acid synthesis minus of course the oxaloacetate and purple TCA cycle. Citrate through the citrate shuttle, citrate to acetyl-CoA. Acetyl-CoA to melanocoy and melanocoy to palmitate is fatty acid synthesis as you need to know it on USMLE and COMLEX. Now let's pause and talk about a couple high yield facts for this pathway that you should keep in mind. Like all the pathways that we have to learn in biochemistry, you absolutely need to memorize the rate limiting enzyme. In fatty acid synthesis, the rate limiting enzyme is acetyl-CoA carboxylase shown here in bold red letters. Again, The rate-limiting enzyme in fatty acid synthesis is acetyl-CoA carboxylase. And this catalyzes the conversion of acetyl-CoA to melanocoy. Again, guys, I'm a huge fan, as you know from watching my videos, of looking at the enzyme's name to tell you what step it is involved in. Acetyl-CoA is being carboxylased, which means the reactant has to be acetyl-CoA. So really all you need to memorize is the product melanocoy. Now how do you remember that the rate-limiting enzyme in fatty acid synthesis is acetyl-CoA carboxylase? Well the way that I remember this is I say fatty acid synthesis and ACC reminds me of acetyl-CoA carboxylase, fatty acid synthesis. And acid is ACC, A for acetyl, C for CoA, and the second C for carboxylase. Acetyl-CoA carboxylase is the rate-limiting enzyme of fatty acid synthesis. The next thing that you need to know beyond just the rate-limiting enzyme is a couple cofactors scattered throughout fatty acid synthesis. So I've shown them here in green. These are the really important ones. In the step that goes from acetyl-CoA to melanocoy, you need to put carbon dioxide in. And in the final step that goes from melanocoy to our 16-carbon chain fatty acid palmitate, you put NADPH into the equation and you end up getting out. NADP+. But it's important to memorize that NADPH goes in and carbon dioxide goes in at the two steps here shown in green. The last really important thing to keep in mind is what causes this fatty acid synthesis to take place in terms of what excites the pathway and what inhibits the pathway. in terms of what blocks it and prevents it from taking place. So shown here in green is what stimulates fatty acid synthesis and shown here in red is what inhibits fatty acid synthesis in the top left hand part of the slide. So insulin and citrate are going to positively affect this and glucagon and palmitoyl-CoA are going to negatively inhibit fatty acid synthesis. And if you think about it this should make perfect sense, right? Why does insulin stimulate fatty acid synthesis? So When there's a ton of glucose, we know that insulin is going to be released to cause that glucose to go through glycolysis. And at the beginning of this lecture, we talked about that excess glucose gets converted to fatty acids through fatty acid synthesis. So when insulin is present, the body is going to be aware that there's a lot of glucose load present in the body and therefore it's going to stimulate fatty acid synthesis to take whatever leftover glucose there is that glycolysis can't process and shuttle it. to palmitate or fatty acids. Now anything that insulin acts on, glucagon is also going to act on, but it's just going to do the opposite. So always remember that glucagon follows insulin, but it does the opposite effect. So if insulin is stimulating, glucagon is inhibiting. And if insulin is inhibiting, then glucagon is stimulating. So in this case, because insulin is stimulating fatty acid synthesis, then glucagon is inhibiting fatty acid synthesis. Citrate is also easy to remember because if you think about it, in the presence of citrate, what the hell are you going to do with it other than convert it into acetyl-CoA, melanocoy, and palmitate, right? So if you have citrate sitting there, then the body needs to do something with it. So it's going to convert it through these steps into fatty acids. So that's why citrate will positively influence fatty acid synthesis. Palmitoyl-CoA is a downstream product once you have palmitate. So if you have palmitate, aka palmitoyl-CoA, then there's really no need to go through fatty acid synthesis because you already have one of the downstream end products. So again, pretty easy to reason through, but just memorize that insulin and citrate will positively influence fatty acid synthesis, whereas glucagon and palmitoyl-CoA, which you should think about palmitoyl-CoA basically as palmitate, both that and glucagon are going to inhibit fatty acid synthesis. Here's the summary slide in terms of... the net equation. So eight acetyl-CoAs plus seven ATP molecules plus 14 NADPH molecules will go to palmitate plus seven ADP plus seven phosphate plus 14 NADP plus six waters plus eight CoAs. Now again big picture you're going from acetyl-CoA which is a two carbon molecule to one palmitate which is a 14 carbon molecule. And palmitate is your fatty acid that you're trying to produce when it's all said and done. So this is the final slide. This is a gigantic overview of everything we've talked about so far in dirty biochemistry as it relates to the important pathways. So again, glucose to pyruvate through glycolysis, pyruvate to acetyl-CoA through one of the pyruvate metabolism pathways, acetyl-CoA entering the purple TCA cycle, spitting out citrate as that wheel continues to spin. That all occurs in the mitochondria. Citrate leaving the mitochondria going into the cytoplasm through the citrate shuttle shown in green, then entering the first step of fatty acid synthesis being converted back into acetyl-CoA, and then acetyl-CoA going through two more steps being converted to palmitate your 16-carbon fatty acid end product. If you're with me right now, then you are in amazing shape for fatty acid synthesis and you just mastered another biochemical pathway.

come up not only in scientific textbooks and primary literature, but also in just the layperson's conversations. You've probably heard of things like saturated fats, unsaturated fats, and polyunsaturated fats. Now, there's a lot of confusion regarding what makes a fatty acid saturated versus unsaturated.

And for the purposes of this discussion, it's really appropriate to just keep it simple. Saturated fatty acids have no double bonds. Unsaturated fatty acids do have double bonds.

Now you can see clearly in this picture that these are carbon chains and there's no double bond between carbons. That is what makes something a saturated fatty acid. But in the unsaturated fatty acid you can clearly see, depicted for your convenience in the middle of this molecule, that there is a double bond between the carbon molecules.

Now I would like to pause for a second and state that biochemically speaking when you look at a molecule it's very important to realize that the double bond that we're talking about must be between carbon molecules. There, of course, is going to be a double bond between a carbon molecule and an oxygen molecule all the way on the left side of these molecules. But that does not count. That double bond absolutely does not count because the only way that a fatty acid will qualify to be at least monounsaturated will be to have a double bond between carbon molecules.

So once you make the distinction of whether or not it has double bonds, that's how you know is it saturated or is it unsaturated. Once you're in the unsaturated category, you can then further categorize fatty acids based on how many double bonds there are. So if there's only one double bond, as you see here in this example, that would be called a monounsaturated fatty acid. And if there were more than one double bond, you would have a polyunsaturated fatty acid. Poly meaning multiple and mono meaning So the prefix tells you exactly how many double bonds we're talking about between carbon molecules.

Mono is just one and poly is two or more. Now the polyunsaturated fatty acids also have another distinction that we need to categorize. And these are referred to as essential fatty acids. Now just like in the previous lesson, if something is essential, it means the body cannot make it. Therefore, it has to be included in the diet.

in order to get it into the body. So essential fatty acids are polyunsaturated fatty acids, which again, just to quickly summarize, means that they have two or more double bonds between carbon molecules. They are not synthesized by the body, hence the name essential fatty acids, because it's essential to get them in the diet since the body cannot make them.

And they decrease the risk of cardiovascular disease. And this is probably why you've already heard this term before. In all of the different documentaries on Netflix and on HBO and on Hulu and in the news and on Oprah and Dr. Oz and any mainstream media outlet that you're familiar with, you've probably heard a lot of hype about unsaturated fats.

And when people use that term, what they're referring to is polyunsaturated fatty acids. But of course, Joe Schmo down the street who's not in medicine is not going to refer to it as a polyunsaturated fatty acid. He's just going to call it the good fat, in quotes.

So these decrease the risk of cardiovascular disease. And the other way that lay people refer to these and the way that medical professionals also refer to these are omega-6 and omega-3 fats. Now, there's a distinction between omega-6 fatty acids and omega-3 fatty acids. The omega-6 fatty acid is known as linoleic acid. There are a few omega-3 fatty acids and they include alpha-linolenic acid, also known as ALA, icosapenta.

tenoic acid, also known as EPA, and docosehexanoic acid, also known as DHA. So there are three different types of omega-3s, but only one omega-6. And the truth is, is that really the ratio between the omega-3s to the omega-6s is what determines how much of a decrease there is in the cardiovascular disease risk modification.

So it's not just, you can't just shove your mouth with omega-6s and omega-3s and expect that. to have your arteries not have plaques in them. It's really about the ratio between omega-3s and omega-6s.

What you should remember for the purposes of medical school exams and board examinations, such as USMLE and COMLEX, is that ALA has to come first, and EPA and DHA both come. from ALA as a derivative. So you start with alpha-linolenic acid, and then you can derive from that EPA and DHA. So because again, these are all essential, none of this stuff is made by the body. So you have to ingest linoleic acid, alpha-linolenic acid, and then from the alpha-linolenic acid, the body can produce EPA and DHA, but you still need to ingest it in the diet first in the form of ALA.

So the question is... is how do you remember these different molecules for the purposes of exams? How do you know which ones are omega-3s and how do you know which one is the omega-6? Well the omega-6 is easy to remember because it's only one, right? It's linoleic acid.

It has the shortest name, it's the omega-6. But the three that you need to remember as omega-3s are ALA, EPA, and DHA. So the way that I always remember this is very stupid but very simple, is that these all have three letters and therefore these are your omega-3s.

Now that all of that categorization is out of the way, and you have a basic working knowledge of double bonds between carbon molecules, and I apologize if I cause any of you to have post-traumatic stress disorder thinking about organic chemistry from undergraduate school. But now that you've got all of that up, let's talk about fatty acid synthesis. So this is the meat and potatoes of this lesson, right? This is the biochemical pathway in which fatty acids are synthesized.

So just as an overview, fatty acid synthesis... is a process by which the saturated fatty acid palmitate is formed. Now, in order for fatty acid synthesis to take place, there has to be some signal from the body telling it to make fatty acids.

And if you're thinking to yourself, why the hell would the body want to make fat when all I hear about in the news is that fat causes heart disease and plaque and everything like that, well, then your thinking is pretty rational. But the reason is that excess carbohydrates get converted to fatty acids, which are really a way for the body to store energy so that it can be broken down for future energy use. So if you think about it, if you're sitting down and you eat a massive meal with a ton of carbohydrates, you're going to exceed your body's ability in terms of what it needs for glucose.

So let's say that you eat a soft pretzel, a hamburger, and a slice of pizza. That's a ton of carbohydrates, right? It's a ton of glucose.

Now glycolysis can only work so hard to break that glucose down. But at some point, it's used up all of the glucose that it could possibly use. And it doesn't need any more glucose to make any more ATP because it's hit its maximum. That is when fatty acid synthesis starts because you can take that excess glucose and convert it into fat and store that fat in the body to later be broken down for future energy use. And if you think about this, imagine somebody who gets stranded on an island.

They have no food and all of a sudden they get skinnier and skinnier over time. The reason that that happens is because they have fat stores that were built up over time converting glucose into fatty acids, and now in a period of starvation, or a period of low intake of different macronutrients, they're breaking down those pre-stored fats to be harnessed as energy. So that's the big sort of if you take a step back approach to fatty acid synthesis. Now let's go to our summary slide and go through what we've already talked about up to this point in the Dirty Biochemistry series.

Glucose goes to pyruvate, shown there in red. going through glycolysis. Pyruvate can be converted to acetyl-CoA, shown there in blue, through pyruvate metabolism.

Acetyl-CoA can enter the TCA cycle, shown in purple, and one of the products of the TCA cycle is citrate. Now, normally, everything that you see here in this dotted box is occurring in the mitochondria. And under normal circumstances, we could simply convert acetyl-CoA into fatty acids. But the problem is that acetyl-CoA is in the mitochondria because that's where it's occurring in the TCA cycle, but fatty acids actually get produced in the cytoplasm. And this is a problem because you can't shuttle acetyl-CoA out of the mitochondria into the cytoplasm.

You simply cannot do it. It's one of the rules of the body. I'm not sure exactly what the evolutionary mechanism behind that is, but just memorize that you cannot shuttle acetyl-CoA out of the mitochondria. into the cytoplasm to be converted to fatty acids.

So because of that, we need some way to go from glucose to fatty acids. Remember again that the big picture idea here is that there's excess glucose and we want to convert it to fatty acids to be stored for future energy utilization. So how do we go from glucose to fatty acids if acetyl-CoA is stuck in the mitochondria? Well, unlike acetyl-CoA, citrate can be shuttled out of the mitochondria. And it does that through something called the citrate shuttle.

Pretty easy to memorize because it tells you exactly what's happening. Citrate is being shuttled out of the mitochondria into the cytoplasm. That is shown here in green. Citrate can then be converted back to acetyl-CoA, and once we've reformed acetyl-CoA, we can go through a series of reactions to convert that acetyl-CoA into the fatty acids, since now acetyl-CoA is in the cytoplasm.

That whole reaction that I just described is what's going to take place in fatty acid synthesis with a few intermediary steps. Now, let's go through fatty acid synthesis step by step to help you understand how this pathway works. So again, we start with citrate which is stuck in the mitochondria.

But citrate, unlike acetyl-CoA, can leave the mitochondria through the citrate shuttle. So citrate gets on a bus, leaves the mitochondria, and is now in the cytoplasm. At this point, the body wants to convert the citrate back into acetyl-CoA, and it does that through ATP citrate lyase. Again, remember this slide.

We couldn't move acetyl-CoA out of the mitochondria into the cytoplasm. So we had to move citrate out first to convert it back into acetyl-CoA. Once we've reformed acetyl-CoA, we're in good shape.

But the other thing that you need to know is that citrate, in addition to becoming acetyl-CoA, also gets split into oxaloacetate, which is going to keep feeding the TCA cycle. Remember, oxaloacetate is one of the inputs in the TCA cycle. And the fact that citrate can become both acetyl-CoA and oxaloacetate means that you have this cycle going in circles.

where citrate can go to oxaloacetate to stimulate the TCA cycle, which means more citrate can jump out of the mitochondria to become acetyl-CoA for ultimate conversion into fatty acids. So it's a very important feedback mechanism. Now, acetyl-CoA will then be converted into something called melanocoy.

And the enzyme that does this conversion is acetyl-CoA carboxylase. Once you have melanocoy, there's one final step where melanocoy is turned into palmitate. which is a 16 carbon fatty acid, and the enzyme that does this is fatty acid synthase.

So pretty easy to remember because the enzyme is synthasing or synthesizing fatty acids. So this is the final step of fatty acid synthesis. Now let's pause for a second. Everything that you see on this slide is what is referred to as fatty acid synthesis minus of course the oxaloacetate and purple TCA cycle.

Citrate through the citrate shuttle, citrate to acetyl-CoA. Acetyl-CoA to melanocoy and melanocoy to palmitate is fatty acid synthesis as you need to know it on USMLE and COMLEX. Now let's pause and talk about a couple high yield facts for this pathway that you should keep in mind.

Like all the pathways that we have to learn in biochemistry, you absolutely need to memorize the rate limiting enzyme. In fatty acid synthesis, the rate limiting enzyme is acetyl-CoA carboxylase shown here in bold red letters. Again, The rate-limiting enzyme in fatty acid synthesis is acetyl-CoA carboxylase.

And this catalyzes the conversion of acetyl-CoA to melanocoy. Again, guys, I'm a huge fan, as you know from watching my videos, of looking at the enzyme's name to tell you what step it is involved in. Acetyl-CoA is being carboxylased, which means the reactant has to be acetyl-CoA. So really all you need to memorize is the product melanocoy.

Now how do you remember that the rate-limiting enzyme in fatty acid synthesis is acetyl-CoA carboxylase? Well the way that I remember this is I say fatty acid synthesis and ACC reminds me of acetyl-CoA carboxylase, fatty acid synthesis. And acid is ACC, A for acetyl, C for CoA, and the second C for carboxylase. Acetyl-CoA carboxylase is the rate-limiting enzyme of fatty acid synthesis. The next thing that you need to know beyond just the rate-limiting enzyme is a couple cofactors scattered throughout fatty acid synthesis.

So I've shown them here in green. These are the really important ones. In the step that goes from acetyl-CoA to melanocoy, you need to put carbon dioxide in.

And in the final step that goes from melanocoy to our 16-carbon chain fatty acid palmitate, you put NADPH into the equation and you end up getting out. NADP+. But it's important to memorize that NADPH goes in and carbon dioxide goes in at the two steps here shown in green. The last really important thing to keep in mind is what causes this fatty acid synthesis to take place in terms of what excites the pathway and what inhibits the pathway. in terms of what blocks it and prevents it from taking place.

So shown here in green is what stimulates fatty acid synthesis and shown here in red is what inhibits fatty acid synthesis in the top left hand part of the slide. So insulin and citrate are going to positively affect this and glucagon and palmitoyl-CoA are going to negatively inhibit fatty acid synthesis. And if you think about it this should make perfect sense, right? Why does insulin stimulate fatty acid synthesis?

So When there's a ton of glucose, we know that insulin is going to be released to cause that glucose to go through glycolysis. And at the beginning of this lecture, we talked about that excess glucose gets converted to fatty acids through fatty acid synthesis. So when insulin is present, the body is going to be aware that there's a lot of glucose load present in the body and therefore it's going to stimulate fatty acid synthesis to take whatever leftover glucose there is that glycolysis can't process and shuttle it.

to palmitate or fatty acids. Now anything that insulin acts on, glucagon is also going to act on, but it's just going to do the opposite. So always remember that glucagon follows insulin, but it does the opposite effect.

So if insulin is stimulating, glucagon is inhibiting. And if insulin is inhibiting, then glucagon is stimulating. So in this case, because insulin is stimulating fatty acid synthesis, then glucagon is inhibiting fatty acid synthesis.

Citrate is also easy to remember because if you think about it, in the presence of citrate, what the hell are you going to do with it other than convert it into acetyl-CoA, melanocoy, and palmitate, right? So if you have citrate sitting there, then the body needs to do something with it. So it's going to convert it through these steps into fatty acids. So that's why citrate will positively influence fatty acid synthesis.

Palmitoyl-CoA is a downstream product once you have palmitate. So if you have palmitate, aka palmitoyl-CoA, then there's really no need to go through fatty acid synthesis because you already have one of the downstream end products. So again, pretty easy to reason through, but just memorize that insulin and citrate will positively influence fatty acid synthesis, whereas glucagon and palmitoyl-CoA, which you should think about palmitoyl-CoA basically as palmitate, both that and glucagon are going to inhibit fatty acid synthesis. Here's the summary slide in terms of... the net equation.

So eight acetyl-CoAs plus seven ATP molecules plus 14 NADPH molecules will go to palmitate plus seven ADP plus seven phosphate plus 14 NADP plus six waters plus eight CoAs. Now again big picture you're going from acetyl-CoA which is a two carbon molecule to one palmitate which is a 14 carbon molecule. And palmitate is your fatty acid that you're trying to produce when it's all said and done.

So this is the final slide. This is a gigantic overview of everything we've talked about so far in dirty biochemistry as it relates to the important pathways. So again, glucose to pyruvate through glycolysis, pyruvate to acetyl-CoA through one of the pyruvate metabolism pathways, acetyl-CoA entering the purple TCA cycle, spitting out citrate as that wheel continues to spin.

That all occurs in the mitochondria. Citrate leaving the mitochondria going into the cytoplasm through the citrate shuttle shown in green, then entering the first step of fatty acid synthesis being converted back into acetyl-CoA, and then acetyl-CoA going through two more steps being converted to palmitate your 16-carbon fatty acid end product. If you're with me right now, then you are in amazing shape for fatty acid synthesis and you just mastered another biochemical pathway.

Transcript for:Dirty Med - Fatty Acid Synthesis

Transcript for:
Dirty Med - Fatty Acid Synthesis