in this lesson of dirty biochemistry in the dirty medicine series we're going to be talking about fatty acid oxidation this is also known commonly as beta oxidation as a general overview fatty acid oxidation aka beta oxidation is the process by which fatty acids are broken down into acetyl co a to form ketones and other metabolic fuel for various biochemical pathways beta oxidation actually forms the majority of energy that's available to the liver it forms ketone bodies in the liver which are available to brain and muscle the size of the fatty acid that you're breaking down determines where it is oxidized and you're going to see that on the next few slides because this is actually a very high yield discussion so the size of the fatty acid basically determines where it's broken down and where that beta oxidation occurs and the reason that this is high yield and the reason that test writers and exam writers go after this concept is because it's just some my new show that you have to memorize and unfortunately that's the theme when it comes to biochemistry on USMLE and comlex so the way that you should mentally triage this in your brain is to use a chart and and I love charts because it simplifies concepts so the three different fatty acid sizes that you should be familiar with mentally are short and medium chain fatty acids long chain fatty acids and very long chain fatty acids I kind of find it hilarious that they named long chain fatty acids and very long chain fatty acids those names because they're they're literally very long chain fatty acids is what they call the biggest group but anyway the short and medium chain fatty acids have two to 12 carbons the long chain fatty acids have between 14 and 20 carbons and the very long chain fatty acids have greater than 20 carbons so 21 or more so how do you remember this I know this I said this is high-yield it's definitely important to know you've got to have a way to remember which carbon number corresponds to which category because you're going to question on this so the way that I do this is I compare the number of carbons to your age in school and then I based on that age I say do you only have to study for a short or medium amount of time do you have to study for a long amount of time already have to study for a very long amount of time and this will make sense in just a second so this is the dirty medicine pneumonic so if we look at the first one short and medium chain fatty acids have between two and twelve carbons so I say that when you are between two and twelve years of age or in elementary school and anyone who's in elementary school really only needs to study for a short or medium amount of time and it's really not that difficult it's Elementary School you know how hard is it really what's six plus six you know so the way that I go through fatty acids again is to figure out which category they go into I do what age you are in school and how long you have to study so two to twelve you're in elementary school you only study for a short or medium amount of time and when you're 14 to 20 you're in high school / college and this is where you actually have to start studying for a long amount of time so you know think about undergraduate school when you were studying organic chemistry and biology 101 you you probably did have to study for a long amount of time to do well and get to medical school where you are now very long-chain is greater than 20 so when you're greater than 20 years old this is the time in your life where you're actually in medical school and when you're in medical school as you very well know you have to study for a very long amount of time so again this was the stupid mnemonic that I came up with because there's really no other way to memorize this it sort of sucks to have to memorize two to twelve short medium 14 to 20 long greater than 20 very long so I do this in terms of years and then how long you'd have to be studying at that time to do well in school so again that's my way of memorizing this but let's come back to the chart because the chart always simplifies everything now in addition to knowing the short medium and how many carbons there are long and how many carbons there are very long and how many carbons there are you need to know where beta-oxidation is occurring this is another very high yo topic so not only can they go after how many carbons there are in the chain but they can ask you where beta oxidation or a fatty acid oxidation or fatty acid breakdown will actually occur so in the short and medium chain fatty acids these will diffuse freely into the mitochondria and then in the mitochondria beta oxidation will occur there in the long-chain fatty acids you have to use what's called a carnitine transport to get into the mitochondria for beta oxidation to occur and this is the highest yield of the three and what we're gonna spend the bulk of this video talking about because that carnitine transport system is very complex and that is where the majority of your biochemistry questions will come from when they're testing you on beta oxidation and then just for completeness sake the very long-chain fatty acids the ones that have more than 20 carbons those actually have to be oxidized inside of a peroxisome because they're just way too big to do anywhere else so you really need the heavy duty peroxisomal process to oxidize those fatty acids now I told you that that long-chain group the 14 to 20 carbons is the highest yield of the three and that's where we're gonna spend the majority of today's video and we're gonna start by talking about what exactly is a carnitine transport system because before you can really get to beta oxidation itself there's this slew of biochemistry that comes first and that is referred to as carnitine transport so carnitine transport is really the precursor to beta oxidation and it's gonna be the precursor of what all of your questions will probably be if they're gonna ask you questions about beta oxidation because this in and of itself is its own little biochemistry pathway that precedes the ability to do beta oxidation of long-chain fatty acids so in our discussion of carnitine transport we have to start with a little background a little diagram here so the top of the slide is the cytoplasm between the two dotted lines is the mitochondrial membrane and then that bottom line and down is the mitochondria so you start with your fatty acid right in the previous lesson we talked about fatty acid synthesis and at this point you've got fatty acids in the body ready to be mobilized and converted into fuel so you've got your fatty acid and that fatty acid gets converted into a fatty acyl Co a by the enzyme fatty acyl Co a synthetase look at the name of the enzyme if you're tired of hearing me say this it's gonna happen much more throughout this course so get used to it fatty acyl Co a synthetase u r sin theta C or synthesizing fatty acyl Co a so the name of the enzyme always tells you what either your reactants are or what your products going to be now fatty acyl co a can go into the mitochondrial membrane and this is a high-yield point because fatty acids cannot so in order to get it into the mitochondria first you have to put it into the mitochondrial membrane so fatty acyl co a will diffuse into the mitochondrial membrane and it's here that the key conversion occurs in the carnitine transport system so fatty acyl co a gets converted to fatty acyl carnitine by carnitine acyltransferase 1 this enzyme is also known as cat cat1 so cat 1 is the same thing as carnitine acyltransferase 1 now in this step all you're doing is substituting the co a for the carnitine because once that carnitine is on the fatty acyl group it could proceed down the pathway so far just to quickly summarize where we are we started with fatty acids and the body wants to break them down to use them for energy and this is a long-chain fatty acid again we're talking about the carnitine transport system because for long-chain fatty acids they have to go through carnitine transport to get into the mitochondria so the fatty acid gets a co a slapped on it and it becomes fatty acyl Co a fatty acyl Co a enters the mitochondrial membrane and then substitutes that co a for a carnitine group by the enzyme carnitine acyl transferase one now the first really high yield point that i need to bring up is that this step is inhibited by Milanoo co a now remember from the video on fatty acid synthesis that Milanoo co a is one of the downstream products in that pathway so obviously if you have Milanoo co a floating around it means that you're doing fatty acid synthesis because it's formed in that pathway and ultimately will be converted into palmitate which is the end product of fatty acid synthesis so this is just a feedback mechanism because if you have Millan Alcoa and therefore you're making palmitate and therefore you're synthesizing fatty acids why in the hell would you want to break them down so if there's Milan Alcoa a present it will inhibit this step and prevent the oxidation aka the breakdown of fatty acids so I think that that makes perfect sense but enable you know in order for you to be able to recall that and make sense of that you need to have first watched the video on fatty acid synthesis so refer back to that video if you need more clarification but just to summarize once more because this is a very high yield point Milan Alcoa is formed in fatty acid synthesis so therefore milano co a will inhibit beta oxidation which is just the opposite where you break down the fatty acids so milano co a will specifically inhibit this step where cat one AKA carnitine acyltransferase one takes plates now after this step fatiah acyl carnitine will go into the mitochondria and once it's in the mitochondria it can be converted into fatty acyl co a and the carnitine group kind of just splits off and is present as a product now as you can see the whole goal of this carnitine transport system was to get the fatty acyl co a into the mitochondria but the only way to do that was to slap carnitine on it and put it through a carnitine transporter so that is the goal of the carnitine shuttle system or the carnitine transport system and the enzyme that converts fatty acyl carnitine to fatty acyl co a plus carnitine when you rip the carnitine off and put the co a back on is carnitine acyl transferase to AKA cat - so don't get confused there's cat one and cat - cat one is the enzyme in the mitochondrial membrane that puts the carnitine in place of the co a and then carnitine acyltransferase - or cat two is the enzyme in the mitochondria that puts the co a back on the fatty acyl in place of the carnitine so they're really having opposite effects very very high yield to understand that difference now everything you see on this slide is all referred to as part of the carnitine transport system sometimes called the carnitine shuttle this is technically not beta oxidation right fatty acid oxidation is what comes after this once you've gotten the fatty acyl koay into the mitochondria so everything you see here I'm gonna put in a little gray box and summarize it and kind of shrink it down a little bit this is what we've just talked about the fatty acid went into the membrane went through cat one came into the mitochondria went through cat two and now you've got a fatty acyl Co a which was transported through the carnitine shuttle and is now finally ready for the meat and potatoes of fatty acid oxidation so the first step of fatty acid oxidation is to take that fatty acyl Co a and convert it to a siedel Co a the enzyme that does this is fatty acyl Co 8 dehydrogenase again look at the name of the enzyme it's D hydrogenating fatty acyl Co a so you know by memorizing the name of the enzyme you also know the reactant it's fatty acyl co a and your product is acetyl co a now something that's very high yield to understand about this enzyme is that the name fatty acyl Co a dehydrogenase is how you'll see it written on exams but you may see it as either medium chain a so Co a dehydrogenase where long-chain acyl Co a dehydrogenase so basically depending on the number of carbons in the fatty acid the name of the enzyme changes because the enzyme medium chain bla bla bla breaks down medium chain fatty acyl Co a and the enzyme long chain acyl bla bla bla breaks down long chain fatty acyl Co a so the only thing that changes in the enzyme name is based on which reactant you have is it a medium chain is it a long chain etc etc now once you have acetyl co a it can be converted into two products one is ketone bodies that occurs in the liver and the other is it can actually go back into the TCA cycle because if you recall from the TCA cycle acetyl co a is what's formed from pyruvate and enters the TCA cycle so the whole goal of fatty-acid breakdown or beta-oxidation is to provide fuel for the body and when you get to acetyl co a you're at the end step and now the biochemistry has two choices one is it can do ketone body synthesis in the liver shown there in orange now that is its own pathway that we're gonna talk about in the next lesson but when you form ketone bodies it's a primary source of fuel when the body is in a period of starvation and the other option is to have that acetyl co simply go back and feed the TCA cycle to generate ATP for the electron transport chain and to generate the other factors that you need for the electron transport chain which we've already discussed in a prior video so this is a key step and I'm gonna summarize one more time because it's very important you understand the big picture we've gone through the carnitine shuttle to get fatty acyl Co a ready for beta oxidation beta oxidation takes place and converts fatty acyl coa into acetyl co a through fatty acyl Co a dehydrogenase which you may see written as medium or long chain fatty acyl Co a dehydrogenase depending on how long the fatty acyl is you form acetyl co a which has two options one if the body needs to form ketones in a period of starvation or to fuel the brain etc it'll go through ketone body synthesis which is a pathway that we'll discuss in the next lesson the other option if it wants to generate ATP for the body through the electron transport chain is to shunt the acetyl co a into the TCA cycle to generate all of the factors that you need such as your fa DS in your na DS etc to go into the electron transport chain and generate massive amounts of ATP refer to the electron transport chain lesson which was earlier in the dirty biochemistry series for more information about how that works that is the overview of the carnitine shuttle system + beta oxidation and it's not that many steps so you already know everything that you need to know about the actual pathway the other things that we need to talk about which are extremely high-yield are things like the rate-limiting enzyme what negatively impacts this pathway and a couple diseases that take place when certain enzymes are deficient or knocked out so first let's talk about the rate-limiting enzyme of fatty as oxidation or beta oxidation so cat one is the rate-limiting enzyme and I want to pause for a second I know that I told you that everything in the gray box is technically the carnitine transport system or the carnitine shuttle and not truly beta oxidation but if you put that together with the steps outside of the gray box people still refer to everything you see on this slide as beta oxidation and therefore the rate-limiting enzyme of beta oxidation is cat one so you absolutely need to memorize that how do you remember this well I've got a mnemonic for you now the enzyme name that's the rate limiting enzyme is cat one also known as carnitine acyltransferase one and there are two ways that I used to remember this one is that you can remember that carnitine acyl transferase one is the rate-limiting enzyme that is responsible for the carnage of fatty acids or the destruction of fatty acids fatty acid breakdown the carnage of fatty acids Karn in carnage carne in carnitine acyltransferase one the other way that you can remember this is to just memorize the enzyme and know that it's cat 1 and when I think of a cat I think of a cat that's eating a lot of fast fatty acids that are being broken down into nough because cats just for whatever reason love tuna so cat one cat cat fatty acids being broken down in tuna I know these are rather stupid but they're gonna give you free points on test day so don't don't hate on these mnemonics now the thing that is going to inhibit this pathway inhibit beta oxidation is Milanoo KO a and we already talked about exactly where that takes place and just to refresh your memory remember this slide Milana KO a inhibited cat one and inhibited the conversion of fatty acyl KO a to fatty acyl carnitine again just a really hammer home this extremely high yield point Millan Alcoa is formed in fatty acid synthesis so if you're doing fatty acid synthesis Milanoo co a is going to inhibit fatty acid breakdown it just makes perfect sense so please understand this because it's an extremely high yield point the next thing that we need to talk about which is probably the highest yield point that we'll talk about this entire video are the diseases that can manifest when you have certain problems with your end times and to have that discussion we're gonna use this slide but I want to clean this up so that you only focus on the diseases so I'm gonna erase all of the crap here and just leave our two enzymes cat one and cat two the first disease is what's known as systemic primary carnitine deficiency and this occurs when you can't get the fatty acyl Co a into the mitochondrial membrane so you have a problem with exactly where that brown X is shown in this disease what you're gonna have is obviously no transport into the mitochondrial membrane but the symptoms that you'll get are hypo ketotic hypoglycemia now look at the words hypo ketotic so few ketones hypoglycemia few glucose or low glucose so low ketones low glucose think about it if you can't get fatty acyl koay into the mitochondrial membrane then you can never do all of the steps after it so you never get to beta oxidation you never form acetyl co a and you never have the option to do ketone body synthesis so it's no surprise that the first thing you'll see are low ketones the other thing that you'll see is low glucose because if you can never mobilize energy stores then you can't break down fat to help provide more energy and to provide more glucose okay so I want you to memorize hypo ketotic hypoglycemia and the problem in systemic primary carnitine deficiency is that you can't transport your fatty acyl Co a in to the mitochondrial membrane the next disease that we're going to talk about is what's known as my o Pathak cat 2 deficiency and the name of the disease tells you exactly what the problem is the problem is that cat 2 is either deficient or knocked out in this disease what you'll see is myoglobin iriya hypotonic and weak muscles and an increase an increase of triglycerides in the muscle so you'll see things like rhabdomyolysis and all of the sequelae of having muscle breakdown because the triglycerides are accumulating in the muscle now look at what's happening here if cat 2 gets knocked out and you can't break down fatty acyl carnitine then you have an accumulation of these carnitine products or these carnitine bound fatty acyl x' in the must and because of that you're having an abnormal accumulation of triglyceride type products in the muscle so the muscle breaks down and anytime that muscle breaks down you get classic symptoms so you get myoglobin area so muscle breakdown products entering the urine that's very damaging to the kidney so you'll see an increased creatinine in your labs the urine will look dark so if someone urinates and they have myoglobin in it it'll look very dark and because muscle is breaking down you have an elevation in your CKD enzyme so if they give you lab printouts and they have a vignette about beta-oxidation with the deficiency of cat to look for the labs of an increased creatinine since the kidney is damaged because the myoglobin is passing through the kidney look for dark urine look for signs and symptoms of rhabdomyolysis so weak muscles painful muscles tender muscles hypotonic because there's too much abnormal triglyceride in the muscles so the muscles don't work correctly and look for an elevated CK because muscle breakdown raises the enzyme CK which you classically see in rhabdomyolysis so this is my o Pathak cat 2 deficiency the third disease that we need to talk about will do so on this slide and just to summarize what we've already talked about again everything that we've talked about on the previous slide is still shown here in the gray box so the brown knockout and the orange knockout but our third and final disease which is very very high yield is when you have a problem with fatty acyl Co a dehydrogenase so when you have a problem with the enzyme that converts the fatty acyl Co a into acetyl co a so if you knock that out you get what's called medium chain fatty acyl Co a dehydrogenase deficiency so specifically this is a deficiency where the enzyme that breaks down the medium chain fatty acyl z' doesn't work and in this what you'll see is non-ketotic hypoglycemia hepatic dysfunction leading to hyper MO anemia and then we'll talk about the treatment in just a second but let's look at what's happening here so in this case you can't get the fatty acyl is converted into acetyl co a so you can never make your ketone bodies you can't send a pseudo code back into the TCA cycle so what's gonna happen here is that you're gonna get non ketotic hypoglycemia so hypoglycemia because you can't mobilize your energy stores and nonketotic because you absolutely cannot form the ketone bodies this will lead to an abnormal accumulation of products in the liver and lead to hepatic dysfunction because the majority of ketone body synthesis occurs in the liver so if you knock this out then you're disrupting a normal physiologic process that's occurring in the liver so you'll get liver dysfunction also known as hepatic dysfunction which could in very rare cases progressed a hepatic failure and when you have hepatic dysfunction and hepatic failure you get hyper AB anemia so signs and symptoms of too much ammonia in the body so look for things like asterixis etc and the treatment here is going to be to avoid fasting so we'll talk about this more in the ketone body synthesis lesson which will be after this video but whenever you're in a period of starvation that is when ketone bodies are going to be formed but if you have this disease and you can't form ketone bodies then you can't put the body into a fasting state because in a fasting state the body relies on ketone synthesis to provide fuel to the body and to provide fuel to the brain so if you have this disease and there's absolutely no way of making ketones but you're in a period of starvation where you're relying on ketones then that's gonna be really really bad so the treatment here is to avoid fasting and constantly eat carbohydrates because if you eat carbohydrates you'll never be in a period where your body needs to form ketones instead so just to summarize the three diseases I put them in this chart again systemic primary carnitine deficiency problem that leads to hypo ketotic hypoglycemia Myo Pathak cat2 deficiency look for things like rhabdomyolysis and myoglobin urea dark urine elevated CK some kidney damage so increased creatinine etc etc and finally medium chain fatty acyl Co a dehydrogenase deficiency leading to nonketotic hypoglycemia and remember to avoid fasting because there's no way to make ketones so if you fast and can't make ketones you could really have significant problems especially when you can't feed the brain the ketones that it needs so that's the end of this lesson was everything that you needed to know about fatty acid breakdown also known as fatty acid oxidation also known as beta oxidation remember that fatty acid oxidation has two parts to it the first part is the carnitine shuttle or the carnitine transport system and the second part is the actual beta oxidation itself which is a very short part of the pathway but when you combine these two that is what together is referred to as fatty acid oxidation I hope that this was enjoyable for you and that you learned a lot we're going to continue our next discussion in the next lesson with ketone body synthesis