in this dirty biochemistry lesson we're going to continue our discussion and talk about ketone body synthesis ketone body synthesis as an overview is a process by which ketone bodies are formed from fatty acids in the liver to provide fuel to the body when glucose is otherwise unavailable it typically occurs when glycogenolysis and gluconeogenesis substrates are both exhausted and as you'll see later in this video that typically occurs in periods of starvation ketone body synthesis may also occur if the TCA cycle or the Krebs cycle is unable to function and as you'll see later on in this video again and this sort of goes with bullet point number two this occurs in states such as diabetic ketoacidosis also known as DKA and in chronic alcoholism now this is everything that you have already seen in the previous lesson on fatty acid oxidation and just to review we need to quickly summarize what we've talked about because that segues beautifully into ketone body synthesis so everything that you see here in blue is fatty acid oxidation again the fatty acids come all the way down get converted to fatty acyl Co a are then converted to acetyl co a and once you're at acetyl co a you have the option of either directing that toward the TCA cycle for further production of metabolic intermediates and ultimately ATP in the electron transport chain or by directing it to form ketone bodies through ketone synthesis so shown here in red is what this video is going to be talking about today it's how we start with acetyl co a and ultimately produce ketone bodies now let's get right into the biochemistry of ketone synthesis so obviously as I just told you we're gonna start with acetyl co a and specifically we're going to start with two acetyl COAS so the two reactants that start ketone body synthesis are two acetyl co ace and those acetyl co ace will combine to form acetyl acetyl co a so pretty easy right you're literally combining two acetals and you leave the co a the enzyme that catalyzes this conversion is called thiolase the next step converts a seat Lucido a into hmg-coa the enzyme that catalyzes this conversion is an extremely important enzyme known as hmg-coa synthase so look at the name of the enzyme it's CIN facing or synthesizing h mg co a hmg-coa is written out and known as three hydroxy three methyl glute RL co a for the purposes of USMLE and comlex you should be able to recognize that name but you absolutely don't need to memorize it so hmg-coa is what is formed by h mg Co a synthase now it's important to note that in this step you have to put in another acetyl co a so look how interesting this is guys you started with two acetyl co a s and you formed acetyl acetyl co a and then in the second step you took an already combined basically double acetyl co a and you added a third and once you did that you formed h mg co a now the next step is going to convert hm g co a into acetyl acetate and the enzyme that catalyzes this conversion is h mg co a lie ace and in this step you actually have one of the products being acetyl co a so what's very important to notice if we pause for a second and take a step back is that the acetyl co a is basically being recycled between steps 2 & 3 and this is very important in terms of feedback and driving ketone body synthesis now what's very important to know is that acetyl acetate is the first ketone that we've produced in this pathway but it's not going to be the last one of the extremely high yield points to keep in mind when you look and learn about ketone body synthesis is that you form ketones in a stepwise fashion sort of like in the catecholamine lecture when you formed one catecholamine before you could form the next which were actually derived from the first catecholamine the same exact thing is happening here in quito and body synthesis so future ketones can be derived from acetoacetate but acetyl acetate is the first one produced so here's where we are thus far and this is a crucial step in ketone synthesis because once you form that first ketone acetoacetate you have two options the first is that you can form another ketone called tone and the enzyme that catalyzes that conversion from acetyl acetate into acetone is acetoacetate decarboxylase so it's decarboxylation acetyl acetate so that helps you remember that the reactant is acetyl acetate and when you form acetone you'll also form carbon dioxide shown here in pink the other option for acetyl acetate if it goes to the right in this diagram is to form another ketone known as beta hydroxy butyrate at the enzyme that catalyzes this conversion is beta hydroxy butyrate dehydrogenase so here's where we are at this point everything you see here in green our ketones Osito acid is formed first and derived from acetic acid are two other ketones known as acetone and beta hydroxy butyrate now we'll get into a further discussion later in this video in terms of what the significance is of these different ketones and where they can be found in the body and what kind of symptoms they manifest but it's extremely high yield to know once again that acetoacetate is the first ketone from which acetone and beta hydroxy butyrate ketones are derived so this is ketone body synthesis this is the only pathway that you need to know the enzymes are shown in red the special products reactants what-have-you are shown in blue and pink and then along the way you see in black letters the reactants and the products of the basic pathway so the next thing that we need to talk about which is an extremely extremely important in high-yield discussion is when is ketone synthesis used right under what conditions will the body want to form ketones the first one is starvation and the pathophysiology here is gluconeogenesis induced depletion of oxaloacetate and I'm going to show you a diagram that will explain this simplify everything and help you memorize this really high yield concept so in starvation you have gluconeogenesis induced depletion of oxaloacetate now to remind you this is what gluconeogenesis looks like if it's very very simplified you start with pyruvate you convert the pyruvate to oxaloacetate and then you go back up all the way back to glucose so this is basically the opposite of glycolysis see the calluses versus new gluconeogenesis lecture if you need more information but this is what gluconeogenesis is again it's forming glucose from pyruvate and the first step is converting pyruvate into oxaloacetate so what happens in this state of starvation well when you're starving the body wants glucose so what it's going to do is it's gonna convert pyruvate to oxaloacetate and go all the way back up to glucose now in gluconeogenesis when it's occurring over repeated repeated amounts of time the oxaloacetate will be greatly reduced because think about it you're converting pyruvate to oxaloacetate and then up that oxaloacetate is going up to glucose so over time and prolonged periods of starvation you deplete all of your oxaloacetate now what happens next well shown here on the right is the TCA cycle and remember that the first step in the TCA cycle is to combine acetyl co a with oxaloacetate but what happens if you've been going through gluconeogenesis repeatedly over the course of hours or days due to starvation you're not gonna have any oxaloacetate so because oxaloacetate is depleted the TCA cycle can not work it absolutely cannot work now if the TCA cycle cannot work and you can't produce energy from the TCA cycle then the body needs another fuel source and that is where ketones will be formed because ketones can act as fuel when other fuel sources cannot so again just to quickly summarize what starvation really means for ketones in prolonged periods of starvation you deplete all of your oxaloacetate because you're going through gluconeogenesis repeatedly once the oxaloacetate is gone there's no action at the TCA cycle once there's no action at the TCA cycle you obviously cannot form the intermediates that are required for the electron transport chain and the body is going to need some other type of fuel besides glucose that doesn't really cost a lot of ATP it can't get ATP from the electron transport chain because the TCA cycle doesn't work and it can no longer get more glucose because we've exhausted all of our oxaloacetate which not only prevents us from getting more glucose from gluconeogenesis but it prevents the TCA cycle from working as well so this is a very complex interplay between the TCA cycle and gluconeogenesis as I'm sure you can now appreciate high yield bottom line is that in states of starvation oxaloacetate gets depleted due to repeated attempts to go through gluconeogenesis which means not only can you not form glucose for fuel but you can't go through the TCA cycle and ultimately the electron transport chain to get more ATP that is what starvation is now in a similar state known as diabetic ketoacidosis pretty much the same exact pathophysiology is taking place and I'm going to prove it to you here so I'm just switching the title from starvation to diabetic ketoacidosis and in a nutshell diabetic ketoacidosis is a period of starvation for type 1 diabetics so let's talk about what happens in DKA and prove to you that the same exact pathophysiology takes place so diabetic ketoacidosis aka DKA is still gluconeogenesis induced depletion of oxaloacetate so let's consider for a moment what happens in DKA so a type 1 diabetic has a blood sugar of 604 you know let's say five or six hours so very high blood glucose known as hyperglycemia what happens in states of hyperglycemia in a type 1 diabetic well the reason that they're hyperglycemic is because they don't have insulin so insulin levels are down in a normal person your body would compensate and produce insulin but in a type 1 diabetic the beta cells of the pancreas cannot secrete insulin and therefore insulin levels are low now you should know by now after our thorough discussion in this biochemistry series that whatever insulin does glucagon does the opposite so if insulin levels are low then glucagon levels are high now consider for a second what happens to glycolysis and gluconeogenesis under these conditions of low insulin and high glucagon because insulin is down glycolysis is not taking place and because glucagon is elevated gluconeogenesis is taking place so over time due to profound hyperglycemia in DKA low levels of insulin will inhibit glycolysis and elevated glucagon levels will promote gluconeogenesis so if we take this set of conditions and sort of slide it to the bottom of the slide let's look at what happens in gluconeogenesis and the TCA cycle and it shouldn't surprise you that this is going to be identical two periods of starvation so again elevated glucagon will drive gluconeogenesis so pyruvate will be converted to oxaloacetate oxaloacetate will go all the way up to glucose and over time the levels of oxaloacetate will be very much depleted because oxaloacetate is shot there is no action at the TCA cycle because you cannot combine oxaloacetate with acetyl co a therefore you cannot spin through the TCA cycle therefore you cannot make the intermediates which will ultimately go to the electron transport chain to ultimately form massive amounts of ATP so to summarize DKA is the same gluconeogenesis induced depletion of oxaloacetate the reason here being there are decreased levels of insulin and increased levels of glucagon so DKA and starvation are functionally identical when it comes to the reasons that they form ketones so when is ketone synthesis used remember that was the question that we were considering before we had this discussion and again I'm going to use a chart to summarize everything that we've talked about so far so first condition is prolonged starvation and the pathophysiology is gluconeogenesis induced depletion of oxaloacetate and because oxaloacetate is gone you cannot form glucose you can't run the TCA cycle and you can't make ATP so the body says gimme dem ketones it needs some fuel source to keep the brain active the second and functionally identical situation is diabetic ketoacidosis again it's gluconeogenesis induced depletion of oxaloacetate in this case insulin down glucagon up drives gluconeogenesis depletes oxaloacetate can no longer make glucose can no longer run the TCA cycle body says gimme dem ketones so memorize that it's extremely high yield and now we're going to talk about the third and final situation which is extremely high yield when ketones are synthesized now this third and final state is alcoholism and the pathophysiology here is alcohol induced NADH to NAD+ ratio so in other words you're increasing the ratio of NADH to NAD+ and I'm going to explain exactly why that is a problem and why the body needs ketones to compensate now it's extremely important to understand how alcohol or how ethanol is metabolized and there's a separate video in the dirty biochemistry series about alcohol metabolism and see that video for a full discussion of this pathway but in a nutshell alcohol also known as ethanol is first broken down to acetaldehyde and then acetaldehyde gets broken down to acetate this is how the body metabolizes alcohol and what's extremely high yield to know for the purposes of ketone synthesis is that in the first step of this pathway when you convert ethanol to acetaldehyde nad plus gets converted to NADH so in somebody who is an alcoholic who's constantly introducing ethanol into the body you're gonna have to metabolize loads and loads of ethanol and over time that will lead to a decreased amount of nad Plus and an increased amount of NADH now normally the body has a perfect balance between NAD+ and NADH but in your alcoholics who constantly are introducing ethanol into the body there is an exorbitant amount of NADH because in the process of breaking down all of that unnecessary alcohol that they are drinking you're forming NADH and you're depleting nad plus so to summarize this is what you find increased ethanol leads to decrease nad plus and increase NADH so how the hell does this make the body form ketones well let's refer back to the TCA cycle in the TCA cycle we already discussed that you form a product by combining acetyl co a and oxaloacetate what's extremely important to know and you can see the TCA cycle video in the dirty biochemistry series for more information but in the formation of oxaloacetate in the step where oxaloacetate is formed you convert NAD+ to NADH so you cannot form oxaloacetate unless you convert NAD+ to NADH now think about what we already said in states of alcoholism there is decreased amounts of NAD+ and effectively the amount is zero so if you knock out an ad plus then you can never form oxaloacetate if you can never form oxaloacetate not only can you not do gluconeogenesis and form glucose but you can't do the TCA cycle so this is very similar pathophysiology to what we've already been talking about some deficit in the body knocks out the ability to make oxaloacetate which prevents you from doing gluconeogenesis and forming glucose and prevents you from spinning the TCA cycle and forming the intermediates required to do the electron transport chain so the body says damn I'm gonna have to use ketones and that is why ketone synthesis occurs in states of alcoholism it's a high yield point that we should also bring up now in alcoholics they can actually have baseline levels of hypoglycemia and the reason there is because if you knock out the ability to make oxaloacetate because you're depleting your nad Plus then you can't do gluconeogenesis so your blood sugar is gonna be a little bit lower so this is why some alcoholics have hypoglycemia so in summary this is what we see in alcoholism now how do you remember this I'm gonna give you a cool mnemonic so because the problem with alcoholism is an increased ratio of NADH to NAD+ the way that I remember this is by thinking about the beer natural light so you've probably heard people refer to this beer as natty light and what I think of is nad elight nad for nad plus so natty light if you're alcoholics like natty light then the problem with alcoholism causing ketones to be formed is because you're depleting your nad plus or you're increasing your NADH and either way it's natty light so for completeness sake here is our chart we're gonna add alcoholism and the pathophysiology is the increased NADH to NAD+ ratio again due to the fact that we are depleting nad plus when we metabolize ethanol so here is the pathway that we've talked about this is ketone synthesis a couple other high-yield things that we need to mention first like every biochemical pathway you need to memorize the rate-limiting enzyme so in ketone body synthesis the rate-limiting enzyme is h mg co a synthase shown here in bolded red letters so again that's the enzyme that converts acetyl acetyl co a into h mg co a so the rate-limiting enzyme is h mg co a synth a so how do you remember this well instead of h mg synthase my pneumonic is to think what is the purpose of ketone formation so ketones are formed in periods of starvation so i think of someone who's starving and instead of h mg i kind of think of OMG and you know people sometimes go oh my god so h OMG i'm starving for h mg synthase so the essence starving for synthase and the h mg really is h OMG or just l mg if you would prefer but again the reason that i remember this mnemonic is because h jim g synthase is the rate-limiting enzyme of ketone synthesis and we do ketone synthesis in periods that are functionally identical to starvation so starvation DKA alcoholism and i think of oh my god I'm starving and for your pleasure this is a picture of adam richman the guy who did man vs. food so here again is our summary of the biochemical pathway everything that you need to know in terms of ketone synthesis is shown here on this slide let's just wrap up by talking about some quick other high yields that you might see on your exam and I'll give you some cool pneumatics to remember all this stuff so the other high yields that you should know is that red blood cells cannot use ketones and the way that I remember this is that RBC's are really basic cells and really basic cells can't use ketones because they're just so basic second point is that urine ketone dips only detect acetoacetate so we have dip sticks that you can dip in in someone's urine and you can see how many ketones are in the urine this is particularly useful in type 1 diabetics who want to see if they're in diabetic ketoacidosis or not but the the thing here and that's what's really how you'll to know for USMLE and comlex is that the urine ketone dipstick only detects acetoacetate it doesn't detect acetone and it doesn't detect beta hydroxy butyrate so the way that I remember this is that instead of acetoacetate I remember a pitot acetate and pee for urine so I remember that when you do a urine dip you only can detect acetoacetate so remember a pitot acetate the third and final high yield is that in a state of ketosis there in any of these starvation periods but especially in DKA the person's breath will smell fruity and the reason is because they're actually breathing out acetone they're breathing out the acetone and that's has a fruity odor to it so keep that in mind it's extremely high yield but this is it guys that's everything that you need to know about ketone synthesis to summarize and to close really quickly remember the pathway remember the rate-limiting enzyme really try to understand why DKA starvation and alcoholism leads to ketone synthesis in these periods of starvation where the body needs alternative fuel source because it can't make glucose and can't do the TCA cycle it all boils down to the inability to get oxaloacetate into the body in some states because you're depriving the body of the oxaloacetate as you do more gluconeogenesis and in others because you don't have the NAD+ necessary to actually create the oxaloacetate to begin with but that is everything that you need to know about ketone body synthesis