all right engineers in this video we're going to talk about Ketone metabolism okay so when does the body actually you know utilize ketones it's not usually a preferable source of energy it is usually usually utilized whenever we're in certain conditions so let's say that you have low blood glucose levels let's say that's one reason all right so let's say that you have extreme low blood glucose levels another reason this pathway could occur this Ketone metabolism could be if you actually have prolonged starvation so another reason could be prolonged starvation so prolonged starvation another reason this pathway could occur is because of diabetic condition so in other words you have diabetes malius and it's not being well regulated so you're not taking your insulin properly so it could be due to uncontrolled diabetes malius specifically though type one it's less common in type two but it can happen in type two and the last thing is it could be due to a uh some type of diet where you're restricting carbohydrates for example the Atkins diet okay so these could be certain conditions or reasons upon why you're exhibiting this Ketone metabolism now why are these things stimuli for that okay if you're actually having low blood glucose levels your body is going to have to utilize some form of energy now the brain this is the brain's primary source of energy so the brain's primary source of energy is going to be that of glucose but in any condition in which there is extremely low blood glucose levels whether it be due to prolonged starvation uncontrolled Diabetes metis Type 1 or some type of specialized diet where you're avoiding carbohydrates more of a ketogenic diet like the Atkins diet this can cause the brain to have to switch from its primary choice of fuel to a secondary choice of fuel which is that of Ketone bodies also the muscles our muscle tissues can also utilize these Ketone bodies so our muscles they also prefer to use fatty acids and glucose as their source of energy but whenever there is a situation which the blood glucose levels are extremely low and there's excessive fatty acid oxidation they can utilize Ketone bodies so again we know why it's occurring it's occurring because of low blood glucose levels whether that be du do prolonged starvation uncontrolled type 1 diabetes militis or the Atkins diet or some type of diet which is restricting carbohydrates now we know that the uh organs that can utilize that as sources of fuel is going to be the brain and the muscles now the next question is where is this ketogenesis actually occurring it's mainly occurring in the liver so this is mainly occurring in the liver this is where the the Genesis of these Ketone bodies are being formed but the Lis the breaking down of those Ketone bodies to generate energy is occurring within the muscles and the Brain okay now let's go over how this process is occurring and why it's occurring in a little bit more detail so you know uh inside of our liver cell it's utilizing glucose it can utilize glucose and you guys remember that glucose uh under goes oxidation to produce pyruvate and then if you remember pyate can get converted into what eventually it can get converted into acetyl COA and then what does acetyl COA combine with you know aceto COA combines with oxaloacetate I'm going to denote that as OAA and what happen happens if you guys remember oxaloacetate and aceto COA actually do what they fuse together right to form what molecule what is this next molecule that it forms it forms a molecule called citrate and then the kreb cycle will continue right it'll go from citrate to isocitrate to alphaet toluate to soxo to soate to fate to malate to OA okay you know there's another path that can occur if the glucose levels on our body body is low we have low blood glucose levels wouldn't that mean that we have very little pyruvate if we have very little pyruvate we have very little acetyl COA and there's going to be less kreb cycle activity and now what that means is is you know your body has to take this to a specific point in the body you know it takes it to the electron transport chain you know the nadhs that you get from this the nadh's and the fadh2s they'll take those hydrides to the electron transport chain and what will come out of the electron transport chain ATP you'll generate ATP so you'll produce ATP now in a situation in which our body has what low blood glucose levels this pathway is not going to be utilized as much our body switches gears so now this is our primary I told you guys again let's write it above it glucose are carbohydrates in general so let's write it above like this this is our carbs this this is our first source of fuel it's our primary source of fuel this is the one that we would actually go to first we want to go to carbs first but in a situation in which these are not available or they're very Li limited amounts our body will switch to a second source of fuel and that second source of fuel is going to be fatty acids okay so again let's write it up here this is our second source of of fuel now what happens with these fatty acids you know these fatty acids they undergo specific process that you guys have we've already talked about remember beta oxidation beta oxidation was that four-step process that was literally generating acetylcoa now if we're having excessive breakdown of fatty acids because our glucose levels are low and our ATP levels what was going on with our ATP levels because there was low glucose there was low at ATP our cells are going to require that ATP for many many different activities transport pumps contraction even uh generating DNA and transcription translation tons of processes so our body switches gears it goes to the second source of energy Fuel and starts breaking down lots of fatty acids and again what is this process called when you're breaking down these fatty acids this is called beta oxidation so beta oxidation is the process in which there is actually going to be the breakdown of fat acids into acetyl COA and we already talked about in an individual video now what happens as a result of making lots of breaking down these fatty acids what do you make a lot of a lot of acetyl COA so as I start making a lot of acetyl COA I'm going to have a lot of crab cycle activity and produce a lot of ATP so again what's going to happen as a result I'm going to have a lot of acetyl COA and then as as a result I'm going to have a lot of nadh's a lot of fadh2s I'll go to the electron trans transport chain and what will happen to my ATP levels it'll go up problem is though when our blood glucose levels are low you remember that that mechanism our body does it's called gluconeogenesis where the oxaloacetate can be utilized for what remember the oxaloacetate can actually get converted into a molecule called malate and it can get pushed out of the mitochondria when it gets pushed let's say that for example this is the mitochondria Mito there malet can get pushed out can get converted back into OAA and then OAA can get converted into a special molecule which was called what what was that molecule called phospho enol pyruvate and then that could get converted into glucose and if you remember what was the enzyme was regulating this step from OA to pep it was called pep c k this enzyme was stimulating this step so whenever there is low blood glucose levels our body deals with that with trying to make gluc glucose through this process of gluconeogenesis so what is this process here called this process is called gluco neo genesis okay well as a result then what happens to your oxyacetate levels if you're utilizing that oxyacetate to make glucose won't his concentration start going down yes and look what happens when his concentration starts going down as his concentration starts going down this acetyl COA can't react with this oxaloacetate anymore because there's very little of them so very little acyoa is going to react with the OA and you're going to make less citrate now what happens in response to this very little citrate our body decides to shuttle or shift this acetyl COA production into a different molecule so now look what happens this acetyl COA is going to go into a special pathway I'm going to have a lot of acetal coas here what I'm going to do is I'm going to take an acetyl COA here and another acetyl COA and I'm going to fuse them together okay so I'm going to take these two acetyl coas and I'm going to fuse these two acetyl coas together and as I fuse them one of the coas is going to have to come off and so out of this reaction will come off a CO enzyme a so I lose a CO enzyme a in this process another thing that's happening is what enzyme is triggering this pathway because this enzyme isn't just occurring like automatically there has to be an enzyme that's triggering this pathway this enzyme is called acetal acetal COA AAL transferase okay so this aceto COA acal transferase enzyme is doing what it's taking the the aceto COA and the other aceto COA and fusing them together and as a result what is the molecule that you're forming as a result you're going to form a molecule called aceto aceto COA so what's this new molecule here formed this called molecule is called aceto actil COA so I went from two acetyl coas reacting with the presence of acoa AAL transferase and I'm going to get rid of co-enzyme a and I'm going to form aceto aceto coate it's just these two guys fused together without a COA then I'm going to take this aceto aceto COA and I'm going to do another special reaction with it I'm going to add in another COA okay so I'm gonna add in another COA another acetyl COA so look what I'm going to do here I'm going to take this acetyl COA and I'm G to add in another acetyl COA so what I'm going to do is I'm going to take acetyl COA here and I'm going to add this puppy in right there and I'm going to get rid of another COA so I'm going to lose another COA as a result of this so what am I going to do I'm going to lose a COA as a result of this Co enzyme a then when I have this aceto acoa combined with another aceto COA I'm going to get a new molecule and this new molecule that I'm going to form as a result of this reaction is going to be specifically called they abbreviated I'm going to write down the abbreviation but I'll write down the name also just for the heck of it it's called HMG COA so HMG COA stands for three hydroxy three methyl glutaral COA so now you guys see why people refer to this as HMG COA because it's it's a heck of a name okay so HMG COA is going to be formed by what taking aceto aceto COA reacting with another aceto because you have tons of those aceto why not use them up so now when we do that when we take this aceto aceto COA put in another aceto COA we form HMG COA which is also referred to as three hydroxy three methyl gluto COA some literatures because the three carbon is usually also the beta carbon you might hear it written as beta hydroxy beta methyl gluto COA but we can just refer to it as HMG COA now what enzyme is catalyzing this step the enzyme catalyzing this step is specifically called HMG COA synthes HMG COA synthes if you don't remember any of these enzymes please remember this one because this enzyme is the rate limiting enzyme so this step right here that we're going to right now this is called the rate limiting step so the rate limiting step okay so it's one of the most important steps within this process now this HMG COA what's going to happen with him this HMG COA is going to do something really cool he's going to get acted on by another enzyme okay and this enzyme that's going to work on this HMG COA okay we already know the name of this molecule okay but again you can refer to it as HMG COA or three hydroxy three methyl glutaral COA but look what enzymes coming into this area this enzyme is going to stimulate this step now you're probably going to be like I don't get why we keep doing this Zach but it's all part of our body's amazing way to deal with this see how we put in a COA in this step we're going to get rid of it we're going to get rid of an acetal COA so what we're going to do is we're going to take an enzyme here and we're going to cut this molecule with a molecule called h mg COA lias so this HMG COA lias is going to be an enzyme and this enzyme is going to cut the HMG COA or the three hydroxy 3 methyl gluta COA and it's going to pop out an acetylcoa so it's going to pop out an acetylcoa and as a result this new molecule that I'm going to get is going to be referred to as aceto acetate okay so I'm going to get acetoacetate out of that reaction now one more thing can happen as a result of this the ceto acetate can get put directly into the blood so this aceto acetate can literally get put right into the blood but some of this acetoacetate is converted into another molecule another type of Ketone body because this is one of the Ketone bodies let's actually write that this is actually one of the Ketone bodies so this is the one of the types of Ketone bodies that we're going to call it that's going to be utilized for energy for the muscles and for the brain right now acetyl acetate has a special mechanism here what it can do is let's do with a different color here I can take this acetoacetate and I'm going to have this molecule called nadh come into play this nadh is going to drop some hydrides off into this acetoacetate and convert him into n a positive right because he's going to drop the hydrides off onto the acetoacetate so this acetoacetate is going to get reduced it's going to get reduced to a molecule referred to as beta hydroxy butyrate okay so you're going to get beta hydroxy butyrate which is going to be one of the Ketone B so this is the other Ketone body that you can develop here this is the other Ketone body body right and what can happen this beta hydroxy beate can get spit right into the bloodstream so we can spit this into the bloodstream so what are the two things that we spit into the bloodstream out here we've put into the bloodstream two types of Ketone bodies and again what are those Ketone bodies that we put in one is aceto acetate the other one is going to be beta hydroxy berate these two guys can get taken into this actual muscle cell or again what other cell it can be taken into the muscle cells or they can be taken into the brain cells right so the our neurons can utilize that okay none one more thing that I need to point out you know this acetoacetate okay in order for us this aceto acetate be converted into this beta hydroxy berate you had to have an enzyme o what did I have here n to n positive you know that whenever you see that there's a dehydrogenase enzyme and I'm synthesizing beta hydroxy butyrate so this enzyme here must be what do you think this enzyme is called this enzyme is called beta hydroxy berate dehydrogenase and this enzyme is stimulating this step okay the beta hydroxy butter dehydrogen is converting acetoacetate into beta hydroxy beate and then it's getting pushed into blood one thing we need to realize again these molecules are your Ketone bodies they can get taken up by muscles and by the brain now something happens with this aceto acetate there's another enzyme for the aceto acetate when it's in the blood so let's show this acetoacetate here let's say that we spit some acetoacetate right here also from this process this acetyl acetate can be acted on by another enzyme and this enzyme is called acetoacetate decarboxylase this enzyme is called aceto acetate D carboxylase and what it's going to do is it's going to rip off a carbon off of the acetoacetate now generally aceto acetate is a four carbon long structure so this is about four carbons but what I'm going to do is I'm going to rip off a carbon and when I do that I turn it into a very very dangerous molecule inside of our body and that dangerous molecule that can actually cause certain problems is called acetone why is that relevant okay in certain um people who have uncontrolled Diabetes metis Type 1 one of the diagnostic tools is to smell their breath you know whenever someone's having uncontrolled diabetes mtis and they're having a lot of this keto metabolism they're going to be having a lot of acetone that they're going to try to breathe off now you know why these I'm mentioning that is because the acetyl acetate and beta hydroxy butyrate are naturally acidic um you might have heard of this term in chemistry these generally have a PKA um around four to five which is meaning that they're pretty acidic okay so if it has a pka of around four to five normally a good buffer is going to be plus or one minus the pH right now if this pka of these Ketone bodies are excessively you know low it can be very acidic what does that mean that means that these Ketone bodies can donate protons into the bloodstream and if they donate protons into the bloodstream what does that do to our blood it makes our blood acidic so if it's donating protons into the actual bloodstream it's making the blood really really acidic this can lead to acidosis so this can lead to acidosis specifically they refer to it as keto acidosis and again it's because this acetoacetate and beta hydroxy beate generally have a PKA around four to five so they're naturally acidic and they can donate protons so one thing you're going to notice with this person who might have prolong starvation uncontrolled type 1 diabetes metis or a very very prolonged Atkin diet is they'll have acetone breath a fruity breath because they're trying to breathe it out also they're going to have acidosis their pH might be a little a little bit low but you can also test this you know uh doctors don't necessarily just go straight by the pH they also go by another test and a way that they can look for this is what's called an annion Gap and if they take this person and they see an elevated annion Gap you know usually above approximately 11 Millar this person could actually have some type of acidosis okay whether that be a keto acidosis or something else generally whenever is significantly larger than about 11 Millar per liter that can actually say okay this person has a high an Gap we should evaluate that and we'll talk about this whenever we talk about acid base balance okay now now that we understand there can be acetone breath there could be acidosis they would have a high annion Gap what is going to happen with the ceto acetate and the beta hydroxy berate besides that okay you know these guys here are pretty interesting they can be utilized by certain tissues but when they are caught whenever there is too much of these Whenever there is excessive excessive excessive amounts of these molecules right here too much of this beta hydroxy beate and too much of this aceto acetate there's a particular part of our brain stem and that particular part of our brain stem is called the area Posta it's where the chemo trigger zone is whenever there is excessive levels of this acetoacetate and beta hydroxy berate these molecules can stimulate the arop poost streamer within the trio trigger Zone you know what that's going to do it's going to trigger vomiting and when they're vomiting excessively what happens to these people then if they're vomiting excessively what are you losing you're losing a lot of fluid so another complication that can come with these individuals is not just acetone breath not just a high an Gap not just acidosis but also let's add to the list vomiting and the D with vomiting is that if they're vomiting too much this can lead to hypo volia which is low blood pressure right and if this gets significant if hypovolemia becomes so much to where the the person becomes dehydrated significantly it can lead to Leading the person into a comos state right so they can go into a com state so it's extremely dangerous on top of that one of the ways that our body tries to be able to deal with this acidosis um is that we try to do three different mechanisms one is we have a specifically a bicarbonate carbonic acid buffer system but that doesn't last for too long it usually gets um drawn up within about you know a couple minutes or maybe even seconds but our respiratory system we're trying to hyperventilate so if we're going to be consistently trying to hyperventilate to get some of that actual CO2 out decrease in the carbonic acid and decrease in the proton levels that to be able to alleviate the problem so you're also going to see Within These people what's called a classical sign which is called cmal breathing so they're going to have cus small breathing and cus small breathing is basically where and I think there's two s's in this sorry cus small breathing it's going to be whenever they're having excessive and very very deep and Rapid Inspirations trying to be able to breathe off some of that acid in the form of CO2 okay and also if they're having elevated levels of this aceto acetate and this beta hydroxy uate in the blood eventually they're going to spill that out into the urine and so what's one of the other signs that you can find within this person you can also find what's called keto Uria which just means they have elevated ketones within the urine and that could be some diagnostic signs of this okay now what can we do with these molecules now now that we've generated them within the liver now we have to take it to the organs that are going to utilize it which is the muscles and the Brain how do they do that exact opposite of what we just did so let's fly through that now first off we have to start up here with who technically we have to bring this beta hydroxy buttery up here first and then we'll bring this acetoacetate down here and I'll explain why in just a second aceto acetate okay and then up here we're going to have beta hydroxy berate okay if you guys remember from one of the steps there the last steps now we're just going to be working our way backwards if we want to go from beta hydroxy butyrate to acetoacetate you remember this was a reversible step so going from aeto acetate to a beta hydroxy beate I had to do what I had to unload nadhs well to go in this way I need to generate nadh's so this would be the exact opposite reaction I'll be taking NAD positives and generating nadh is okay what else is going to happen let's get this Arrow out of the way just now that we know that what enzyme was controlling this step you remember this was a dehydrogenase because anytime you see nadh you know a dehydrogenase so it's called a beta hydroxy butyrate what dehydrogenase enzyme and this enzyme is stimulating this Pathway to make acetoacetate now aceto acetate can come straight from the blood into this cell now now when it's in the cell what's going to happen to the acetoacetate the acetoacetate is actually going to get converted back into another molecule that next molecule that we're going to make is called acetoacetyl COA so we're going to make another molecule which is called aceto acoo now in order for this to happen something really weird is going to happen because if you remember the only thing that was really different whenever we were going from aceto aceto Co we had to go to an intermediate which which was called HMG COA and then to acetoacetate we're going to go straight from acetoacetate to aceto acetyl COA so we need a different intermediate in this case remember from the kreb cycle you generate a specific molecule so let's say here's our kreb cycle with your acetal COA and then you go through the kreb cycle you know there's a specific molecule from the Krab cycle that we actually can generate for this pathway it's called suon COA you see that COA there there's no COA there there guess what he does he comes into this process and drops off his COA because he's going to come out as soate then when this happens in order for us to be able to take this acetoacetate into the aceto aceto COA we had to transfer a COA on to this guy so when we transfer the COA on to this guy then we're going to get the aceto aceto COA then the aceto aceto COA is going to be broken down broken down into what aetl COA and acetal COA oh man that's awesome so we can take this acetyl COA this aceto acetyl COA and we can break it down into two different types of molecules now what is the name of the enzyme controlling this step the enzyme controlling this step is specifically a special enzyme called tho foras so this soperas enzyme was catalyzing this conversion of aceto acetate to aceto acetylcoa then the aceto acetylcoa was getting broken down when it was getting broken down it was getting cleaved into two different structures this aceto COA and this aceto COA so what must have happened here I must have had to transfer a co-enzyme a in there somewhere so I had to bring a co-enzyme a in there so I must have had some type of acetylcoa AAL transfer enzyme so must have had some enzyme in here it's called a ACL COA AAL transferase enzyme who is stimulating this step then I have these acetyl coas these acetyl Coes we doing what with these acetyl Coes we could actually bring them down where we could bring them down into the creb cycle out of the crab cycle what do I generate what do I generate from this I generate nadh's I generate fadh2s I generate ATP wouldn't it be the same for this guy also yes so this guy's also going to go through the creb cycle when he goes through the CB cycle what's he going to give up he's going to give away again nadh's fadh2s as well as some ATP and then what can these nadhs and these fadh2s do these can come to the electron transport chain and what happens at the electron transport chain specifically remember these molecules come to the electron transport chain and they're utilized to make what so these guys over here will come to the electron transport chain and be utilized to make ATP so as a result you'll produce a TP which was the overall goal ah it's beautiful okay so now that we've done that we basically took those Ketone bodies that we took from the liver that we synthesized in the liver brought them over into the muscles skeletal muscles cardiac muscles and brain and then utilize them for energy and why the question is why is the brain using that when it can't use like fatty acids because fatty acids have a hard time being able to cross the bloodb brain barrier Ketone bodies can okay so now that we brought the Ketone bodies in we can make ATP and now the brain is satisfied because it can produce some ATP from this reaction okay now I hope all of this made sense ninja ners I hope you guys enjoyed it I know it was a lot of information thanks for sticking in there with me if you guys did like it this video hit the like button comment down in the comment section and please subscribe all right Ninja nerds until next time