welcome back to dirty medicines biochemistry series in this video we're going to be talking about the urea cycle the urea cycle is a very important biochemical pathway whose main goal is to eliminate ammonia from the body by converting it into urea in this video today we're going to start by going through the pathway of the urea cycle will then talk about things like rate limiting enzymes and what happens when you have certain enzymatic deficiencies along the pathway we'll touch on the importance of getting ammonia out of the body and what happens when there's too much ammonia in the body and how we can treat it let's start with an overview when you ingest protein or when you break down protein in your body you're of course breaking them down into amino acids because amino acids are the protein building blocks of everything that we put together in the body when amino acids get catabolized or broken down they form ammonia now normally ammonia is not a problem for a healthy body but a problem occurs when you can't get ammonia outside of the body because it builds up to toxic levels ammonia is sent to the liver where it's turned into urea the urea is then sent to the kidney and eliminated from the body only the kidney can eliminate urea from the body now everything that you see on this slide shown here in a gray box is the urea cycle the urea cycle specifically takes ammonia sets it through a series of very specialized chemical reactions in the liver forms urea and then takes that urea and ships it to the kidney where the kidney can urinate it out that is the urea cycle and that's what we're going to be talking about in this lesson today let's start with the beginning of the urea cycle so you start with ammonia I showed you on the previous slide that ammonia is formed as a byproduct of amino acid or protein breakdown ammonia is combined with carbon dioxide and forms carbamoyl phosphate the enzyme that catalyzes this conversion is carbamoyl phosphate synthetase one carbamoyl phosphate then combines with ornithine to form citrulline that reaction is catalyzed by ornithine transcarbamylase now let's pause for a second we've only talked about two reactions so far but everything that you see here is not only occurring in the liver but specifically it's occurring in the mitochondria this is a very high yield point that often shows up on exams everything that you see here is occurring in the liver and specifically in the hepatic mitochondria everything else that you'll see on this slide and the rest of the urea cycle is going to be occurring in the liver but not in the mitochondria rather it will be occurring in the cytoplasm so now that we've formed citrulline citrulline will combine with aspartate and ATP to form arginine o succinate the enzyme that catalyzes this conversion is argininosuccinate synthetase let's pause for one more second remember when you're filling out biochemical pathways if you're not sure what the enzyme is or what the product or reactants are try to think about the enzyme name let's look at this example argininosuccinate synthetase the word synthetase always tells you that whatever comes before it is being synthesized or synthetized if you will so in this case the enzyme name is argininosuccinate synthetase therefore we know that this enzyme must be forming argininosuccinate and hence citrulline combines with aspartate and ATP to form arginine o succinate now arginine of succinate will go on to form arginine and in the process it will spit off a fumarate as a byproduct the enzyme that catalyzes this conversion is arginine of succinate let's pause again when there's an enzyme that ends in ace ASE but it's one word and it's not synthetase it means that whatever's in front of it is being broken down so let's look this enzyme arginine of succinate this is telling you that arginine o succinate is being broken down because it's the same exact word as the reactant with ASE at the end so arginine o succinate goes through arginine o sucks and ace so it's breaking down arginine Oh sucks and forming arginine now this is the important step arginine will go back to ornithine but in the process will convert to urea so we've completed the major major goal of the urea cycle we've started with ammonia nh3 we've sent it through a series of reactions and in the process we've packaged that ammonia into urea the urea will then go to the kidney and be excreted in a normal healthy individual this is exactly what must occur in order to get that ammonia outside of the body now here's the overview of our cycle so far and there are a few important high-yield concepts to keep in mind one the rate-limiting enzyme is carbamoyl phosphate synthetase one whenever you're studying or learning biochemistry the most important thing that you can take away from every different chemical reaction is what is the rate-limiting enzyme in this case it's carbamoyl phosphate synthetase one now how do we remember that carbamoyl phosphate synthetase one has the initials cps when i think about what the urea cycles main goal is it's to urinate out urea it's to convert ammonia to urea and pee it out so that we can get it outside of the body but what happens if you had trouble peeing in real life you would probably need to go and get some medicine to help you urinate and where would you get that medicine you would get it at CVS CPS reminds me of CVS and I make the mental connection between the urea cycle and urinating out urea and the inability to urinate in real life and having to go to CVS to get some medicine so it carbamoyl phosphate synthetase one has the letters cps which reminds me of the national american pharmacy CVS and if somebody had trouble urinating out their urea which is the goal of the urea cycle they'd have to go to CVS so whenever i think of the rate-limiting enzyme this is how you make the connection a stupid mnemonic yes but it absolutely works so the takeaway from this slide is that the rate-limiting enzyme of the urea cycle is carbamoyl phosphate synthetase one AKA cps AKA CBS where you go to get your medicine to help you urinate out your urea let's come back to our overview slide the next thing that's important to know is what happens if you have a certain deficiency of one of these enzymes the one that classically shows up on exams is ornithine transcarbamylase there is a disease called an ornithine transcarbamylase deficiency so in this instance you knock out ornithine transcarbamylase now if we knock out that enzyme it has profound effects on what comes before and what comes after it since it can no longer form citrulline citrulline goes down but since it can no longer convert carbamoyl phosphate into citrulline you have a buildup of carbon oil phosphate now as a general principle anytime you have a buildup of any reactant it can be extremely toxic to the body so the body in attempts to decrease this level of accumulating carbamoyl phosphate will actually convert it into something called a rhotic acid now erotic acid in itself is very toxic so in an ornithine transcarbamylase deficiency you have an accumulating level of a rhotic acid which is the body's attempt to decrease an accumulating level of carbamoyl phosphate and this leads to some pretty bad symptoms so in an order fene transcarbamylase deficiency there are a few things that you need to know for the purposes of exams the first is that this is an x-linked recessive disease so ornithine transcarbamylase deficiency is the only x-linked recessive disease that can occur due to an enzyme deficiency in the urea cycle the other perhaps higher yield thing to know is what's happening to each of the names that you see on this slide you need to know how these things change do they go up or do they go down so because it's an ornithine transcarbamylase deficiency obviously the enzyme ornithine transcarbamylase goes down when this happens you have citrulline as the product of what ornithine transcarbamylase usually forms is obviously going to go down but carbamoyl phosphate will go up because ornithine transcarbamylase can no longer convert the carbamoyl phosphate into the citrulline again this leads to a buildup of our reactants and a decrease in our products now when this happens the body looks at all of the accumulating carbamoyl phosphate and says hmmm this is abnormal we need to do something about this so it attempts to convert the carbon oil phosphate into a rhotic acid therefore you have a buildup of a rhotic acid and when this happens ammonia gets trapped inside the body because think about it if you can't form citrulline you can't proceed through the urea cycle and you can't ultimately form urea to excrete the ammonia so the ammonia builds up please make sure that you understand everything on this slide as it is extremely high yield now this is a perfect segue because it'll allow us to talk about what happens when ammonia builds up in the body after all why do we even need to urinate it out in the form of urea can't we just keep ammonia in the body well the answer is an overwhelming no hyper ammonia or too much ammonia in the body is extremely toxic and can ultimately lead to death if left untreated and while there are a number of symptoms that you should be familiar with the two highest yield are what we're about to talk about now the first is asterixis also sometimes referred to as negative myoclonus to test this you would ask your patient to put their hands up at a 90-degree angle with the forearm as you see in this picture you would then ask them to hold that position with both arms doing this at the same time for approximately 60 seconds if there's too much ammonia in the body you'll observe negative myoclonus or asterixis all of a sudden they'll have a flapping tremor of their hands while they're trying to hold it at this 90-degree angle if you see that that is positive asterixis and that tells you that there is a toxic level of ammonia in the body now in real life this could be due to a few things notably it's usually usually due to liver failure again there yet the urea cycle takes place in the liver so if the liver is shot or the person drinks too much alcohol or the person has hepatitis and develops cirrhosis and they can't carry out the normal cellular functions in the liver then instead of going through the urea cycle ammonia will just build up and you'll observe the clinical symptoms of hyper ammonia namely asterixis the other classic symptom is cerebral edema so you have this toxic accumulating level of ammonia in the body and ultimately it'll go to the brain and cause an osmotic shift in the brain causing cerebral edema now what happens when the brain swells well you get certain symptoms and those symptoms are slurred speech ataxia altered mental status for the person can become delirious confused not know their name not know where they are do things that they wouldn't otherwise normally do blurred vision and vomiting so as you can see as these levels accumulate and build up more they're extremely toxic and can lead to death if left untreated so with that said how do we treat too much ammonia in the body well remember this slide that we talked about in the beginning of the lesson protein or amino acid catabolism leads to the build-up of ammonia ammonia in the liver is converted to urea it goes through the urea cycle and ultimately urea goes to the kidney where it's eliminated so we've got a couple options when it comes to decreasing the level of ammonia in the body if you have some type of enzymatic deficiency leading to a toxic accumulation the first option is to simply decrease the dietary protein intake after all if you have any protein to break down into ammonia then you won't have toxic levels of ammonia accumulating in the body so people who have some type of enzymatic deficiency are usually counseled by their physician very early in life to decrease their intake of protein the second option which you'll see very often as you progress through your medical career is to actually decrease the level of ammonia itself if we knock out that ammonia then the ammonia will not have to be converted to urea and eliminate it because there simply will be less ammonia in the body now how do we do that there are two medications that are used one is called lactulose and the other is an antibiotic called refax Imman lactulose works by increasing the excretion of ammonia through the GI tract so this will be in the form of diarrhea very often people will have bowel movements where they're literally pooping out excess levels of ammonia refax imman is an antibiotic that kills bacteria in the colon and how does that work well those bacteria usually produce ammonia so if you destroy the bacteria in the colon then less ammonia will be formed by those bacteria which makes it easier to get ammonia levels down and out of the body those are the two main options when it comes to decreasing toxic levels of ammonia and again in the case of somebody who has something like liver failure you'll quite often see lactulose and refax Imman used in the hospital the dietary protein option is really for those who have some type of enzymatic deficiency and from Earth they have to be carefully counseled not to have a protein in their diet now let's come back to our overview slide this is again the urea cycle everything that you see here is extremely high yield understanding that ammonia goes through the urea cycle and is ultimately converted into urea which then goes to the kidney and is excreted out is the big picture that you need to keep in mind again to quickly summarize the rate-limiting enzyme is carbamoyl phosphate synthetase one or cps which should remind you of the pharmacy CVS which should allow you to make the mental connection but the urea cycle and going to a pharmacy to get medicine to help you urinate again the main goal of the urea cycle is to urinate out ammonia in the form of converted urea this is it this is the summary it's everything you need to know please remember also that too much ammonia in the body is very toxic it causes negative myoclonus aka asterixis which is a flapping tremor when somebody tries to flex their hands up to a 90 degree angle with the forearm it could also lead to cerebral edema with slurred speech altered Mental Status vomiting blurred vision and other destructive toxic changes if you understand everything that I've quickly summarized then you're in great shape when it comes to the urea cycle