Hello and welcome to MedSimplified. In this video, we are gonna talk about the urea cycle. Many students have requested me for an update on the urea cycle video that I made a few years ago.
Many of you liked that video so I decided to do a new video on this topic that will be better yet simplified. So let's begin. In simple words, urea cycle is a biochemical pathway that converts the ammonia present in our body to urea.
This is done mainly because ammonia cannot be dissolved in water easily and is a toxic compound while urea can be easily dissolved in water and is a far less toxic compound than ammonia. What does that mean? It basically means that you can excrete urea in your urine and not ammonia. Now before diving into how this ammonia is converted into urea, it is very important for you to understand where does this ammonia come from and how is it transported to the liver for the urea cycle. Proteins are the most abundant organic compounds and constitute a major part of the dry body weight approximately 10 to 12 kilogram in an adult.
They perform a wide variety of functions in our body. In almost every biological process proteins are required. Enzymes, hormones, clotting factors, receptors all are proteins.
About half of the body protein is present in the skeleton and connective tissue while the other half is intracerebral. Each day humans turn over 1-2% of their total body protein, principally the muscle protein. Breakdown of proteins is known as proteolysis and upon proteolysis the proteins are broken down into individual amino acids.
These amino acids are nitrogen containing compounds and the proteins are the major source of nitrogenous waste in our body. This waste is highly toxic and millions of proteins are broken down in our body every single day and that produces a lot of nitrogenous waste. If you look at the structure of an amino acid, you can see that it consists of a nitrogen in the form of an amino group.
Now most of the protein breakdown occurs in our muscles and the peripheral body and the nitrogenous waste produced there must be taken to the liver because it is here in the liver that this nitrogenous waste is converted into a less toxic water soluble compound known as urea. Now these nitrogen containing amino groups cannot be released into our blood directly because free ammonium ions are highly toxic to our body. So there must exist a way to transport this nitrogenous waste to the liver without converting it into its ionic form i.e. the free ammonium ions or ammonia as that can enter our brain and can lead to lots of bad stuff. So there are basically two steps that take place before the urea cycle begins. These steps are done in order to transport the nitrogenous waste to liver without releasing it freely in the blood.
The first step is known as transamination and the second is the oxidative deamination. If you look at the word transamination, it is made up of two words, trans and amination, which basically mean transfer of an amino group. Now what essentially happens is that the amino group in an amino acid which contains the nitrogen, is taken from the amino acid and is transferred to some other molecule.
This molecule can be the alanine or most commonly the alpha-ketoglutarate, which on receiving the amino group gets converted to glutamate. This glutamate can freely circulate in the blood, carrying the excess nitrogenous waste with it, without releasing it into our circulation. So this was the first step that takes place before the urea cycle begins and this was known as the transamination and as you can see in this reaction we are transferring an amino group from an amino acid to another so that the excess nitrogenous waste of our body can be directly transferred to the liver without releasing it into the blood.
When glutamate reaches the liver it undergoes the second step and this is known as the oxidative deamination and as you can tell by the name deamination you it basically means removal of the amino group. So the glutamate is the only amino acid that undergoes oxidative deamination to a significant extent to liberate the free ammonia for urea synthesis. The ammonia that is liberated in the mitochondria of the liver by oxidative deamination is then used to synthesize urea by a biochemical cycle that is known as the urea cycle. This urea is far less toxic to our body than free ammonia and is a water soluble compound meaning it can be excreted by the kidneys in the form of urine So now you know from where is this ammonia coming from and how is it transported to the liver. Now let's begin with the urea cycle.
You can get the lecture handouts and flashcards from the topic of urea cycle by joining our channel or joining our community at patreon.com. This will also unlock some of the cool features like behind the scenes, early notifications and much more. Urea cycle is the first metabolic cycle that was described by Hans Krebs.
and Kurt Henselit in 1932. Hence it is known as the Krebs-Henselit cycle. The individual reactions however were described in more detail later by Ratner and Cohen. So urea synthesis is a 5 step cyclic process with 5 distinct enzymes.
The first two enzymes are present in the mitochondria while the rest are present in the cytosol. So in the first reaction of the urea cycle, one molecule of ammonia combines with one molecule of carbon dioxide and this leads to the formation of a compound known as carbamoyl phosphate. The enzyme involved here is the carbamoyl phosphate synthase 1. And this reaction also uses two molecules of ATP.
The phosphate in the carbamoyl phosphate is derived from ATP only. Two molecules of ATP get converted to two molecules of ADP. The enzyme involved here is the carbamoyl phosphate synthase 1 or the CPS1. This enzyme is located in the mitochondria so this reaction takes place in the mitochondria only. An acetyl glutamate is necessary for the activation of this enzyme.
Our next reaction also takes place in the mitochondria where the carbamoyl phosphate that we just synthesized from ammonia combines with one molecule of ornithine and this leads to the formation of citrulline. Now let's understand what just happened in this reaction. Ornithine is also an amino acid but it only has a role in our urea cycle. It is not a part of any protein or any other biochemical cycle in our body.
As you can see in the structure of ornithine, it already has two nitrogen containing groups. In the urea cycle, the ornithine serves as a carrier which picks up the ammonia from the mitochondria by attaching carbamoyl phosphate with it which leads to formation of a bigger molecule which now has three nitrogen containing groups and this is known as citrulline. The combination of ornithine with carbamoyl phosphate uses the enzyme ornithine transcarbamylase also known as OTC. Again you can remember what this enzyme does by just looking at its name. One molecule of inorganic phosphate is released in this reaction.
So these were our first two reactions of urea cycle and these two reactions, the formation of carbamoyl phosphate and combination of carbamoyl phosphate with ornithine takes place in the mitochondria of the cell. The citrulline then leaves the mitochondria to enter the cytoplasm for the rest of the urea cycle. The citrulline undergoes a few more reactions and ultimately produces urea and liberates back the ornithine. Thus, Ornithine gets recycled back to enter into the mitochondria. For our next reaction, the Citrulline moves out of the mitochondria into the cytoplasm and gets condensed with one molecule of Aspartate to form Argininosuccinate.
Aspartate is another amino acid and this serves as a source of additional amino group that gets attached to Citrulline. This reaction is ATP dependent. and is catalyzed by the enzyme argininosuccinate synthetase.
Note that in this reaction the ATP is converted into AMP and inorganic phosphate group gets released. So up till now we are just adding molecules one after another that has led to the formation of one big molecule that is this argininosuccinate. We started with combining ammonia, carbon dioxide, ATP to form the carbonyl phosphate. which was then combined with ornithine.
We also added one molecule of aspartate to this which led to the formation of this big molecule known as argininosuccinate. Now the next two reactions involve the systematic breakdown of argininosuccinate to finally release urea. First, the argininosuccinate is broken down by the enzyme argininosuccinate lyase here at this point in its structure.
This split leads to the formation of two molecules, arginine and fumarate. The arginine that is produced is again broken down, this time by the enzyme known as arginase. And this finally leads to the formation of two compounds. The first one is urea and the second is the ornithine only.
One molecule of water is also used in this reaction. Now let's take a closer look as to what happened here. So we have the enzyme arginase. that breaks up arginine here at this level. This part of the molecule of arginine combines with oxygen that is provided by the water molecule and leads to the formation of one molecule of urea.
The two hydrogen atoms from the water molecule get attached here and if you just pause this video for a few seconds and closely analyze you would see that this leads to the formation of ornithine again. The ornithine gets transported back into the mitochondria to receive another molecule of carbamoyl phosphate to form citrulline and hence the cycle repeats again. The urea that is produced here is passed into the blood and since it is a water soluble molecule it gets easily excreted with urine. So this was an overview about the topic of urea cycle.
I hope you liked the video. And if you like the video, you can take a look at our next video in this series which is the trick to remember the urea cycle. I have included two mnemonics, one to remember all the intermediate molecules of urea cycle and one mnemonic to remember all the enzymes of the urea cycle. Now as I said previously, you can get all the lecture handouts and flashcards from the topic of urea cycle and all our other previous videos on YouTube by clicking the join button below.
You can also get these by signing up on our community on patreon.com. I'll be highly thankful to you. Thank you so much for watching this video.