Overview of the Urea Cycle

See that is urea cycle. It is a part of a question that is formation of ammonia, disposal, transport, storage and functions of ammonia along with urea cycle. It is a frequently asked question in university examination. So another name for urea cycle is ornithine cycle. This ornithine take part in the urea cycle and again regenerated. That's why it is known as Ornithine cycle. It is also known as Krebs and Henslitt cycle because it is the first cycle elucidated by Hans Krebs and Kurt Henslitt. That's why it is known as Krebs and Henslitt cycle. Now coming to the side, the urea cycle occurs in the liver because the arginase is only present in the liver. That's why urea cycle occurs in the liver. Then it is partly cytosolic means the first two reactions, first two reactions occurs in the mitochondria while next three reactions occurs in the cytosol. So this pathway is partly mitochondrial and partly cytosolic. Then five important enzymes are required for this pathway. Five important enzymes are required. N-A-G-N-acetylglutamate is an activator and it is known as the sixth enzyme which regulates this pathway. Okay, it is required for the CPS1. Then there are five important disorders. Due to the deficiency of these five enzymes, these are the five important disorders and one syndrome that is HHH syndrome. Now coming to the steps in the urea cycle. The carbon dioxide which is produced in the TCA cycle is utilized here. TCA cycle is the final common oxidative pathway. It leads to the generation of carbon dioxide. Carbon dioxide and NH4 ions or ammonia, they get condensed in presence of the enzyme carbamoyl phosphate synthase 1. This is carbamoyl phosphate synthase. One, it requires two molecules of ATP. ATPs are converted into ADP and there is synthesis of carbamoyl phosphate. So this is the first step. It requires. N-acetylglutamate. This N-acetylglutamate is the allosteric activator of carbamoyl phosphate synthase 1. There is carbamoyl phosphate synthase 2 which is involved in the pyrimidine synthesis. This enzyme is mitochondrial. CPS2 is the cytosolic enzyme required for the pyrimidine synthesis. Then N-acetylglutamate is required for the CPS1 while it is not required for the CPS2. Then this carbamoyl phosphate it gets condensed with the ornithine. In this reaction, in the condensation reaction it gives citrulline. And the enzyme required in this step is ornithine. Transcarbo Molybdenum. So this is the first enzyme. This is the second that is Ornithine Transcarbo Molybdenum. Convert this Ornithine into the Citrulline. These two steps are mitochondrial. The enzyme starts with the A. They are cytosolic enzyme. For example, this Citrulline Accept Aspartate Condenses with Aspartate and this citrulline is converted into arginosuccinate. The two ATP's, two high energy phosphate bonds are utilized in this reaction. ATP molecule is consumed, one ATP is utilized which is converted into AMP and inorganic pyrophosphate. So here is utilization of two phosphate bonds that's why there is consumption of two ATP molecule okay so two ATP utilized in the first step and two ATP's are two phosphate bonds are utilized in the third step that is conversion of ATP into AMP. The enzyme in this step is argininosuccinate synthase. This is a ligase type of reaction. It requires ATP, causes the conversion of citrulline into arginino succinate with condensation of aspartate. Now this arginino succinate, it is converted into with the help of arginino succinate. Lies are arginosuccinate. This arginosuccinate is converted into fumarate and arginine and this arginine is converted into ornithine. In this reaction. There is generation of urea occurs with the help of arginase enzyme. So this is the first CPS1 which is mitochondrial. Ornithine transcarbomyelase it is a mitochondrial. Then there is formation of citrulline. The two transporter exist here ornithine transporter and citrulline transporter. The defect in the ornithine transporter that is ORNT1 gene lead to the disorder known as HHH syndrome. Now third is the arginosuccinate synthase. This is the third enzyme. Then arginosuccinate lyase. This is the fourth. And arginate this is the fifth enzyme. So these are the five enzymes which are involved in the urea cycle. There is generation of one molecule of urea. It has two nitrogen. The one is from the ammonia that is NH3 and another is from the aspartate. Aspartate. This is the MCQ. The source of nitrogen in urea is ammonia and aspartate. So these are the five and NHG is the regulator. So coming to the regulation of this pathway. This pathway is allosterically regulated by NAG. NAG is the allosteric activator of CPS1, carbamoyl phosphate synthase 1. And another minor regulation is the compartmentalization. Two pathway occurs in the mitochondria while three steps occurs in the cytosol compartmentalization. This is the second minor regulation. Then coming to the energetics. In energetics, two ATP's are utilized in the first step. Two high energy phosphate bonds are utilized in the third step. So it is equivalent to the utilization of two ATP. So four ATP's are consumed in the urea cycle. If you see the net consumption of ATP there is liberation of fumarate which undergoes TCA cycle and in TCA cycle fumarate is converted into malate and malate it gives NADH. Malate dehydrogenase it gives NADH. So there is generation of 2.5 ATP. From one molecule of NADH. Fumarate is converted into malate in the TCA cycle and this gives the one NADH molecule which gives 2.5 ATP. So if you minus 2.5 ATP, the net ATP consumption in the urea cycle is 1.5 ATP. This is energetics. After the energetics, we will discuss the disorders of urea cycle. the five important disorders in the urea cycle. Coming to the hyperammonemia type 1, it is due to the deficiency of CPS1. Then second is the hyperammonemia type 2, it is due to the deficiency of Ornithine Transcarbamylase Then third one is the Citrulinemia This is due to the deficiency of Arginino succinate synthase Then fourth one is the Arginino succinate Aciduria It is due to the deficiency of arginosuccinate lyes. And the fifth one is the hyperargininemia. It is due to the defect in arginase. Defect in arginase. So this is the first enzyme defect. This is the second. This is the third. This is the fourth. And this is the fifth enzyme defect. Generally, these disorders manifest as increase in the NH3 concentration that is hyperammonemia which leads to the neurological manifestations. There is tremor, there is ataxia. So, these are the problems due to the increased ammonia concentration. It is toxic to the brain because it diverts the glutamate. It combines with the alpha-ketoglutarate and gives glutamate so there is deficiency of this alpha-ketoglutarate which causes the decrease in the ATP production because it hampers the PCA cycle this is the first reason second it decreases the inhibitory neurotransmitter GABA and it increases the production of serotonin that's why there is neurological manifestation in uv cycle defect so these are the five disorder and the sixth one is the HHH syndrome It is hyperammonemia, hyperornithinemia and homocytrulline urea. It is due to the defect in ornithin transporter, ornithin transporter 1 gene that lead to this syndrome. So this is all about the urea cycle. If there is question on urea cycle, write about the site. Then it is partly mitochondrial, partly cytosolic pathway. They require 5 enzymes, then steps in the pathway, the regulation by the N-acetylglutamate, energetics, 4 ATPs are utilized in this pathway, net ATP consumption 1.5 ATP, 5 urea cycle disorders, hypo-ramonemia type 1, type 2, citrullinemia, arginino-succinate acid urea and argininemia. This is all about the urea cycle. So there is question in university exam. Describe the formation, transport, storage, disposal and toxicity of ammonia along with urea cycle. So this is a complete question and this is a most frequently asked question in university examination along with the another important question in the biochemistry is the regulation of blood glucose level. So these two questions are very very important in biochemistry. first is the regulation of blood glucose level and second one is the ammonia metabolism and urea cycle so this is all about the today's lecture keep watching thank you

So another name for urea cycle is ornithine cycle. This ornithine take part in the urea cycle and again regenerated. That's why it is known as Ornithine cycle.

It is also known as Krebs and Henslitt cycle because it is the first cycle elucidated by Hans Krebs and Kurt Henslitt. That's why it is known as Krebs and Henslitt cycle. Now coming to the side, the urea cycle occurs in the liver because the arginase is only present in the liver. That's why urea cycle occurs in the liver. Then it is partly cytosolic means the first two reactions, first two reactions occurs in the mitochondria while next three reactions occurs in the cytosol.

So this pathway is partly mitochondrial and partly cytosolic. Then five important enzymes are required for this pathway. Five important enzymes are required.

N-A-G-N-acetylglutamate is an activator and it is known as the sixth enzyme which regulates this pathway. Okay, it is required for the CPS1. Then there are five important disorders.

Due to the deficiency of these five enzymes, these are the five important disorders and one syndrome that is HHH syndrome. Now coming to the steps in the urea cycle. The carbon dioxide which is produced in the TCA cycle is utilized here. TCA cycle is the final common oxidative pathway. It leads to the generation of carbon dioxide.

Carbon dioxide and NH4 ions or ammonia, they get condensed in presence of the enzyme carbamoyl phosphate synthase 1. This is carbamoyl phosphate synthase. One, it requires two molecules of ATP. ATPs are converted into ADP and there is synthesis of carbamoyl phosphate.

So this is the first step. It requires. N-acetylglutamate.

This N-acetylglutamate is the allosteric activator of carbamoyl phosphate synthase 1. There is carbamoyl phosphate synthase 2 which is involved in the pyrimidine synthesis. This enzyme is mitochondrial. CPS2 is the cytosolic enzyme required for the pyrimidine synthesis. Then N-acetylglutamate is required for the CPS1 while it is not required for the CPS2. Then this carbamoyl phosphate it gets condensed with the ornithine.

In this reaction, in the condensation reaction it gives citrulline. And the enzyme required in this step is ornithine. Transcarbo Molybdenum. So this is the first enzyme. This is the second that is Ornithine Transcarbo Molybdenum.

Convert this Ornithine into the Citrulline. These two steps are mitochondrial. The enzyme starts with the A.

They are cytosolic enzyme. For example, this Citrulline Accept Aspartate Condenses with Aspartate and this citrulline is converted into arginosuccinate. The two ATP's, two high energy phosphate bonds are utilized in this reaction. ATP molecule is consumed, one ATP is utilized which is converted into AMP and inorganic pyrophosphate. So here is utilization of two phosphate bonds that's why there is consumption of two ATP molecule okay so two ATP utilized in the first step and two ATP's are two phosphate bonds are utilized in the third step that is conversion of ATP into AMP.

The enzyme in this step is argininosuccinate synthase. This is a ligase type of reaction. It requires ATP, causes the conversion of citrulline into arginino succinate with condensation of aspartate.

Now this arginino succinate, it is converted into with the help of arginino succinate. Lies are arginosuccinate. This arginosuccinate is converted into fumarate and arginine and this arginine is converted into ornithine.

In this reaction. There is generation of urea occurs with the help of arginase enzyme. So this is the first CPS1 which is mitochondrial. Ornithine transcarbomyelase it is a mitochondrial. Then there is formation of citrulline.

The two transporter exist here ornithine transporter and citrulline transporter. The defect in the ornithine transporter that is ORNT1 gene lead to the disorder known as HHH syndrome. Now third is the arginosuccinate synthase. This is the third enzyme. Then arginosuccinate lyase.

This is the fourth. And arginate this is the fifth enzyme. So these are the five enzymes which are involved in the urea cycle. There is generation of one molecule of urea.

It has two nitrogen. The one is from the ammonia that is NH3 and another is from the aspartate. Aspartate. This is the MCQ.

The source of nitrogen in urea is ammonia and aspartate. So these are the five and NHG is the regulator. So coming to the regulation of this pathway.

This pathway is allosterically regulated by NAG. NAG is the allosteric activator of CPS1, carbamoyl phosphate synthase 1. And another minor regulation is the compartmentalization. Two pathway occurs in the mitochondria while three steps occurs in the cytosol compartmentalization.

This is the second minor regulation. Then coming to the energetics. In energetics, two ATP's are utilized in the first step.

Two high energy phosphate bonds are utilized in the third step. So it is equivalent to the utilization of two ATP. So four ATP's are consumed in the urea cycle. If you see the net consumption of ATP there is liberation of fumarate which undergoes TCA cycle and in TCA cycle fumarate is converted into malate and malate it gives NADH. Malate dehydrogenase it gives NADH.

So there is generation of 2.5 ATP. From one molecule of NADH. Fumarate is converted into malate in the TCA cycle and this gives the one NADH molecule which gives 2.5 ATP.

So if you minus 2.5 ATP, the net ATP consumption in the urea cycle is 1.5 ATP. This is energetics. After the energetics, we will discuss the disorders of urea cycle.

the five important disorders in the urea cycle. Coming to the hyperammonemia type 1, it is due to the deficiency of CPS1. Then second is the hyperammonemia type 2, it is due to the deficiency of Ornithine Transcarbamylase Then third one is the Citrulinemia This is due to the deficiency of Arginino succinate synthase Then fourth one is the Arginino succinate Aciduria It is due to the deficiency of arginosuccinate lyes.

And the fifth one is the hyperargininemia. It is due to the defect in arginase. Defect in arginase. So this is the first enzyme defect. This is the second.

This is the third. This is the fourth. And this is the fifth enzyme defect. Generally, these disorders manifest as increase in the NH3 concentration that is hyperammonemia which leads to the neurological manifestations.

There is tremor, there is ataxia. So, these are the problems due to the increased ammonia concentration. It is toxic to the brain because it diverts the glutamate. It combines with the alpha-ketoglutarate and gives glutamate so there is deficiency of this alpha-ketoglutarate which causes the decrease in the ATP production because it hampers the PCA cycle this is the first reason second it decreases the inhibitory neurotransmitter GABA and it increases the production of serotonin that's why there is neurological manifestation in uv cycle defect so these are the five disorder and the sixth one is the HHH syndrome It is hyperammonemia, hyperornithinemia and homocytrulline urea. It is due to the defect in ornithin transporter, ornithin transporter 1 gene that lead to this syndrome.

So this is all about the urea cycle. If there is question on urea cycle, write about the site. Then it is partly mitochondrial, partly cytosolic pathway. They require 5 enzymes, then steps in the pathway, the regulation by the N-acetylglutamate, energetics, 4 ATPs are utilized in this pathway, net ATP consumption 1.5 ATP, 5 urea cycle disorders, hypo-ramonemia type 1, type 2, citrullinemia, arginino-succinate acid urea and argininemia. This is all about the urea cycle.

So there is question in university exam. Describe the formation, transport, storage, disposal and toxicity of ammonia along with urea cycle. So this is a complete question and this is a most frequently asked question in university examination along with the another important question in the biochemistry is the regulation of blood glucose level. So these two questions are very very important in biochemistry. first is the regulation of blood glucose level and second one is the ammonia metabolism and urea cycle so this is all about the today's lecture keep watching thank you

Transcript for:Overview of the Urea Cycle

Transcript for:
Overview of the Urea Cycle