Steps of the Urea Cycle
What is the Urea Cycle?
The conversion of ammonia into urea through a series of biochemical reactions is known as the urea cycle or ornithine cycle. It takes place in the liver with the help of mitochondrial and cytosolic enzymes. It is an important pathway in amphibians and mammals as they help in disposing highly toxic ammonia by converting it into urea. The animals that excrete in the form of urea are called ureotelic.
The urea cycle was discovered by Hans Krebs and Kurt Henseleit in 1932. Ammonia is produced in our bodies by amino acid catabolism, deaminations and prolonged starvations. All animals need to excrete ammonia in one way or another. Animals that directly excrete ammonia, such as aquatic organisms are called ammonotelic.
Mammals and amphibians cannot excrete ammonia directly, so they convert it into a simpler form of urea. The urea converted in the liver is transported to the kidney via the bloodstream and then finally excreted in the form of urine. This process is important because, if the nitrogenous waste is not excreted, it starts building up in the body and can be detrimental. Urea is inert in nature, soluble in water and can be easily excreted in urine, whereas ammonia is highly toxic.
Steps
The urea cycle starts in the mitochondria of hepatocytes (liver cells) and the final step takes place in the cytoplasm. The final product formed is then transported to the kidney, where it is excreted out of the body.
Entry into the Urea Cycle
Ammonia and carbon monoxide are converted into carbamoyl phosphate in this rate limiting step by the enzyme carbamoyl phosphate synthetase I (CPS I). Two ATP molecules are utilised in this step.
Ammonia becomes the source of the first amine group in urea. The CPS I requires an obligate activator, namely, N-acetyl glutamate (NAG). NAG is formed by a reaction between glutamate and acetyl-CoA in the presence of NAG synthase.
First Step
In the first step, carbamoyl phosphate enters the urea cycle and combines with ornithine to form citrulline in the presence of enzyme ornithine transcarbamylase (OTC). The citrulline formed is then transported out of the mitochondria into the cytoplasm by ornithine translocase.
Second Step
Citrulline and aspartate undergo a condensation reaction to form argininosuccinate in the presence of the enzyme argininosuccinate synthetase. Here, aspartate becomes the source of the second amine group on urea. This reaction utilises one ATP molecule.
Third Step
Argininosuccinate is cleaved off to make arginine and fumarate in the presence of enzyme argininosuccinate lyase. The fumarate is used up in the production of NADH in the TCA cycle, and the arginine moves forward for the next step of the urea cycle.
Fourth Step
Arginine undergoes hydrolysis to yield urea and ornithine in the presence of arginase. Ornithine is transported back to the mitochondria, which is used up in the second step of the cycle to form citrulline by combining with carbamoyl phosphate.
The overall reaction equation of the urea cycle is:
|
NH3 + CO2 + aspartate + 3 ATP + 3 H2O → urea + fumarate + 2 ADP + 2 Pi + AMP + PPi + H2O |
|---|
Regulation of the Urea Cycle
- N-acetyl glutamate (NAG): In the urea cycle, the enzyme CPS I is allosterically activated by NAG. It is an obligate activator of carbamoyl phosphate synthase. NAG is produced by the reaction of acetyl CoA and glutamate in the presence of NAG synthase, and the reaction is stimulated by both arginine (Arg) and glutamic acid (Glu). Therefore, Glu is both a substrate and activator for the urea cycle.
- Substrate Concentrations: All the enzymes in the urea cycle work based on the concentrations of their substrates except arginase.
Disorders of the Urea Cycle
- Ornithine Transcarbamylase (OTC) Deficiency: It is the only X-linked recessive enzyme deficiency disorder in the urea cycle. The deficiency of the enzyme leads to an increased concentration of carbamoyl phosphate in the mitochondria. The carbamoyl phosphate is rechanneled to the pyrimidine synthesis pathway in the cytoplasm. It is then converted into orotic acid. Orotic acid is built up in the blood and urine, and appears as orange crystals in the diapers of infants.
- Argininosuccinate Synthetase Deficiency: Argininosuccinate synthetase deficiency, also known as citrullinemia type I, is an autosomal recessive disorder of the urea cycle. This disorder is associated with build up of citrulline and, ultimately, ammonia. In infants, the disease is represented by seizures, lethargy, anorexia and respiratory distress. In adulthood, it appears in milder forms and symptoms include vomiting, ataxia and lethargy.
- Carbamoyl Phosphate Synthetase I (CPS I) Deficiency: It is an autosomal recessive metabolic disorder that is commonly seen in infants. It makes the child lethargic, unwilling to eat, altered body temperature and respiratory rate. In other affected individuals, it shows symptoms only later in life.
Keep exploring BYJU’S Biology for more interesting articles.
You might be interested in:
- Difference between Oedipus Complex and Electra Complex
- Ginkgophyta Living or Extinct
- Lac Operon Regulation Gene Expression
