MCAT Biochemistry
In the urea cycle, a series of biochemical reactions convert toxic ammonia to non-toxic urea for excretion in the urine. The urea cycle occurs primarily in the liver and to a smaller extent in the kidneys. The first two steps take place in the mitochondria, and the last three steps happen in the cytosol. Key enzymes such as carbamoyl phosphate synthetase-1 (CPS-1) help create carbamoyl phosphate from ammonia and carbon dioxide. N-acetyl glutamate (NAG) activates CPS-1, and ornithine transcarbamylase (OTC) catalyzes the reaction between ornithine and carbamoyl phosphate to make citrulline.
Hyperammonemia is a metabolic disturbance that causes irritability, headache, asterixis, somnolence, blurry vision, and cerebral edema. The most common cause of hyperammonemia is liver disease, but urea cycle disorders, such as OTC deficiency, can also cause hyperammonemia. Treatment options for hyperammonemia include low protein diets, lactulose, antibiotics (neomycin or rifaximin), and ammonia scavengers like benzoates, phenylacetate, or phenylbutyrate.
Lesson Outline
<ul> <li>Urea cycle: biochemical reactions converting toxic ammonia to non-toxic urea for excretion in urine</li> <ul> <li>Occurs mainly in liver and to a smaller extent in kidneys</li> <li>Steps:</li> <ul> <li>1 & 2 in mitochondria</li> <li>3, 4, & 5 in cytosol</li> </ul> </ul> <li>Enzymes in the urea cycle</li> <ul> <li>CPS-1: uses 2 ATP to make carbamoyl phosphate from ammonia and CO2, activated by NAG</li> <li>OTC: catalyzes reaction between ornithine and carbamoyl phosphate to make citrulline</li> <li>Argininosuccinate synthetase: uses ATP to make argininosuccinate from citrulline and aspartate</li> <li>Argininosuccinase: cleaves argininosuccinate into arginine and fumarate</li> <li>Arginase: hydrolyzes arginine to make ornithine and urea</li> </ul> <li>Hyperammonemia</li> <ul> <li>Metabolic disturbance causing irritability, headache, asterixis, somnolence, blurry vision, and cerebral edema</li> <li>Excess ammonia increases glutamine concentrations in the brain, causing cerebral edema by shifting water into astrocytes</li> <li>Common causes: liver disease and urea cycle disorders</li> </ul> <li>Ornithine transcarbamylase (OTC) deficiency</li> <ul> <li>Most common hereditary urea cycle disorder</li> <li>Inherited in X-linked recessive fashion</li> </ul> <li>Treatment of hyperammonemia</li> <ul> <li>Low protein diets</li> <li>Lactulose</li> <li>Antibiotics (neomycin, rifaximin)</li> <li>Benzoates, phenylacetate, or phenylbutyrate</li> </ul> </ul>
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FAQs
The urea cycle is a series of biochemical reactions that occur in the liver and are responsible for the conversion of ammonia, a toxic byproduct of protein catabolism, into urea. This urea is then excreted from the body through the urine. The urea cycle plays a crucial role in maintaining nitrogen balance in the body and preventing the toxic accumulation of ammonia.
Hyperammonemia refers to elevated levels of ammonia in the blood. It can occur due to dysfunction or deficiency in one of the urea cycle enzymes, leading to an impaired urea cycle, which fails to remove ammonia effectively from the body. High levels of ammonia in the blood are toxic, particularly to the brain, and can cause symptoms such as lethargy, irritability, and neurological dysfunction, among others.
OTC (ornithine transcarbamylase) deficiency is an inherited metabolic disorder caused by a mutation in the OTC gene, which encodes the enzyme ornithine transcarbamylase. This enzyme is involved in the second step of the urea cycle, where it catalyzes the conversion of ornithine and carbamoyl phosphate to citrulline. A deficiency in OTC impairs the urea cycle, leading to decreased protein catabolism and the toxic accumulation of ammonia in the body, resulting in hyperammonemia.
N-acetyl glutamate (NAG) is a key allosteric activator of the enzyme carbamoyl phosphate synthetase I (CPS1), which is involved in the first step of the urea cycle. NAG is essential for the proper functioning of the urea cycle as it stimulates the activity of CPS1, enabling the conversion of ammonia into carbamoyl phosphate. A deficiency in NAG can lead to disrupted urea cycle function, resulting in hyperammonemia.
Treatment strategies for congenital urea cycle diseases include dietary modifications, such as a low protein diet, and medications to aid in the removal of ammonia. A low protein diet is recommended because it reduces the amount of amino acids being catabolized, thereby decreasing the production of ammonia. By lowering the overall ammonia load in the body, a low protein diet can help manage the symptoms of hyperammonemia and prevent further complications associated with urea cycle diseases. Additional treatments may include supplements like arginine or citrulline, as well as pharmacological interventions, depending on the specific urea cycle defect.
