Transamination and Oxidative Deamination:
In muscle cells, the amino acid alanine undergoes transamination with alpha-ketoglutarate to form pyruvate and glutamate. This process is catalyzed by alanine aminotransferase (ALT), which is reversible.
The glutamate produced travels to the liver.
2. Glutamate Conversion and Ammonia Production:
Inside the liver, glutamate undergoes oxidative deamination by the enzyme glutamate dehydrogenase, producing alpha-ketoglutarate and releasing ammonia.
The ammonia is toxic, especially in high amounts, and needs to be converted to less toxic substances.
3. Ammonia Toxicity and Brain Effects:
Ammonia can convert to ammonium (NH₄⁺), which is toxic when accumulated.
Ammonium in the brain leads to cerebral edema (swelling), as astrocytes (brain cells) convert excess glutamate into glutamine using the enzyme glutamine synthetase. Excessive glutamine draws water into brain cells, increasing intracranial pressure, which can lead to brain herniation or even coma.
4. Urea Cycle:
The urea cycle begins when ammonium enters the mitochondria and combines with bicarbonate and ATP to form carbamoyl phosphate. This reaction is catalyzed by carbamoyl phosphate synthetase I.
Ornithine then combines with carbamoyl phosphate to form citrulline, catalyzed by ornithine transcarbamylase.
Citrulline reacts with aspartate to form argininosuccinate (catalyzed by argininosuccinate synthetase).
Argininosuccinate is then converted to arginine by argininosuccinate lyase, releasing fumarate.
Finally, arginine is broken down by arginase, releasing urea, which is less toxic and can be excreted by the kidneys.
5. Excretion of Ammonia:
Urea is transported to the kidneys, where it is excreted in the urine. This process helps eliminate toxic ammonia in a safer form.
Excessive ammonia can cause glutamine and glycine buildup, leading to further brain damage. To help alleviate this, medications like benzoate and phenylbutyrate can bind to glutamine and glycine, facilitating their excretion in urine.
6. Defects in Urea Cycle:
Defects or mutations in enzymes of the urea cycle (such as ornithine transcarbamylase or argininosuccinate synthetase) can lead to a buildup of ammonia, causing toxicity and potential brain damage.
Treatment with benzoate or phenylbutyrate can help by binding and removing glutamine and glycine from the bloodstream, reducing ammonia levels.
Summary:
The urea cycle is a crucial pathway in detoxifying ammonia, a byproduct of amino acid metabolism. Ammonia is converted into urea, which is excreted in urine, preventing toxic buildup. Disruptions in the urea cycle can lead to high ammonia levels, causing brain swelling and potential coma. The body has mechanisms to handle ammonia, but in cases of metabolic disorders, medications like benzoate or phenylbutyrate may be required to reduce toxicity by promoting the excretion of glutamine and glycine.
P.S:
Much of the information in this post is derived from Ninja Nerd's educational video series on Urea cycle. I highly recommend watching their content for a deeper dive into the subjec