Sunday, June 13, 2021
Mitochondrial Health

Urea Cycle Made Ridiculously Simple Biochemistry Video .Easy steps tricks | Mnemonics in 5 minutes!
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The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body.
Nitrogenous excretory products are removed from the body mainly in the urine.
Ammonia, which is very toxic in humans, is converted to urea, which is nontoxic, very soluble, and readily excreted by the kidneys.
The urea excreted each day by a healthy adult (about 30 g) accounts for about 90% of the nitrogenous excretory products.
Urea is formed in the urea cycle from NH4+, CO2, and the nitrogen of aspartate.
The cycle occurs mainly in the liver
Location of Urea Cycle
Cytosol and mitochondria of hepatocytes.
Substrates: NH3 (as derived from oxidative deamination of glutamate); CO2; aspartate; three ATP.
Products: Urea; fumarate; H2O.
Steps in the Urea Cycle
1. Transport of nitrogen to the liver

Ammonia is very toxic, particularly to the central nervous system.
The concentration of ammonia and ammonium ions in the blood is normally very low.
(NH3 + H+ ↔ NH4+)

Ammonia travels to the liver from other tissues, mainly in the form of alanine and glutamine.
It is released from amino acids in the liver by a series of transamination and deamination reactions.
Ammonia is also produced by bacteria in the gut and travels to the liver via the hepatic portal vein.
2. Reactions of the urea cycle

NH4+ and aspartate provide the nitrogen that is used to produce urea, and CO2 provides the carbon. Ornithine serves as a carrier that is regenerated by the cycle.

Carbamoyl phosphate is synthesized in the first reaction from NH4+, CO2, and two ATP. Inorganic phosphate and two ADP are also produced.
Enzyme: carbamoyl phosphate synthetase I, which is located in mitochondria and is activated by N-acetylglutamate.
Ornithine reacts with carbamoyl phosphate to form citrulline. Inorganic phosphate is released.
Enzyme: ornithine transcarbamoylase, which is found in mitochondria. The product, citrulline, is transported to the cytosol in exchange for cytoplasmic ornithine.
Citrulline combines with aspartate to form argininosuccinate in a reaction that is driven by the hydrolysis of ATP to AMP and inorganic pyrophosphate.
Enzyme: Argininosuccinate synthetase
Argininosuccinate is cleaved to form arginine and fumarate.
Enzyme: argininosuccinate lyase. This reaction occurs in the cytosol.
The carbons of fumarate, which are derived from the aspartate added in reaction 3, can be converted to malate.
In the fasting state in the liver, malate can be converted to glucose or to oxaloacetate, which is transaminated to regenerate the aspartate required for reaction 3.
Arginine is cleaved to form urea and regenerate ornithine.
Enzyme: arginase, which is located primarily in the liver and is inhibited by ornithine.
Urea passes into the blood and is excreted by the kidneys.
Ornithine is transported back into the mitochondrion (in exchange for citrulline) where it can be used for another round of the cycle.
When the cell requires additional ornithine, it is synthesized from glucose via glutamate.
Arginine is a nonessential amino acid in adults. It is synthesized from glucose via ornithine and the first four reactions of the urea cycle.
Important enzymes in Urea Cycle
Carbamoyl phosphate synthetase I: Converts ammonium and bicarbonate into carbamoyl phosphate. This is the rate-limiting step in the urea cycle. This reaction requires two ATP and occurs in the mitochondria.
Ornithine transcarbamoylase: Combines ornithine and carbamoyl phosphate to form citrulline. Located in mitochondria.
Argininosuccinate synthetase: Condenses citrulline with aspartate to form arginosuccinate. This reaction occurs in the cytosol and requires one ATP.
Argininosuccinate lyase: Splits argininosuccinate into arginine and fumarate. Occurs in the cytosol.
Arginase: Cleaves arginine into one molecule of urea and ornithine in the cytosol. The ornithine is then transported back into the mitochondria for entry back into the cycle.
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Carbamoyl phosphate synthetase I catalyzes the rate-limiting step of the cycle and is stimulated by N -acetylglutamate.


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