Urea cycle - Revision history

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	[[Category:Metabolic pathways]]		[[Category:Metabolic pathways]]
	[[Category:Biochemistry]]		[[Category:Biochemistry]]
			<gallery>
			File:Urea_cycle.svg\|Diagram of the Urea Cycle
			File:Urea-Cycle_scheme_2006-01.svg\|Urea Cycle Scheme 2006
			File:Urea_cycle_2.png\|Urea Cycle
			</gallery>

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← Older revision		Revision as of 00:02, 10 February 2025
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	~~'''~~Urea cycle''' is a series of biochemical reactions that produces urea from ammonia. This cycle occurs in ureotelic organisms. The urea cycle was the first metabolic cycle to be discovered (Hans Krebs and Kurt Henseleit, 1932), five years before the discovery of the TCA cycle. This cycle is also known as the '''ornithine cycle'''.		== Urea Cycle ==

	~~== Overview ==~~		[[File:Urea_cycle.svg\|thumb\|Diagram of the urea cycle]]
	~~The~~ urea cycle ~~consists of five reactions~~: ~~two mitochondrial and three cytosolic~~. ~~The cycle converts two amino groups, one from NH4+ and one from Aspartate, and a carbon atom from HCO3-, to~~ the ~~relatively nontoxic excretion product~~ urea ~~at the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one AMP).~~		[[File:Urea-Cycle_scheme_2006-01.svg\|thumb\|Alternative schematic of the urea cycle]]
			[[File:Urea_cycle_2.png\|thumb\|Another representation of the urea cycle]]

	~~== Reactions ==~~		The '''urea cycle''' is a series of biochemical reactions that produce [[urea]] ((NH_)_CO) from [[ammonia]] (NH_). This cycle occurs in the [[liver]] and is essential for the removal of excess nitrogen from the body. The urea cycle is also known as the ornithine cycle, named after one of its key intermediates, [[ornithine]].
	The reactions of the cycle ~~are~~ as ~~follows:~~

	~~1. '''Carbamoyl phosphate synthetase I''' (CPS1) catalyzes~~ the ~~condensation of ammonia~~ and ~~bicarbonate to form carbamoyl phosphate~~. This ~~is the rate-limiting step of the urea cycle. The reaction requires two molecules of ATP~~, ~~one~~ of ~~which is hydrolyzed to AMP and pyrophosphate~~.		== History ==
			The urea cycle was the first metabolic cycle to be discovered, identified by [[Hans Krebs]] and [[Kurt Henseleit]] in 1932. This discovery was pivotal in understanding how organisms detoxify ammonia, a byproduct of protein metabolism.

	~~2. '''Ornithine transcarbamylase''' (OTC) catalyzes the condensation~~ of ~~ornithine and carbamoyl phosphate to form citrulline~~, ~~with the release of phosphate.~~		== Biochemical Pathway ==
			The urea cycle consists of five main steps, each catalyzed by a specific enzyme:

	3. '''~~Argininosuccinate~~ synthetase''' ~~(ASS)~~ catalyzes the ~~condensation~~ of ~~citrulline and aspartate~~ to form ~~argininosuccinate, with~~ the ~~release of AMP and pyrophosphate~~. ~~This reaction~~ is ~~driven to completion by the hydrolysis~~ of the ~~pyrophosphate, catalyzed by inorganic pyrophosphatase~~.		# '''Carbamoyl phosphate synthetase I''': This enzyme catalyzes the reaction of ammonia with bicarbonate to form carbamoyl phosphate. This step occurs in the [[mitochondria]].
			# '''Ornithine transcarbamylase''': Carbamoyl phosphate reacts with ornithine to form [[citrulline]], which is then transported out of the mitochondria.
	4. '''Argininosuccinate lyase''' ~~(ASL) catalyzes the cleavage of argininosuccinate~~ to form arginine and fumarate.		# '''Argininosuccinate synthetase''': Citrulline combines with [[aspartate]] to form argininosuccinate.
			# '''Argininosuccinate lyase''': Argininosuccinate is cleaved to form [[arginine]] and [[fumarate]].
	5. '''Arginase''' ~~(ARG1) catalyzes the hydrolysis of arginine~~ to form ~~ornithine~~ and ~~urea. The~~ ornithine ~~is transported back to the mitochondria to begin~~ the cycle ~~again~~.		# '''Arginase''': Arginine is hydrolyzed to form urea and regenerate ornithine, which re-enters the cycle.

	== Regulation ==		== Regulation ==
	The urea cycle is regulated ~~at two levels. The first level of regulation is~~ by ~~substrate~~ availability~~. If there is an excess~~ of ~~dietary protein, then there will be an increase in~~ the ~~amino acids that are metabolized to form urea. The second level~~ of ~~regulation is through allosteric regulation~~. N-acetylglutamate is an essential ~~allosteric~~ activator of ~~CPS1~~ in ~~mammals, and it is produced from glutamate and acetyl-CoA by~~ the ~~enzyme N-acetylglutamate synthase (NAGS). NAGS is activated by arginine, so when dietary protein is high, arginine concentrations increase, stimulating the production~~ of ~~N-acetylglutamate, which in turn activates CPS1 and~~ the ~~urea~~ cycle.		The urea cycle is regulated by the availability of its substrates and by the activity of its enzymes. N-acetylglutamate acts as an essential activator of carbamoyl phosphate synthetase I, thus playing a crucial role in the regulation of the cycle.

	== Clinical ~~significance~~ ==		== Clinical Significance ==
	Deficiencies in the enzymes of the urea cycle lead to urea cycle disorders ~~(UCDs). UCDs are a group of rare genetic disorders that affect~~ the ~~body's ability to get rid~~ of ammonia. Symptoms ~~of UCDs~~ include ~~a decreased level of consciousness, poor feeding~~, vomiting~~, seizures~~, and ~~coma. These disorders are usually diagnosed~~ in ~~infancy and early childhood~~.		Deficiencies in any of the enzymes of the urea cycle can lead to urea cycle disorders, which result in the accumulation of ammonia in the blood, a condition known as [[hyperammonemia]]. Symptoms can range from mild to severe and may include lethargy, vomiting, and in severe cases, neurological damage.

	== ~~See also~~ ==		== Related Pages ==
	* [[Amino acid metabolism]]
	* [[Ammonia]]		* [[Ammonia]]
	* [[~~Urea~~]]		* [[Liver]]
	* [[~~Urea cycle disorder~~]]		* [[Metabolism]]
	* [[~~Hans Adolf Krebs]]~~		* [[Ornithine]]
	* [[Kurt Henseleit]]

	== References ==		== References ==
	~~<references />~~		* Krebs, H. A., & Henseleit, K. (1932). "Studies on the urea cycle." Biochemische Zeitschrift, 210, 33-66.
			* Brusilow, S. W., & Horwich, A. L. (2001). "Urea cycle enzymes." In The Metabolic and Molecular Bases of Inherited Disease (8th ed.).

	[[Category:Metabolic pathways]]		[[Category:Metabolic pathways]]
	[[Category:~~Urea cycle~~]]		[[Category:Biochemistry]]
	~~[[Category:Ammonia metabolism]]~~
	~~[[Category:Urea]]~~

	~~{{stub}}~~

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'''Urea cycle''' is a series of biochemical reactions that produces urea from ammonia. This cycle occurs in ureotelic organisms. The urea cycle was the first metabolic cycle to be discovered (Hans Krebs and Kurt Henseleit, 1932), five years before the discovery of the TCA cycle. This cycle is also known as the '''ornithine cycle'''.

== Overview ==
The urea cycle consists of five reactions: two mitochondrial and three cytosolic. The cycle converts two amino groups, one from NH4+ and one from Aspartate, and a carbon atom from HCO3-, to the relatively nontoxic excretion product urea at the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one AMP).

== Reactions ==
The reactions of the cycle are as follows:

1. '''Carbamoyl phosphate synthetase I''' (CPS1) catalyzes the condensation of ammonia and bicarbonate to form carbamoyl phosphate. This is the rate-limiting step of the urea cycle. The reaction requires two molecules of ATP, one of which is hydrolyzed to AMP and pyrophosphate.

2. '''Ornithine transcarbamylase''' (OTC) catalyzes the condensation of ornithine and carbamoyl phosphate to form citrulline, with the release of phosphate.

3. '''Argininosuccinate synthetase''' (ASS) catalyzes the condensation of citrulline and aspartate to form argininosuccinate, with the release of AMP and pyrophosphate. This reaction is driven to completion by the hydrolysis of the pyrophosphate, catalyzed by inorganic pyrophosphatase.

4. '''Argininosuccinate lyase''' (ASL) catalyzes the cleavage of argininosuccinate to form arginine and fumarate.

5. '''Arginase''' (ARG1) catalyzes the hydrolysis of arginine to form ornithine and urea. The ornithine is transported back to the mitochondria to begin the cycle again.

== Regulation ==
The urea cycle is regulated at two levels. The first level of regulation is by substrate availability. If there is an excess of dietary protein, then there will be an increase in the amino acids that are metabolized to form urea. The second level of regulation is through allosteric regulation. N-acetylglutamate is an essential allosteric activator of CPS1 in mammals, and it is produced from glutamate and acetyl-CoA by the enzyme N-acetylglutamate synthase (NAGS). NAGS is activated by arginine, so when dietary protein is high, arginine concentrations increase, stimulating the production of N-acetylglutamate, which in turn activates CPS1 and the urea cycle.

== Clinical significance ==
Deficiencies in the enzymes of the urea cycle lead to urea cycle disorders (UCDs). UCDs are a group of rare genetic disorders that affect the body's ability to get rid of ammonia. Symptoms of UCDs include a decreased level of consciousness, poor feeding, vomiting, seizures, and coma. These disorders are usually diagnosed in infancy and early childhood.

== See also ==
* [[Amino acid metabolism]]
* [[Ammonia]]
* [[Urea]]
* [[Urea cycle disorder]]
* [[Hans Adolf Krebs]]
* [[Kurt Henseleit]]

== References ==
<references />

[[Category:Metabolic pathways]]
[[Category:Urea cycle]]
[[Category:Ammonia metabolism]]
[[Category:Urea]]

{{stub}}