Urea cycle
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adding czech interwiki
The '''urea cycle''' (also known as the '''ornithine cycle''') is a cycle of [[biochemistry|biochemical]] reactions occurring in many animals that produces [[urea]] ([[nitrogen|N]][[hydrogen|H]]<sub>2</sub>)<sub>2</sub>[[carbon|C]][[oxygen|O]] from [[ammonia]] (NH<sub>3</sub>). This cycle was the first metabolic cycle discovered ([[Hans Adolf Krebs|Krebs]] and Kurt Henseleit, 1932). In mammals, the urea cycle takes place only in the [[liver]].
==Function==
Organisms that cannot easily and quickly remove ammonia usually have to convert it to some other substance, like [[urea]] or [[uric acid]], which are much less toxic. Insufficiency of the urea cycle occurs in some [[genetic disorder]]s ([[inborn error of metabolism|inborn errors of metabolism]]), and in [[liver failure]]. The result of liver failure is accumulation of nitrogenous waste, mainly ammonia, which leads to [[hepatic encephalopathy]].
== Reactions ==
The urea cycle consists of five reactions - two [[mitochondria]]l and three [[cytosol]]ic. The cycle converts two amino groups, one from NH<sub>4</sub><sup>+</sup> and one from [[Aspartic acid|Asp]], and a carbon atom from HCO<sub>3</sub><sup>-</sup>, to relatively nontoxic excretion product, [[urea]], at the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one AMP). [[Ornithine|Orn]] is the carrier of these carbon and nitrogen atoms.
Reactions of cycle:
{| class="wikitable"
| '''Step''' || '''Reactant''' || '''Product''' || '''Catalyzed by''' || '''Location'''
|-
| 1 || 2[[Adenosine triphosphate|ATP]] + HCO<sub>3</sub><sup>-</sup> + NH<sub>4</sub><sup>+</sup> || [[carbamoyl phosphate]] + 2[[Adenosine diphosphate|ADP]] + P<sub>i</sub> || [[Carbamoyl phosphate synthetase 1|CPS1]] || mitochondria
|-
| 2 || [[carbamoyl phosphate]] + [[ornithine]] || [[citrulline]] + P<sub>i</sub> || [[Ornithine transcarbamoylase|OTC]] || mitochondria
|-
| 3 || [[citrulline]] + [[Aspartic acid|aspartate]] + [[Adenosine triphosphate|ATP]] || [[Arginosuccinic acid|argininosuccinate]] + [[Adenosine monophosphate|AMP]] + [[pyrophosphate|PP<sub>i</sub>]] || [[Argininosuccinate synthetase|ASS]] || cytosol
|-
| 4 || [[Arginosuccinic acid|argininosuccinate]] || [[Arginine|Arg]] + [[fumarate]] || [[Argininosuccinate lyase|ASL]] || cytosol
|-
| 5 || [[Arginine|Arg]] + H<sub>2</sub>O || [[ornithine]] + [[urea]] || [[Arginase 1|ARG1]] || cytosol
|}
[[Image:Urea cycle_2.png|thumb|450px|center|<div style="border-width: 0px; border-bottom: 1px solid black; text-align: left;">'''The reactions of the urea cycle'''.</div>The color scheme is as follows: <span style="font-weight: bold;"><span style="color: blue;">enzymes</span>, <span style="color: rgb(219,155,36);">coenzymes</span>, <span style="color: rgb(151,149,45);">substrate names</span>, <span style="color: rgb(128,0,0);">inorganic molecules</span>, <span style="color: red;">Asp and urea's nitrogen that comes from it</span>, <span style="color: green;">NH<sub>4</sub><sup>+</sup> and urea's nitrogen that comes from it</span>, <span style="color: rgb(125,125,233);">HCO<sub>3</sub><sup>-</sup> and urea's carbon that comes from it</span> </span>]]
Overall energy requirement:
* [[ammonia|NH<sub>3</sub>]] + [[carbon dioxide|CO<sub>2</sub>]] + [[Aspartate]] + 3 [[Adenosine triphosphate|ATP]] + 2 [[water|H<sub>2</sub>O]] → [[urea]] + [[Fumarate]] + 2 [[Adenosine diphosphate|ADP]] + 4 [[phosphate|P<sub>i</sub>]] + [[Adenosine monophosphate|AMP]]
Overall equation of the urea cycle:
* 2 [[ammonia|NH<sub>3</sub>]] + [[carbon dioxide|CO<sub>2</sub>]] + 3 [[Adenosine triphosphate|ATP]] + [[water|H<sub>2</sub>O]] → [[urea]] + 2 [[Adenosine diphosphate|ADP]] + 4 [[phosphate|P<sub>i</sub>]] + [[Adenosine monophosphate|AMP]] + 2 [[hydrogen|H]]
Note that reactions related to the urea cycle also cause the reduction of 2 [[NADH]], so the urea cycle releases slightly more energy than it consumes. These NADH are produced in two ways:
*One NADH molecule is reduced by the enzyme [[glutamate dehydrogenase]] in the conversion of glutamate to ammonium and [[α-ketoglutarate]]. [[Glutamate]] is the non-toxic carrier of amine groups. This provides the ammonium ion used in the initial synthesis of carbamoyl phosphate.
*The fumarate released in the cytosol is converted to [[malate]] by cytosolic [[fumarase]]. This malate is then converted to [[oxaloacetate]] by cytosolic [[malate dehydrogenase]], generating a reduced NADH in the cytosol. [[Oxaloacetate]] is one of the keto acids preferred by [[transaminase]]s, and so will be recycled to [[aspartate]], maintained the flow of nitrogen into the urea cycle.
The two NADH produced can provide energy for the formation of 5 [[Adenosine triphosphate|ATP]], a net production of one high energy phosphate bond for the urea cycle. However, if [[gluconeogenesis]] is underway in the cytosol, the latter reducing equivalent is used to drive the reversal of the [[GAPDH]] step instead of generating ATP.
The fate of oxaloacetate is either to produce aspartate via oxidative deamination or to be converted to phosphoenol pyruvate, which is a substrate to glucose.()
An excellent way to memorize the Urea Cycle is to remember the phrase "Ordinarily Careless Crappers Are Also Frivolous About Urination." The first letter of each word corresponds to the order in which reactants are combined to give products or intermediates that break apart as one progresses through the cycle.
== Regulation ==
===N-Acetylglutamic acid===
The synthesis of carbamoyl phosphate and the urea cycle are dependent on the presence of [[NAcGlu]], which [[allosterically]] activates CPS1. Synthesis of NAcGlu by [[Protein:NAGS|NAGS]], is stimulated by Arg - allosteric stimulator of NAGS, and Glu - a product in the transamination reactions and one of NAGS's substrates, both of which are elevated when free [[amino acids]] are elevated. So, Arg is not only a substrate for the urea cycle reactions but also serves as an activator for the urea cycle.
===Substrate concentrations===
The remaining enzymes of the cycle are controlled by the concentrations of their substrates. Thus, inherited deficiencies in the cycle enzymes other than [[Protein:ARG1|ARG1]] do not result in significant decrease in urea production (the total lack of any cycle enzyme results in death shortly after birth). Rather, the deficient enzyme's substrate builds up, increasing the rate of the deficient reaction to normal.
The anomalous substrate buildup is not without cost, however. The substrate concentrations become elevated all the way back up the cycle to NH<sub>4</sub><sup>+</sup>, resulting in [[hyperammonemia]] (elevated [NH<sub>4</sub><sup>+</sup>]<sub>P</sub>).
Although the root cause of NH<sub>4</sub><sup>+</sup> toxicity is not completely understood, a high [NH<sub>4</sub><sup>+</sup>] puts an enormous strain on the NH<sub>4</sub><sup>+</sup>-clearing system, especially in the [[brain]] (symptoms of urea cycle enzyme deficiencies include [[mental retardation]] and [[lethargy]]). This clearing system involves [[Protein:GLUD1|GLUD1]] and [[Protein:GLUL|GLUL]], which decrease the [[2OG]] and Glu pools. The brain is most sensitive to the depletion of these pools. Depletion of 2OG decreases the rate of [[TCAC]], whereas Glu is both a [[neurotransmitter]] and a precursor to [[GABA]], another neurotransmitter. [http://www.wiley.com/college/math/chem/cg/sales/voet.html]''(p.734)''
==Pathology==
Diseases associated with the urea cycle include:
[[Citrullinemia]],
[[Hyperammonemia]],
[[Ornithine translocase deficiency]],
[[N-Acetylglutamate synthase deficiency]]
Check out this wiki summary page: [[urea cycle disorders]]
==Additional images==
<gallery>
Image:Urea-Cycle scheme 2006-01.svg|Urea cycle.
</gallery>
==External links==
*[http://www.ufp.pt/~pedros/bq/urea.htm The chemical logic behind the urea cycle]
*[http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.figgrp.3102 ''Basic Neurochemistry''] - amino acid disorders
{{urea cycle}}
{{Urea cycle enzymes}}
[[Category:Metabolic pathways]]
[[Category:Nitrogen metabolism]]
[[ar:دورة يوريا]]
[[cs:močovinový cyklus]]
[[de:Harnstoffzyklus]]
[[es:Ciclo de la urea]]
[[fr:Cycle de l'urée]]
[[it:Ciclo dell'urea]]
[[ja:尿素回路]]
[[pl:Cykl ornitynowy]]
[[pt:Ciclo da uréia]]
[[ru:Цикл мочевины]]
[[sl:Ciklus sečnine]]
[[sr:Циклус урее]]
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[[zh:尿素循环]]