Editing Urea cycle (section)

==Reactions==
The entire process converts two amino groups, one from {{chem|NH|4|+}} and one from [[Aspartic acid|aspartate]], and a carbon atom from {{chem|HCO|3|-}}, to the relatively nontoxic excretion product [[urea]].<ref name=":2">{{Citation|last1=Mew|first1=Nicholas Ah|title=Chapter 57 - Urea Cycle Disorders|date=2015-01-01|url=http://www.sciencedirect.com/science/article/pii/B9780124105294000577|work=Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition)|pages=633–647|editor-last=Rosenberg|editor-first=Roger N.|place=Boston|publisher=Academic Press|language=en|doi=10.1016/b978-0-12-410529-4.00057-7|isbn=978-0-12-410529-4|access-date=2020-11-10|last2=Pappa|first2=Maria Belen|last3=Gropman|first3=Andrea L.|editor2-last=Pascual|editor2-first=Juan M.}}</ref> This occurs at the cost of four "high-energy" [[phosphate]] bonds (3 ATP hydrolyzed to 2 [[Adenosine diphosphate|ADP]] and one [[Adenosine monophosphate|AMP]]). The conversion from ammonia to urea happens in five main steps. The first is needed for ammonia to enter the cycle and the following four are all a part of the cycle itself. To enter the cycle, ammonia is converted to [[carbamoyl phosphate]]. The urea cycle consists of four enzymatic reactions: one [[mitochondria]]l and three [[cytosol]]ic.<ref name=":0" /><ref name=":3">{{Citation|last=Walker|first=Valerie|title=Chapter Three - Ammonia Metabolism and Hyperammonemic Disorders|date=2014-01-01|url=http://www.sciencedirect.com/science/article/pii/S0065242314000031|journal=Advances in Clinical Chemistry|volume=67|pages=73–150|editor-last=Makowski|editor-first=Gregory S.|publisher=Elsevier|language=en|doi=10.1016/bs.acc.2014.09.002|pmid=25735860|access-date=2020-11-10}}</ref> This uses 6 enzymes.<ref name=":2" /><ref name=":3" /><ref name=":4">{{Citation |last=Pearl |first=Phillip L. |title=76 - Inherited Metabolic Epilepsies |date=2017-01-01 |work=Swaiman's Pediatric Neurology (Sixth Edition) |pages=594–599 |editor-last=Swaiman |editor-first=Kenneth F. |url=http://www.sciencedirect.com/science/article/pii/B978032337101800076X |access-date=2020-11-10 |publisher=Elsevier |language=en |doi=10.1016/b978-0-323-37101-8.00076-x |isbn=978-0-323-37101-8 |editor2-last=Ashwal |editor2-first=Stephen |editor3-last=Ferriero |editor3-first=Donna M. |editor4-last=Schor |editor4-first=Nina F. |editor3-link=Donna Ferriero}}</ref>

{| class="wikitable"
 |+ Reactions of the urea cycle
 ! Step || Reactants || Products || Catalyzed by || Location
 |-
 ! 1
 | NH<sub>3</sub> + {{chem|HCO|3|-}} + 2[[Adenosine triphosphate|ATP]] || [[carbamoyl phosphate]] + 2[[Adenosine diphosphate|ADP]] + [[Phosphate#Biochemistry of phosphates|P<sub>i</sub>]]  || [[Carbamoyl phosphate synthetase I|CPS1]] || mitochondria
 |-
 ! 2
 | [[carbamoyl phosphate]] + [[ornithine]] || [[citrulline]] + P<sub>i</sub>  || [[ornithine transcarbamylase|OTC]], zinc, biotin || 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]] + [[fumarate]]  || [[Argininosuccinate lyase|ASL]] || cytosol
 |-
 ! 5
 | [[arginine]] + H<sub>2</sub>O || [[ornithine]] + [[urea]]  || [[Arginase 1|ARG1]], manganese|| cytosol
|}

<blockquote>
::'''The reactions of the urea cycle'''
[[File:Urea cycle.svg|class=skin-invert-image|thumb|480px|left]]

1 <small>L</small>-[[ornithine]]<br>2 [[carbamoyl phosphate]]<br>3 <small>L</small>-[[citrulline]]<br>4 [[argininosuccinate]]<br>5 [[fumarate]]<br>6 <small>L</small>-[[arginine]]<br>7 [[urea]]<br> <small>L</small>-Asp <small>L</small>-[[aspartate]]<br>CPS-1 [[carbamoyl phosphate synthetase I]]<br>OTC [[Ornithine transcarbamoylase]]<br>ASS [[argininosuccinate synthetase]]<br>ASL [[argininosuccinate lyase]]<br>ARG1 [[Arginase|arginase 1]]
</blockquote>
{{clear}}

=== First reaction: entering the urea cycle ===
Before the urea cycle begins ammonia is converted to carbamoyl phosphate. The reaction is catalyzed by [[carbamoyl phosphate synthetase I]] and requires the use of two [[Adenosine triphosphate|ATP]] molecules.<ref name=":0" /> The carbamoyl phosphate then enters the urea cycle.

=== Steps of the urea cycle ===
# Carbamoyl phosphate is converted to [[citrulline]]. With catalysis by [[ornithine transcarbamylase]], the carbamoyl phosphate group is donated to ornithine and releases a phosphate group.<ref name=":0" />
# A [[condensation reaction]] occurs between the amino group of aspartate and the carbonyl group of citrulline to form [[argininosuccinic acid|argininosuccinate]]. This reaction is ATP dependent and is catalyzed by [[Argininosuccinate synthase|argininosuccinate synthetase]].<ref name=":0" />
# Argininosuccinate undergoes cleavage by [[Argininosuccinate lyase|argininosuccinase]] to form [[arginine]] and [[fumarate]].<ref name=":0" />
# Arginine is cleaved by [[arginase]] to form urea and ornithine. The ornithine is then transported back to the mitochondria to begin the urea cycle again.<ref name=":0" /><ref name=":3" />

=== Overall reaction equation ===
In the first reaction, {{chem|NH|4|+}} + {{chem|HCO|3|-}} is equivalent to [[Ammonia|NH<sub>3</sub>]] + [[Carbon dioxide|CO<sub>2</sub>]] + [[Water|H<sub>2</sub>O]].

Thus, the overall equation of the urea cycle is:
* [[Ammonia|NH<sub>3</sub>]] + [[Carbon dioxide|CO<sub>2</sub>]] + [[aspartate]] + 3 [[Adenosine triphosphate|ATP]] + 3 [[Water|H<sub>2</sub>O]] → [[urea]] + [[fumarate]] + 2 [[Adenosine diphosphate|ADP]] + 2 [[Phosphate|P<sub>i</sub>]] + [[Adenosine monophosphate|AMP]] + [[Pyrophosphate|PP<sub>i</sub>]] + [[Water|H<sub>2</sub>O]]
Since fumarate is obtained by removing NH<sub>3</sub> from aspartate (by means of reactions 3 and 4), and PP<sub>i</sub> + H<sub>2</sub>O → 2 P<sub>i</sub>, the equation can be simplified as follows:
* 2 [[Ammonia|NH<sub>3</sub>]] + [[Carbon dioxide|CO<sub>2</sub>]] + 3 [[Adenosine triphosphate|ATP]] + 3 [[Water|H<sub>2</sub>O]] → [[urea]] + 2 [[Adenosine diphosphate|ADP]] + 4 [[Phosphate|P<sub>i</sub>]] + [[Adenosine monophosphate|AMP]]
Note that reactions related to the urea cycle also cause the production of 2 [[NADH]], so the overall reaction releases slightly more energy than it consumes. The NADH is produced in two ways:
* One NADH molecule is produced 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 hydrated to [[malate]] by cytosolic [[fumarase]]. This malate is then oxidized 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]], maintaining the flow of nitrogen into the urea cycle.
We can summarize this by combining the reactions:
* CO<sub>2</sub> + [[glutamate]] + [[aspartate]] + 3 ATP + 2 NAD<sup>+</sup>+ 3 H<sub>2</sub>O → [[urea]] + [[α-ketoglutarate]] + [[oxaloacetate]] + 2 ADP + 2 P<sub>i</sub> + AMP + PP<sub>i</sub> + 2 NADH
The two NADH produced can provide energy for the formation of 5 [[Adenosine triphosphate|ATP]] (cytosolic NADH provides 2.5 ATP with the malate-aspartate shuttle in human liver cell), a net production of two 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 transamination or to be converted to [[Phosphoenolpyruvic acid|phosphoenolpyruvate]], which is a substrate for [[gluconeogenesis]].<!--
An excellent way to memorize the Urea Cycle is to remember the [[mnemonic]] phrase "Ordinarily Careless Crappers Are Also Frivolous About Urination." The first letter of each word corresponds to the first letter of each of the main reactants or products that are combined with each other or produced as one progresses through the five reactions of the cycle (Ornithine, Carbamoyl phosphate, Citrulline, Aspartate, Argininosuccinate, Fumarate, Arginine, Urea).-->