WordNet

pass through a cycle; "This machine automatically cycles"
an interval during which a recurring sequence of events occurs; "the never-ending cycle of the seasons" (同)rhythm, round
recur in repeating sequences
a single complete execution of a periodically repeated phenomenon; "a year constitutes a cycle of the seasons" (同)oscillation
a periodically repeated sequence of events; "a cycle of reprisal and retaliation"
a series of poems or songs on the same theme; "Schuberts song cycles"
cause to go through a recurring sequence; "cycle the laundry in this washing program"
the chief solid component of mammalian urine; synthesized from ammonia and carbon dioxide and used as fertilizer and in animal feed and in plastics (同)carbamide
the sport of traveling on a bicycle or motorcycle

PrepTutorEJDIC

『周期』,循環期;一巡り / 周波,サイクル / (英雄・伝説などを扱った)一連の詩(物語) / 『自転車』;三輪車;オートバイ / 自転車に乗る / 循環する,反復する
尿素(にょうそ)
自転車に乗ること,サイクリング

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/05/12 01:13:21」(JST)

wiki en

The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions occurring in many animals that produces urea ((NH₂)₂CO) from ammonia (NH₃). This cycle was the first metabolic cycle discovered (Hans Krebs and Kurt Henseleit, 1932), five years before the discovery of the TCA cycle. In mammals, the urea cycle takes place primarily in the liver, and to a lesser extent in the kidney.

Function [edit]

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 disorders (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 [edit]

The urea cycle consists of five reactions: two mitochondrial and three cytosolic. The cycle converts two amino groups, one from NH₄⁺ and one from Asp, 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). Ornithine is the carrier of these carbon and nitrogen atoms.

Reactions of the urea cycle
Step	Reactants	Products	Catalyzed by	Location
1	NH₄⁺ + HCO₃⁻ + 2ATP	carbamoyl phosphate + 2ADP + P_i	CPS1	mitochondria
2	carbamoyl phosphate + ornithine	citrulline + P_i	OTC	mitochondria
3	citrulline + aspartate + ATP	argininosuccinate + AMP + PP_i	ASS	cytosol
4	argininosuccinate	Arg + fumarate	ASL	cytosol
5	Arg + H₂O	ornithine + urea	ARG1	cytosol

The reactions of the urea cycle

1 L-ornithine
2 carbamoyl phosphate
3 L-citrulline
4 argininosuccinate
5 fumarate
6 L-arginine
7 urea
L-Asp L-aspartate
CPS-1 carbamoyl phosphate synthetase I
OTC Ornithine transcarbamoylase
ASS argininosuccinate synthetase
ASL argininosuccinate lyase
ARG1 arginase 1

In the first reaction, NH₄⁺ + HCO₃⁻ is equivalent to NH₃ + CO₂ + H₂O.

Thus, the overall equation of the urea cycle is:

NH₃ + CO₂ + aspartate + 3 ATP + 2 H₂O → urea + fumarate + 2 ADP + 2 P_i + AMP + PP_i

Since fumarate is obtained by removing NH₃ from aspartate (by means of reactions 3 and 4), and PP_i + H₂O → 2 P_i, the equation can be simplified as follows:

2 NH₃ + CO₂ + 3 ATP + H₂O → urea + 2 ADP + 4 P_i + AMP

Note that reactions related to the urea cycle also cause the production 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 transaminases, and so will be recycled to aspartate, maintaining the flow of nitrogen into the urea cycle.

The two NADH produced can provide energy for the formation of 4 ATP(cytosolic NADH provides only 1.5 ATP due to the glycerol-3-phosphate shuttle who transfers the electrons from cytosolic NADH to FADH2 and that gives 1.5 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 transamination or to be converted to phosphoenol pyruvate, which is a substrate to glucose.

Regulation [edit]

N-Acetylglutamic acid [edit]

The synthesis of carbamoyl phosphate and the urea cycle are dependent on the presence of NAcGlu, which allosterically activates CPS1. Synthesis of NAcGlu by NAGS, is stimulated by both 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, Glu is not only a substrate for NAGS but also serves as an activator for the urea cycle.

Substrate concentrations [edit]

The remaining enzymes of the cycle are controlled by the concentrations of their substrates. Thus, inherited deficiencies in the cycle enzymes other than 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 NH₄⁺, resulting in hyperammonemia (elevated [NH₄⁺]_P).

Although the root cause of NH₄⁺ toxicity is not completely understood, a high [NH₄⁺] puts an enormous strain on the NH₄⁺-clearing system, especially in the brain (symptoms of urea cycle enzyme deficiencies include mental retardation and lethargy). This clearing system involves GLUD1 and GLUL, which decrease the 2-oxoglutarate (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. [1](p.734)

Pathology [edit]

Anomalies of the urea cycle cause urea cycle disorders:

ornithine transcarbamoylase deficiency
Carbamoyl phosphate synthetase deficiency
Argininosuccinic aciduria
Argininemia
Hyperornithinemia, hyperammonemia, homocitrullinuria syndrome (HHH syndrome, ornithine translocase deficiency)
Lysinuric protein intolerance
Citrullinemia
N-Acetylglutamate synthase deficiency

Most of them are associated with hyperammonemia.

Additional images [edit]

Urea cycle.
Urea cycle colored.

External links [edit]

The chemical logic behind the urea cycle
Basic Neurochemistry - amino acid disorders

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 尿素サイクル障害：臨床的特徴および診断 urea cycle disorders clinical features and diagnosis
2. 尿素サイクル障害：管理 urea cycle disorders management
3. 先天性代謝異常：疫学、病因、および臨床的特徴 inborn errors of metabolism epidemiology pathogenesis and clinical features
4. 遺伝性運動失調の概要 overview of the hereditary ataxias
5. 先天性代謝異常：代謝性救急疾患 inborn errors of metabolism metabolic emergencies

English Journal

Proteome Reference Map of Haloarcula hispanica and Comparative Proteomic and Transcriptomic Analysis of Polyhydroxyalkanoate Biosynthesis under Genetic and Environmental Perturbations.

Liu H, Luo Y, Han J, Wu J, Wu Z, Feng D, Cai S, Li M, Liu J, Zhou J, Xiang H.SourceState Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences , No.1 West Beichen Road, Chaoyang District, Beijing 100101, China.
Journal of proteome research.J Proteome Res.2013 Mar 1;12(3):1300-15. doi: 10.1021/pr300969m. Epub 2013 Jan 25.
Many haloarchaea are known as polyhydroxyalkanoates (PHAs) producers, but a global and integrated view of the PHA biosynthesis is still lacking in this group of archaea. In this study, a combined proteomic and transcriptomic approach was employed in Haloarcula hispanica, a model haloarchaeon that ac
PMID 23301558

Histopathological findings in livers of patients with urea cycle disorders.

Yaplito-Lee J, Chow CW, Boneh A.SourceMetabolic Genetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia. Electronic address: joy.yaplito-lee@vcgs.org.au.
Molecular genetics and metabolism.Mol Genet Metab.2013 Mar;108(3):161-5. doi: 10.1016/j.ymgme.2013.01.006. Epub 2013 Jan 23.
BACKGROUND: Urea cycle disorders (UCD) are caused by genetic defects in enzymes that constitute the hepatic ammonia detoxification pathway. Patients may present with variable clinical manifestations and with hyperammonaemia. Liver abnormalities have been associated with UCD, but only a few reports o
PMID 23403242

Japanese Journal

大豆たん白質が代謝と行動の日周リズムに及ぼす効果に関する研究 (第14回研究報告会記録)

瀧口正樹,松本絵里子,大平綾乃 [他]
大豆たん白質研究 14 (32), 32-37, 2012-03
NAID 40019293843

脂肪酸生合成におけるエノイルACP還元酵素FabIとFabK阻害による抗菌薬の探索

小澤智宏,高畑祥,北川英男
有機合成化学協会誌 70(3), 265-275, 2012
… Bacterial enoyl-acyl carrier protein (ACP) reductases (FabI and FabK) catalyze the final step in each cycle of fatty acid biosynthesis and are attractive targets for the development of new antibacterial agents. … A representative compound, 1-{[4-(4-bromophenyl)-1H-imidazol-2-yl]methyl}-3-[5-(pyridin-2-ylthio)thiazol-2-yl]urea (53) showed strong FabK-inhibitory activity (S. …
NAID 130002143011

Related Pictures

★リンクテーブル★

リンク元	「オルニチン回路」
拡張検索	「disorder of urea cycle metabolism」「urea cycle disorders」「urea cycle enzyme deficiency」
関連記事	「cycle」「cycling」

「オルニチン回路」

　　[★]

英: ornithine cycle
同: 尿素サイクル尿素回路 urea cycle、クレブス-ヘンゼライト回路 Krebs-Henseleit cycle、オルニチンサイクル
関: オルニチン、尿素

オルニチン回路に含まれる分子はアミノ酸である：アミノ基とカルボン酸を両方持つもの
最終産物である尿素の窒素は、アンモニアとアスパラギン酸に由来する

ミトコンドリア内の反応

1) アンモニア + 炭酸 + 2ATP → ADP + Pi + カルバモイルリン酸 
　　　　　　　　　　　　5)から
　　　　　　　　　　　　↓
2) カルバモイルリン酸 + オルニチン → シトルリン + Pi 
　　　　　　　　　　　　　　　　　　　↓
　　　　　　　　　　　　　　　　　　　3)へ

サイトソルの反応

　　2)から
　　↓
3) シトルリン + アスパラギン酸 + ATP → AMP + ピロリン酸 + アルギニノコハク酸 
4) アルギニノコハク酸 → フマル酸 + アルギニン 
5) アルギニン + 水 → 尿素 + オルニチン 
　　　　　　　　　　　　　　　↓
　　　　　　　　　　　　　　　2)へ

|
ornithine
|
----------mitochondria
|
ornithine
|
|<-carbamoyl phosphate {ornithine transcarbamoylase}
|
citrulline
|
----------mitochondria
|
citrulline
|
|<-aspartate {argininosuccinate synthase}
|
argininosuccinate
| 
|->fumarate {argininosuccinase}
|
arginine
|
|<-H2O
|           {arginase}
|->urea
|
ornithine
|