ornithine transcarbamylase

同

OTC

WordNet

1. an amino acid that does not occur in proteins but is important in the formation of urea

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/06/09 02:08:23」(JST)

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Ornithine carbamoyltransferase
Human OTC trimer. From PDB 1OTH.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1C9Y, 1EP9, 1FVO, 1OTH
Identifiers
Symbols	OTC ; OCTD
External IDs	OMIM: 300461 MGI: 97448 HomoloGene: 446 ChEMBL: 2222 GeneCards: OTC Gene
EC number	2.1.3.3
Gene ontology Molecular function • ornithine carbamoyltransferase activity • phospholipid binding • amino acid binding • phosphate ion binding Cellular component • mitochondrion • mitochondrial inner membrane • mitochondrial matrix Biological process • urea cycle • liver development • arginine biosynthetic process • ornithine catabolic process • midgut development • response to zinc ion • citrulline biosynthetic process • response to insulin • cellular nitrogen compound metabolic process • response to drug • small molecule metabolic process • protein homotrimerization • response to biotin • ammonia homeostasis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5009	18416
Ensembl	ENSG00000036473	ENSMUSG00000031173
UniProt	P00480	P11725
RefSeq (mRNA)	NM_000531	NM_008769
RefSeq (protein)	NP_000522	NP_032795
Location (UCSC)	Chr X: 38.21 – 38.28 Mb	Chr X: 10.25 – 10.32 Mb
PubMed search	[1]	[2]

Ornithine transcarbamylase (OTC) (also called ornithine carbamoyltransferase) is an enzyme that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (P_i). In plants and microbes, OTC is involved in arginine (Arg) biosynthesis, whereas in mammals it is located in the mitochondria and is part of the urea cycle.

Structure

OTC is a trimer. The monomer unit has a CP-binding domain and an amino acid-binding domain. Each of the two discrete substrate-binding domains (SBDs) have an α/β topology with a central β-pleated sheet embedded in flanking α-helices.

The active sites are located at the interface between the protein monomers.

Genomics

The gene is located on the short arm of chromosome X (Xp21.1). The gene is located in the Watson (plus) strand and is 68,968 bases in length. The encoded protein is 354 amino acids long with a predicted molecular weight of 39.935 kiloDaltons. The protein is located in the mitochondrial matrix.

Function

The reaction mechanism of OTC.

The side-chain amino group of Orn attacks the carbonyl carbon of CP nucleophilically, left, to form a tetrahedral transition state, middle. Charge rearrangement releases Cit and P_i, right.

Deficiency

Main article: Ornithine transcarbamylase deficiency

OTC monomer

If a person is deficient in OTC, ammonia levels will build up, and this will cause neurological problems. Levels of the amino acids glutamate and alanine will be increased (as these are the amino acids that receive nitrogen from others).

Because newborns are usually discharged from the hospital within 1–2 days after birth, the symptoms of a urea cycle disorder are often not seen until the child is at home and may not be recognized in a timely manner by the family and primary-care physician. The typical initial symptoms of a child with hyperammonemia are non-specific: failure to feed, loss of thermoregulation with a low core temperature, and somnolence. Symptoms progress from somnolence to lethargy and coma. Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure upon the brainstem. About 50% of neonates with severe hyperammonemia have seizures.

Hyperventilation, secondary to cerebral edema, is a common early finding in a hyperammonemic attack, which causes a respiratory alkalosis. Hypoventilation and respiratory arrest follow, as pressure increases on the brainstem. In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be triggered by illness or stress at almost any time of life, resulting in multiple mild elevations of plasma ammonia concentration [Bourrier et al. 1988]. The hyperammonemia is less severe and the symptoms more subtle. In patients with partial enzyme deficiencies, the first recognized clinical episode may be delayed for months or years. One in 70000 adults has an ornithine transcarbamylase deficiency.

Levels of urea cycle intermediates may be decreased, as carbamoyl phosphate cannot replenish the cycle. The carbamoyl phosphate instead goes into the uridine monophosphate synthetic pathway. Here, orotic acid (one step of this alternative pathway) levels in the blood are increased.

A potential treatment for the high ammonia levels is to give sodium benzoate, which combines with glycine to produce hippurate, at the same time removing an ammonium group. Biotin also plays an important role in the functioning of the OTC enzyme and has been shown to reduce ammonia intoxication in animal experiments.

References

Further reading

• Tuchman M, Plante RJ (1995). "Mutations and polymorphisms in the human ornithine transcarbamylase gene: mutation update addendum". Hum. Mutat. 5 (4): 293–5. doi:10.1002/humu.1380050404. PMID 7627182. 
• Tuchman M (1993). "Mutations and polymorphisms in the human ornithine transcarbamylase gene". Hum. Mutat. 2 (3): 174–8. doi:10.1002/humu.1380020304. PMID 8364586. 
• Matsuda I, Tanase S (1997). "The ornithine transcarbamylase (OTC) gene: mutations in 50 Japanese families with OTC deficiency". Am. J. Med. Genet. 71 (4): 378–83. doi:10.1002/(SICI)1096-8628(19970905)71:4<378::AID-AJMG2>3.0.CO;2-Q. PMID 9286441. 
• Wakabayashi Y (1999). "Tissue-selective expression of enzymes of arginine synthesis". Current opinion in clinical nutrition and metabolic care 1 (4): 335–9. doi:10.1097/00075197-199807000-00004. PMID 10565370. 
• Tuchman M, Jaleel N, Morizono H et al. (2002). "Mutations and polymorphisms in the human ornithine transcarbamylase gene". Hum. Mutat. 19 (2): 93–107. doi:10.1002/humu.10035. PMID 11793468.  CS1 maint: Explicit use of et al. (link)
• Feldmann D, Rozet JM, Pelet A et al. (1992). "Site specific screening for point mutations in ornithine transcarbamylase deficiency". J. Med. Genet. 29 (7): 471–5. PMC 1016021. PMID 1353535.  CS1 maint: Explicit use of et al. (link)
• Tuchman M, Holzknecht RA, Gueron AB et al. (1993). "Six new mutations in the ornithine transcarbamylase gene detected by single-strand conformational polymorphism". Pediatr. Res. 32 (5): 600–4. doi:10.1203/00006450-199211000-00024. PMID 1480464.  CS1 maint: Explicit use of et al. (link)
• Dawson SJ, White LA (1992). "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". J. Infect. 24 (3): 317–20. doi:10.1016/S0163-4453(05)80037-4. PMID 1602151. 
• Suess PJ, Tsai MY, Holzknecht RA et al. (1992). "Screening for gene deletions and known mutations in 13 patients with ornithine transcarbamylase deficiency". Biochem. Med. Metab. Biol. 47 (3): 250–9. doi:10.1016/0885-4505(92)90033-U. PMID 1627356.  CS1 maint: Explicit use of et al. (link)
• Grompe M, Caskey CT, Fenwick RG (1991). "Improved molecular diagnostics for ornithine transcarbamylase deficiency". Am. J. Hum. Genet. 48 (2): 212–22. PMC 1683033. PMID 1671317. 
• Hentzen D, Pelet A, Feldman D et al. (1992). "Fatal hyperammonemia resulting from a C-to-T mutation at a MspI site of the ornithine transcarbamylase gene". Hum. Genet. 88 (2): 153–6. doi:10.1007/bf00206063. PMID 1721894.  CS1 maint: Explicit use of et al. (link)
• Strautnieks S, Rutland P, Malcolm S (1992). "Arginine 109 to glutamine mutation in a girl with ornithine carbamoyl transferase deficiency". J. Med. Genet. 28 (12): 871–4. doi:10.1136/jmg.28.12.871. PMC 1017166. PMID 1757964. 
• Carstens RP, Fenton WA, Rosenberg LR (1991). "Identification of RNA splicing errors resulting in human ornithine transcarbamylase deficiency". Am. J. Hum. Genet. 48 (6): 1105–14. PMC 1683104. PMID 2035531. 
• Hata A, Matsuura T, Setoyama C et al. (1991). "A novel missense mutation in exon 8 of the ornithine transcarbamylase gene in two unrelated male patients with mild ornithine transcarbamylase deficiency". Hum. Genet. 87 (1): 28–32. doi:10.1007/BF01213087. PMID 2037279.  CS1 maint: Explicit use of et al. (link)
• Legius E, Baten E, Stul M et al. (1990). "Sporadic late onset ornithine transcarbamylase deficiency in a boy with somatic mosaicism for an intragenic deletion". Clin. Genet. 38 (2): 155–9. doi:10.1111/j.1399-0004.1990.tb03565.x. PMID 2208768.  CS1 maint: Explicit use of et al. (link)
• Finkelstein JE, Francomano CA, Brusilow SW, Traystman MD (1990). "Use of denaturing gradient gel electrophoresis for detection of mutation and prospective diagnosis in late onset ornithine transcarbamylase deficiency". Genomics 7 (2): 167–72. doi:10.1016/0888-7543(90)90537-5. PMID 2347583. 
• Grompe M, Muzny DM, Caskey CT (1989). "Scanning detection of mutations in human ornithine transcarbamoylase by chemical mismatch cleavage". Proc. Natl. Acad. Sci. U.S.A. 86 (15): 5888–92. doi:10.1073/pnas.86.15.5888. PMC 297736. PMID 2474822. 
• Lee JT, Nussbaum RL (1990). "An arginine to glutamine mutation in residue 109 of human ornithine transcarbamylase completely abolishes enzymatic activity in Cos1 cells". J. Clin. Invest. 84 (6): 1762–6. doi:10.1172/JCI114360. PMC 304053. PMID 2556444. 
• Chu TW, Eftime R, Sztul E, Strauss AW (1989). "Synthetic transit peptides inhibit import and processing of mitochondrial precursor proteins". J. Biol. Chem. 264 (16): 9552–8. PMID 2722850. 
• Hata A, Setoyama C, Shimada K et al. (1989). "Ornithine transcarbamylase deficiency resulting from a C-to-T substitution in exon 5 of the ornithine transcarbamylase gene". Am. J. Hum. Genet. 45 (1): 123–7. PMC 1683378. PMID 2741942.  CS1 maint: Explicit use of et al. (link)
• Summar ML, Tuchman M (29 April 2003). "Urea Cycle Disorders Overview" (PDF). University of Washington, Seattle. 

External links

• GeneReviews/NCBI/NIH/UW entry on Urea Cycle Disorders Overview

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：個々の障害の発見 inborn errors of metabolism identifying the specific disorder
• 4. 肝細胞移植 hepatocyte transplantation
• 5. 小児および若年成人における虚血性脳卒中：病因と臨床的特徴 ischemic stroke in children and young adults etiology and clinical features

English Journal

• Novel liver findings in Ornithine Transcarbamylase Deficiency due to Xp11.4-p21.1 microdeletion.

• Gallant NM1, Gui D2, Lassman CR2, Yong WH2, Teitell M2, Mandelker D3, Lorey F4, Martinez-Agosto JA5, Quintero-Rivera F6.
• Gene.Gene.2015 Feb 10;556(2):249-53. doi: 10.1016/j.gene.2014.11.057. Epub 2014 Nov 27.
• Ornithine transcarbamylase deficiency (OTCD, OMIM 311250), the most common urea cycle disorder, results in impaired synthesis of citrulline from carbamoyl phosphate and ornithine. Individuals have been identified with OTCD due to a contiguous gene deletion at Xp11.4-p21.1 and unique clinical feature
• PMID 25434494

• Urea cycle disorders: a life-threatening yet treatable cause of metabolic encephalopathy in adults.

• Blair NF1, Cremer PD1, Tchan MC2.
• Practical neurology.Pract Neurol.2015 Feb;15(1):45-8. doi: 10.1136/practneurol-2014-000916. Epub 2014 Aug 14.
• Urea cycle disorders are inborn errors of metabolism that, in rare cases, can present for the first time in adulthood. We report a perplexing presentation in a woman 4 days postpartum of bizarre and out-of-character behaviour interspersed with periods of complete normality. Without any focal neuro
• PMID 25125564

• Regulation of the Arginine Deiminase System by ArgR2 Interferes with Arginine Metabolism and Fitness of Streptococcus pneumoniae.

• Schulz C1, Gierok P2, Petruschka L1, Lalk M2, Mäder U3, Hammerschmidt S4.
• mBio.MBio.2014 Dec 23;5(6). pii: e01858-14. doi: 10.1128/mBio.01858-14.
• Streptococcus pneumoniae is auxotrophic for arginine, and molecular analysis of the pneumococcal genome showed that the gene encoding an arginine-ornithine antiporter (ArcD) is organized in a cluster together with the arcABC genes encoding the arginine deiminase system (ADS) of pneumococci. The ADS
• PMID 25538192

Japanese Journal

• 19歳で発症したornithine transcarbamylase（OTC）欠損症により急性脳浮腫を来した1例

• 三谷 英範,望月 俊明,大谷 典生,三上 哲,田中 裕之,今野 健一郎,石松 伸一
• 日本救急医学会雑誌 25(11), 833-838, 2014
• … はじめに：尿素サイクル異常症であるornithine transcarbamylase（OTC）欠損症の頻度は日本で14,000人に1人とされ，18歳以降での発症例は稀であるが，発症すると重症化しうる疾患である。 …
• NAID 130004840990

• Elimination and active extrusion of liver mitochondrial proteins during lipopolysaccharide administration in rat

• UNUMA Kana,AKI Toshihiko,MATSUDA Seiji,FUNAKOSHI Takeshi,YOSHIDA Ken-ichi,UEMURA Koichi
• Hepatology research : the official journal of the Japan Society of Hepatology 43(5), 526-534, 2013-05-01
• NAID 10031183486

• 2度の臓器搬送を要し冷阻血時間が長時間となった脳死肝移植の1例

• 阪本 靖介,笠原 群生,濱野 郁美,内田 孟,重田 孝信,金澤 寛之,福田 晃也,堀川 玲子,中澤 温子,小林 めぐみ,長谷川 康,高原 武志,新田 浩幸,若林 剛
• 移植 48(4-5), 259-264, 2013
• … A 17-year-old male underwent a deceased donor liver transplantation (DDLT) due to ornithine transcarbamylase deficiency. …
• NAID 130004640148

Related Links

• Ornithine transcarbamylase - definition of Ornithine ...

ornithine /or·ni·thine/ (or´nĭ-thēn) an amino acid obtained from arginine by splitting of urea; it is an intermediate in urea biosynthesis. or·ni·thine (ôr n-th n) n. Abbr. Orn An amino acid formed by the hydrolysis of arginine and important in ...

• Ornithine transcarbamylase deficiencyとは - goo Wikipedia ...

Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder is the final enzyme in the proximal portion ...

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★リンクテーブル★

リンク元	「解糖系」「代謝系」「OTC」「オルニチントランスカルバミラーゼ」「OTC deficiency」
関連記事	「transcarbamylase」

「解糖系」

　　[★]

英

glycolytic pathway

同

エムデン-マイヤーホフ経路 Embden-Meyerhof pathway

関

解糖、TCA回路

• CH(OH)-CH(OH)-C(OH)H-CH(OH)-C(CH2OH)H-O- グルコース (OHが↓↓↑↓↑)
• CH(OH)-CH(OH)-C(OH)H-CH(OH)-C(CH2O-PO3)H-O- グルコース-6-リン酸 (OHが↓↓↑↓↑)
• C(CH2OH)OH-C(OH)H-CH(OH)-C(CH2O-PO3)H-O- フルクトース-6-リン酸
• C(CH2O-PO3)OH-C(OH)H-CH(OH)-C(CH2O-PO3)H-O- フルクトース-1,6-リン酸

glucose
↓-hexokinase/glucokinase(liver)
glucose 6-phosphate
↓-phosphohexose isomerase
fructose 6-phosphate
↓-phosphofructokinase
fructose 1,6-bisphosphate
↓-aldolase
glyceraldehyde 3-phosphate
↓-glyceraldehyde-3-phosphate dehydrogenase
1,3-bisphosphoglycerate
↓-phosphoglycerate kinase →ATP
3-phosphoglycerate
↓-phosphoglyceate mutase
2-phosphoglycerate
↓-enolase
phosphoenolpyruvate
↓-pyruvate kinase → ATP
pyruvate
　－(pyruvate dehydrogenase)→acetyl-CoA
　－(pyruvate carboxylase)→oxaloacetate－(NADH+H+)→malate

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解糖系の酵素 (first aid step1 2006 p.87, FASTEP1_87_酵素一覧.xls)

1	galactokinase	キナーゼ
2	galactose-1-phosphate uridyltransferase	転移酵素
3	hexokinase/glucokinase	キナーゼ
4	glucose-6-phosphatase	ホスファターゼ
5	glucose-6-phosphate dehydrogenase	脱水素酵素
6	transketolase
7	phosphofructokinase	キナーゼ
8	fructose-1,6-bisphosphatase	ホスファターゼ
9	fructokinase	キナーゼ	フルクトキナーゼ
10	aldolase B		アルドラーゼ
11	pyruvate kinase	キナーゼ	ピルビン酸キナーゼ
12	pyruvate dehydrogenase	脱水素酵素	ピルビン酸デヒドロゲナーゼ
13	HMG-CoA reductase	還元酵素	HMG-CoA還元酵素
14	pyruvate carboxylase	カルボキシラーゼ	ピルビン酸カルボキシラーゼ
15	PEP carboxykinase	キナーゼ	PEPカルボキシキナーゼ
16	citrate synthase	合成酵素	クエン酸合成酵素
17	α-ketoglutarate dehydrogenase	脱水素酵素	α-ケトグルタミン酸脱水素酵素
18	ornithine transcarbamylase	転移酵素	オルニチンカルバモイルトランスフェラーゼ

「代謝系」

　　[★]

英

metabolic pathway

関

代謝経路

• 解糖系
• TCA回路
• 電子伝達系
• 尿酸回路
• 糖新生経路

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• 1 galactokinase
• 2 galactose-1-phosphate uridyltransferase
• 3 hexokinase/glucokinase
• 4 glucose-6-phosphatase
• 5 glucose-6-phosphate dehydrogenase
• 6 transketolase
• 7 phosphofructokinase
• 8 fructose-1,6-bisphosphatase
• 9 fructokinase
• 10 aldolase B
• 11 pyruvate kinase
• 12 pyruvate dehydrogenase
• 13 HMG-CoA reductase
• 14 pyruvate carboxylase
• 15 PEP carboxykinase
• 16 citrate synthase
• 17 α-ketoglutarate dehydrogenase
• 18 ornithine transcarbamylase

「OTC」

　　[★]

• 一般用医薬品、大衆薬、非処方箋薬 non-prescription drug、nonprescription drug、OTC drug、over-the-counter drug
• オキシテトラサイクリン oxytetracycline
• ornithine transcarbamylase

「オルニチントランスカルバミラーゼ」

　　[★]

英

ornithine transcarbamylase

関

オルニチンカルバモイルトランスフェラーゼ

「OTC deficiency」

　　[★]

同

ornithine transcarbamylase

「transcarbamylase」

　　[★]

トランスカルバミラーゼ