Ornithine transcarbamylase

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Ornithine carbamoyltransferase
Ornithine carbamoyltransferase trimer 1OTH.png
Human OTC trimer. From PDB: 1OTH​.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols OTC ; OCTD
External IDs OMIM300461 MGI97448 HomoloGene446 ChEMBL: 2222 GeneCards: OTC Gene
EC number
RNA expression pattern
PBB GE OTC 207200 at tn.png
More reference expression data
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:
38.35 – 38.42 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 (Pi). 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.


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.


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.


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 Pi, right.[1]


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[2] and has been shown to reduce ammonia intoxication in animal experiments.


  1. ^ Langley DB, Templeton MD, Fields BA, Mitchell RE, Collyer CA (June 2000). "Mechanism of inactivation of ornithine transcarbamoylase by Ndelta -(N'-Sulfodiaminophosphinyl)-L-ornithine, a true transition state analogue? Crystal structure and implications for catalytic mechanism". J. Biol. Chem. 275 (26): 20012–9. doi:10.1074/jbc.M000585200. PMID 10747936. 
  2. ^ Nagamine T, Saito S, Kaneko M, Sekiguchi T, Sugimoto H, Takehara K, Takagi H (June 1995). "Effect of biotin on ammonia intoxication in rats and mice". J. Gastroenterol. 30 (3): 351–5. doi:10.1007/bf02347511. PMID 7647902. 

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