Ornithine transcarbamylase

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

Deficiency
If a person is deficient in OTC, ammonia levels will build up, and this will cause neurological problems. Levels of the is_associated_with::amino acids is_associated_with::glutamate and is_associated_with::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 is_associated_with::hyperammonemia are non-specific: failure to feed, loss of thermoregulation with a low core temperature, and somnolence. Symptoms progress from is_associated_with::somnolence to is_associated_with::lethargy and is_associated_with::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 is_associated_with::ornithine transcarbamylase deficiency.

Levels of is_associated_with::urea cycle intermediates may be decreased, as carbamoyl phosphate cannot replenish the cycle. The carbamoyl phosphate instead goes into the is_associated_with::uridine monophosphate synthetic pathway. Here, is_associated_with::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 is_associated_with::sodium benzoate, which combines with is_associated_with::glycine to produce is_associated_with::hippurate, at the same time removing an ammonium group. is_associated_with::Biotin also plays an important role in the functioning of the OTC enzyme and has been shown to reduce ammonia intoxication in animal experiments.