Ornithine transcarbamylase

Ornithine carbamoyltransferase
250px 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 • cytoplasm • mitochondrion • mitochondrial inner membrane • mitochondrial matrix Biological process • urea cycle • liver development • ornithine catabolic process • midgut development • response to zinc ion • citrulline biosynthetic process • response to insulin • cellular nitrogen compound metabolic process • arginine biosynthetic process via ornithine • response to drug • small molecule metabolic process • protein homotrimerization • response to biotin • ammonia homeostasis Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE OTC 207200 at tn.png
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: 38.35 – 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 (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

File:OTC reaction.png

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

File:OTC structure.png

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.

External links

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