Ornithine transcarbamylase

Last updated
OTC
Ornithine carbamoyltransferase trimer 1OTH.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases OTC , OCTD, ornithine carbamoyltransferase, ornithine transcarbamylase, OTCD
External IDs OMIM: 300461 MGI: 97448 HomoloGene: 446 GeneCards: OTC
Orthologs
SpeciesHumanMouse
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: 10.12 – 10.19 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Ornithine transcarbamylase (OTC) (also called ornithine carbamoyltransferase) is an enzyme (EC 2.1.3.3) that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (Pi). There are two classes of OTC: anabolic and catabolic. This article focuses on anabolic OTC. Anabolic OTC facilitates the sixth step in the biosynthesis of the amino acid arginine in prokaryotes. [5] In contrast, mammalian OTC plays an essential role in the urea cycle, the purpose of which is to capture toxic ammonia and transform it into urea, a less toxic nitrogen source, for excretion.

Contents

Reaction mechanism

Reaction mechanism:. 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. OTC reaction.png
Reaction mechanism:. 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.

Structure

OTC is a trimeric protein. There are three active sites of the protein which are located at the cleft between the monomers. The carbamoyl phosphate binding domain resides on the N-terminal end of each monomer, while the C-terminal end contains the binding domain for ornithine. Both binding domains have a similar structural pattern with a central parallel β-pleated sheet bordered by α-helices and loops. [7] In addition to the binding domains, OTCs have SMG loops. These swing to close the binding site once both substrates have bound. SMG stands for the conserved amino acid motif of Ser-Met-Gly. Upon closure, these residues interact with L-ornithine. The binding of CP induces a global conformational change, while the binding of L-ornithine only induces movement of the SMG loop to close and isolate the activation site. [8]

Binding residues in a Human monomer of OTC. Ornithine's (OT) residues are in magenta, carbamoyl phosphate (CP) binding residues are in dark blue, and other residues a part of the SMG loop are in aqua. Binding Motifs of Ornithine Transcarbamylase.png
Binding residues in a Human monomer of OTC. Ornithine's (OT) residues are in magenta, carbamoyl phosphate (CP) binding residues are in dark blue, and other residues a part of the SMG loop are in aqua.

Active site

Depicted is CP situated in OTC's Binding Site with residues that play an important role in binding CP. Carbamoyl Phosphate Binding of Ornithine Transcarbamylase.png
Depicted is CP situated in OTC's Binding Site with residues that play an important role in binding CP.

Ser-Thr-Arg-Thr-Arg motif from one subunit and a His from the neighboring subunit both interact with the phosphate group of CP for binding. Binding the primary nitrogen of CP are residues Gln, Cys, and Arg. The carbonyl oxygen of CP is bound by residues Thr, Arg, and His. [10]

Amino acid composition

 Plant OTCs have the largest difference from other OTCs. There are 50 to 70% less Leu residues, while there are twice as many Arg residues. The number of subunits in OTCs vary from 322 to 340 residues. Animals have the highest density of Leu. This residue breakdown causes a pI for the animal enzyme of 6.8 while the plant enzyme has a pI of 7.6. [11] Rat, bovine, and human OTC have the same C terminal residue of phenylalanine. Their N-terminal residues on the other hand differ. Rat ends with Ser, bovine with aspartate, and human with glycine. [12] [13]

Genomics

The human OTC gene is located on the short arm of chromosome X (Xp21.1). The gene is located in the Watson (plus) strand and is 73 kbases in length. The open reading frame of 1,062 nucleotides is disbursed between 10 exons and nine introns. The encoded protein is 354 amino acids long with a predicted molecular weight of 39.935 kD. Postranscriptional modification leaves the mature peptide with 322 amino acids and a weight of 36.1 kD. [14] The protein is located in the mitochondrial matrix. In mammals, OTC is expressed in the liver and small intestinal mucosa.

Human mutations

341 mutations in human OTC have been reported. At least 259 of these mutations are considered to be disease-causing mutations. [15] 149 of these mutations are known to cause onset of hyperammonemia during the first weeks of life. 70 manifest as hyperammonemia in male patients later in life. Most of the mutations occur in known functional motifs, such as the SMG loop or CP binding domains. [16]

Deficiency

OTC monomer OTC structure.png
OTC monomer

Mutations in the OTC gene can cause Ornithine Transcarbamylase deficiency. It is classified as a urea cycle disorder due to the fact that without proper OTC function ammonia starts to accumulate in the blood. Accumulation of ammonia in the blood is known as hyperammonemia. Although toxic in excess, ammonia is a nitrogen source for the body. Therefore increased ammonia will also increase levels of the nitrogen-containing non-essential amino acids glutamate, glutamine, and alanine. Levels of carbamoyl phosphate (CP) will begin to drop as urea nitrogen levels in the blood decrease. This will cause CP to be diverted to the uridine monophosphate synthetic pathway. Orotic acid is a product of this pathway. Increased levels of orotic acid in urine can be an indicator that a patient is suffering from a disorder linked to hyperammonemia.

OTC deficiency manifests in both early and late onset forms.

Early onset

Early onset is seen in newborns. 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. Symptoms in young children with hyperammonemia are non-specific: not willing to eat, problems with breathing, body temperature, seizures, unusual body movements (twitches) and somnolence. [17] As ammonia build up continues, symptoms progress from somnolence to lethargy potentially ending in a coma. Abnormal posturing (uncontrolled movement) and encephalopathy (brain damage) 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.

Late onset

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]. Patients with partial enzyme deficiencies may have a delay of symptoms for months or years. Indicators that you maybe suffering from OTC deficiency or a urea cycle disorder include "episodes of delirium, erratic behavior, or reduced consciousness, headaches, vomiting, aversion to foods high in protein, and seizures." [18]

Treatment

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 [19] and has been shown to reduce ammonia intoxication in animal experiments. Additionally, the use of whole-body therapeutic hypothermia (TH) has been proposed and studied as a treatment. TH is thought to increase the effectiveness of dialysis to extract ammonia from the body. [20] [21]

Related Research Articles

The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic.

<span class="mw-page-title-main">Ornithine</span> Chemical compound

Ornithine is a non-proteinogenic amino acid that plays a role in the urea cycle. Ornithine is abnormally accumulated in the body in ornithine transcarbamylase deficiency. The radical is ornithyl.

<span class="mw-page-title-main">Carbamoyl phosphate</span> Chemical compound

Carbamoyl phosphate is an anion of biochemical significance. In land-dwelling animals, it is an intermediary metabolite in nitrogen disposal through the urea cycle and the synthesis of pyrimidines. Its enzymatic counterpart, carbamoyl phosphate synthetase I, interacts with a class of molecules called sirtuins, NAD dependent protein deacetylases, and ATP to form carbamoyl phosphate. CP then enters the urea cycle in which it reacts with ornithine to form citrulline.

<span class="mw-page-title-main">Hyperammonemia</span> Medical condition

Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. It is a dangerous condition that may lead to brain injury and death. It may be primary or secondary.

<span class="mw-page-title-main">Ornithine transcarbamylase deficiency</span> Medical condition

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 of the urea cycle, responsible for converting carbamoyl phosphate and ornithine into citrulline. OTC deficiency is inherited in an X-linked recessive manner, meaning males are more commonly affected than females.

<span class="mw-page-title-main">Mitochondrial matrix</span> Space within the inner membrane of the mitochondrion

In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribosomes, soluble enzymes, small organic molecules, nucleotide cofactors, and inorganic ions.[1] The enzymes in the matrix facilitate reactions responsible for the production of ATP, such as the citric acid cycle, oxidative phosphorylation, oxidation of pyruvate, and the beta oxidation of fatty acids.

<span class="mw-page-title-main">Sodium phenylbutyrate</span> Chemical compound

Sodium phenylbutyrate, sold under the brand name Buphenyl among others, is a salt of an aromatic fatty acid, 4-phenylbutyrate (4-PBA) or 4-phenylbutyric acid. The compound is used to treat urea cycle disorders, because its metabolites offer an alternative pathway to the urea cycle to allow excretion of excess nitrogen.

<i>N</i>-Acetylglutamate synthase Class of enzymes

N-Acetylglutamate synthase (NAGS) is an enzyme that catalyses the production of N-acetylglutamate (NAG) from glutamate and acetyl-CoA.

Carbamoyl phosphate synthetase I is a ligase enzyme located in the mitochondria involved in the production of urea. Carbamoyl phosphate synthetase I transfers an ammonia molecule to a molecule of bicarbonate that has been phosphorylated by a molecule of ATP. The resulting carbamate is then phosphorylated with another molecule of ATP. The resulting molecule of carbamoyl phosphate leaves the enzyme.

<span class="mw-page-title-main">N-Acetylglutamate synthase deficiency</span> Medical condition

N-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder.

Carbamoyl phosphate synthetase I deficiency is an autosomal recessive metabolic disorder that causes ammonia to accumulate in the blood due to a lack of the enzyme carbamoyl phosphate synthetase I. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

<span class="mw-page-title-main">Ornithine translocase deficiency</span> Medical condition

Ornithine translocase deficiency, also called hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, is a rare autosomal recessive urea cycle disorder affecting the enzyme ornithine translocase, which causes ammonia to accumulate in the blood, a condition called hyperammonemia.

<span class="mw-page-title-main">Orotic aciduria</span> Medical condition

Orotic aciduria is a disease caused by an enzyme deficiency, resulting in a decreased ability to synthesize pyrimidines. It was the first described enzyme deficiency of the de novo pyrimidine synthesis pathway.

In enzymology, a N-acetylornithine carbamoyltransferase (EC 2.1.3.9) is an enzyme that catalyzes the chemical reaction

In enzymology, an aminoacylase (EC 3.5.1.14) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Aldehyde dehydrogenase 18 family, member A1</span> Protein-coding gene in the species Homo sapiens

Delta-1-pyrroline-5-carboxylate synthetase (P5CS) is an enzyme that in humans is encoded by the ALDH18A1 gene. This gene is a member of the aldehyde dehydrogenase family and encodes a bifunctional ATP- and NADPH-dependent mitochondrial enzyme with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities. The encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene lead to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with neurodegeneration, cataracts and connective tissue diseases. Alternatively spliced transcript variants, encoding different isoforms, have been described for this gene. As reported by Bruno Reversade and colleagues, ALDH18A1 deficiency or dominant-negative mutations in P5CS in humans causes a progeroid disease known as De Barsy Syndrome.

<span class="mw-page-title-main">ATCase/OTCase family</span>

In molecular biology, the ATCase/OTCase family is a protein family which contains two related enzymes: aspartate carbamoyltransferase EC 2.1.3.2 and ornithine carbamoyltransferase EC 2.1.3.3. It has been shown that these enzymes are evolutionary related. The predicted secondary structure of both enzymes is similar and there are some regions of sequence similarities. One of these regions includes three residues which have been shown, by crystallographic studies to be implicated in binding the phosphoryl group of carbamoyl phosphate and may also play a role in trimerisation of the molecules. The N-terminal domain is the carbamoyl phosphate binding domain. The C-terminal domain is an aspartate/ornithine-binding domain.

N-succinylornithine carbamoyltransferase (EC 2.1.3.11, succinylornithine transcarbamylase, N-succinyl-L-ornithine transcarbamylase, SOTCase) is an enzyme with systematic name carbamoyl phosphate:N2-succinyl-L-ornithine carbamoyltransferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Citrullinemia type I</span> Medical condition

Citrullinemia type I (CTLN1), also known as arginosuccinate synthetase deficiency, is a rare disease caused by a deficiency in argininosuccinate synthetase, an enzyme involved in excreting excess nitrogen from the body. There are mild and severe forms of the disease, which is one of the urea cycle disorders.

Carbamoyl Phosphate synthetase III is one of the three isoforms of the Carbamoyl Phosphate Synthetase, en enzyme that catalyzes the active production of carbamoyl phosphate in many organisms.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000036473 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031173 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Cunin R, Glansdorff N, Piérard A, Stalon V (September 1986). "Biosynthesis and metabolism of arginine in bacteria". Microbiological Reviews. 50 (3): 314–52. doi:10.1128/mr.50.3.314-352.1986. PMC   373073 . PMID   3534538.
  6. ↑ 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". The Journal of Biological Chemistry. 275 (26): 20012–9. doi: 10.1074/jbc.M000585200 . PMID   10747936.
  7. ↑ Sankaranarayanan R, Cherney MM, Cherney LT, Garen CR, Moradian F, James MN (January 2008). "The crystal structures of ornithine carbamoyltransferase from Mycobacterium tuberculosis and its ternary complex with carbamoyl phosphate and L-norvaline reveal the enzyme's catalytic mechanism". Journal of Molecular Biology. 375 (4): 1052–63. doi:10.1016/j.jmb.2007.11.025. PMID   18062991.
  8. ↑ Ha Y, McCann MT, Tuchman M, Allewell NM (September 1997). "Substrate-induced conformational change in a trimeric ornithine transcarbamoylase". Proceedings of the National Academy of Sciences of the United States of America. 94 (18): 9550–5. Bibcode:1997PNAS...94.9550H. doi: 10.1073/pnas.94.18.9550 . PMC   23215 . PMID   9275160.
  9. 1 2 PDB: 1C9Y ​; Shi D, Morizono H, Aoyagi M, Tuchman M, Allewell NM (June 2000). "Crystal structure of human ornithine transcarbamylase complexed with carbamoyl phosphate and L-norvaline at 1.9 A resolution". Proteins. 39 (4): 271–7. doi:10.1002/(SICI)1097-0134(20000601)39:4<271::AID-PROT10>3.0.CO;2-E. PMID   10813810. S2CID   22697980.
  10. ↑ Shi D, Morizono H, Yu X, Tong L, Allewell NM, Tuchman M (March 2001). "Human ornithine transcarbamylase: crystallographic insights into substrate recognition and conformational changes". The Biochemical Journal. 354 (Pt 3): 501–9. doi:10.1042/bj3540501. PMC   1221681 . PMID   11237854.
  11. ↑ Slocum RD, Richardson DP (1991-05-01). "Purification and characterization of ornithine transcarbamylase from pea (Pisum sativum L.)". Plant Physiology. 96 (1): 262–8. doi:10.1104/pp.96.1.262. PMC   1080743 . PMID   11538003.
  12. ↑ Kalousek F, François B, Rosenberg LE (June 1978). "Isolation and characterization of ornithine transcarbamylase from normal human liver". The Journal of Biological Chemistry. 253 (11): 3939–44. doi: 10.1016/S0021-9258(17)34781-6 . PMID   25896.
  13. ↑ Lusty CJ, Jilka RL, Nietsch EH (October 1979). "Ornithine transcarbamylase of rat liver. Kinetic, physical, and chemical properties". The Journal of Biological Chemistry. 254 (20): 10030–6. doi: 10.1016/S0021-9258(19)86668-1 . PMID   489581.
  14. ↑ Horwich AL, Kalousek F, Fenton WA, Pollock RA, Rosenberg LE (February 1986). "Targeting of pre-ornithine transcarbamylase to mitochondria: definition of critical regions and residues in the leader peptide". Cell. 44 (3): 451–9. doi:10.1016/0092-8674(86)90466-6. PMID   3943133. S2CID   23799662.
  15. ↑ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC   6901466 . PMID   31819097.
  16. ↑ Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M (July 2006). "Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene". Human Mutation. 27 (7): 626–32. doi: 10.1002/humu.20339 . PMID   16786505. S2CID   26009099.
  17. ↑ "Ornithine transcarbamylase deficiency". Genetics Home Reference. National Library of Medicine, U.S. Department of Health & Human Services. Retrieved 2019-03-03.
  18. ↑ "Ornithine transcarbamylase deficiency". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. National Institutes of Health, U.S. Department of Health & Human Services. Retrieved 2019-03-03.
  19. ↑ 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". Journal of Gastroenterology. 30 (3): 351–5. doi:10.1007/bf02347511. PMID   7647902. S2CID   29888321.
  20. ↑ Lichter-Konecki U, Nadkarni V, Moudgil A, Cook N, Poeschl J, Meyer MT, Dimmock D, Baumgart S (August 2013). "Feasibility of adjunct therapeutic hypothermia treatment for hyperammonemia and encephalopathy due to urea cycle disorders and organic acidemias". Molecular Genetics and Metabolism. 109 (4): 354–9. doi:10.1016/j.ymgme.2013.05.014. PMID   23791307.
  21. ↑ Lichter-Konecki U, Caldovic L, Morizono H, Simpson K (April 2016). "Ornithine Transcarbamylase Deficiency". In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID   24006547.

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