Ornithine aminotransferase - Misplaced Pages

The OAT involved in the ultimate formation of the non-essential amino acid proline from the amino acid ornithine. Ornithine aminotransferase forms the initial intermediate in this process. It catalyzes the reverse reaction as well, and is therefore essential in creating ornithine from the starting substrate proline.

Structure

The OAT gene encodes for a protein that is approximately 46 kDa in size. The OAT protein is expressed primarily in the liver and the kidney but also in the brain and the retina. The OAT protein is localized to the mitochondrion within the cells where it is expressed.

The structure of the OAT protein has been resolved using X-ray crystallography and shows similarity to other subgroup 2 aminotransferases such as dialkyglucine decarboxylatse. The OAT protein functions as a dimer and each monomer consists of a large domain, which contributes most to subunit interface, and a C-terminal small domain, and an N-terminal region containing a helix, loop, and three-stranded beta-meander. In the central large domain is a seven-stranded beta-sheet covered by eight helices. The co-factor of the OAT protein (pyridoxal-5'-phosphate) binds to OAT through a Schiff base at the lysine 292 position situated between two of the seven-stranded beta-sheet. Three amino acids (R 180, E 235, and R413) are thought to be involved in substrate binding at the active site.

Function

Ornithine aminotransferase catalyzes the transfer of the delta-amino group from L-ornithine

L-ornithine + a 2-oxo acid = L-glutamate 5-semialdehyde + an L-amino acid

The reaction requires pyridoxal 5'-phosphate as a co-factor and forms part of the subpathway that synthesizes L-glutamate 5-semialdehyde from L-ornithine.

Clinical significance

Mutations in the OAT gene can lead to malfunctioning proteins, including both point mutations that abolish catalytic activities, large frame-shift mutations, as well as mutated proteins that are not properly targeted to the mitochondrion where its normal functionality occurs. In the latter, abnormality of mitochondrial import causes ectopic accumulation of the OAT protein in the cytosol followed by rapid degradation by proteolysis. Deficiency of OAT activities causes ornithine aminotransferase deficiency, also known as gyrate atrophy of choroid and retina.

The mechanism of gyrate atrophy of choroid and retina is thought to involve the toxicity of glyoxylate.

References

^ Rao GN, Cotlier E (1984). "Ornithine delta-aminotransferase activity in retina and other tissues". Neurochem. Res. 9 (4): 555–62. doi:10.1007/bf00964382. PMID 6462326. S2CID 19775002.
^ Kobayashi T, Ogawa H, Kasahara M, Shiozawa Z, Matsuzawa T (1995). "A single amino acid substitution within the mature sequence of ornithine aminotransferase obstructs mitochondrial entry of the precursor". Am. J. Hum. Genet. 57 (2): 284–91. PMC 1801533. PMID 7668253.
^ Shen BW, Hennig M, Hohenester E, Jansonius JN, Schirmer T (1998). "Crystal structure of human recombinant ornithine aminotransferase". J. Mol. Biol. 277 (1): 81–102. doi:10.1006/jmbi.1997.1583. PMID 9514741.
"Gyrate atrophy of the choroid and retina". National Institutes of Health. Retrieved 2012-08-23.
Kim SJ, Lim DH, Kim JH, Kang SW (2013). "Gyrate atrophy of the choroid and retina diagnosed by ornithine-δ-aminotransferase gene analysis: a case report". Korean J Ophthalmol. 27 (5): 388–91. doi:10.3341/kjo.2013.27.5.388. PMC 3782588. PMID 24082780.
Katagiri S, Gekka T, Hayashi T, Ida H, Ohashi T, Eto Y, Tsuneoka H (2014). "OAT mutations and clinical features in two Japanese brothers with gyrate atrophy of the choroid and retina". Doc Ophthalmol. 128 (2): 137–48. doi:10.1007/s10633-014-9426-1. PMID 24429551. S2CID 713618.
Doimo M, Desbats MA, Baldoin MC, Lenzini E, Basso G, Murphy E, Graziano C, Seri M, Burlina A, Sartori G, Trevisson E, Salviati L (2013). "Functional analysis of missense mutations of OAT, causing gyrate atrophy of choroid and retina". Hum. Mutat. 34 (1): 229–36. doi:10.1002/humu.22233. PMID 23076989. S2CID 205921336.

External links

Ornithine+aminotransferase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Seiler N (September 2000). "Ornithine aminotransferase, a potential target for the treatment of hyperammonemias". Curr Drug Targets. 1 (2): 119–53. doi:10.2174/1389450003349254. PMID 11465067. Archived from the original on April 14, 2013.{{cite journal}}: CS1 maint: unfit URL (link)

Metabolism: Protein metabolism, synthesis and catabolism enzymes

Essential amino acids are in Capitals

K→acetyl-CoA

LYSINE→	Saccharopine dehydrogenase Glutaryl-CoA dehydrogenase
LEUCINE→	3-Hydroxybutyryl-CoA dehydrogenase Branched-chain amino acid aminotransferase Branched-chain alpha-keto acid dehydrogenase complex Enoyl-CoA hydratase HMG-CoA lyase HMG-CoA reductase Isovaleryl coenzyme A dehydrogenase α-Ketoisocaproate dioxygenase Leucine 2,3-aminomutase Methylcrotonyl-CoA carboxylase Methylglutaconyl-CoA hydratase (See Template:Leucine metabolism in humans – this diagram does not include the pathway for β-leucine synthesis via leucine 2,3-aminomutase)
TRYPTOPHAN→	Indoleamine 2,3-dioxygenase/Tryptophan 2,3-dioxygenase Arylformamidase Kynureninase 3-hydroxyanthranilate oxidase Aminocarboxymuconate-semialdehyde decarboxylase Aminomuconate-semialdehyde dehydrogenase
PHENYLALANINE→tyrosine→	(see below)

G→pyruvate
→citrate

glycine→serine→	Serine hydroxymethyltransferase Serine dehydratase glycine→creatine: Guanidinoacetate N-methyltransferase Creatine kinase
alanine→	Alanine transaminase
cysteine→	D-cysteine desulfhydrase
threonine→	L-threonine dehydrogenase

G→glutamate→
α-ketoglutarate

HISTIDINE→	Histidine ammonia-lyase Urocanate hydratase Formiminotransferase cyclodeaminase
proline→	Proline oxidase Pyrroline-5-carboxylate reductase 1-Pyrroline-5-carboxylate dehydrogenase/ALDH4A1 PYCR1
arginine→	Ornithine aminotransferase Ornithine decarboxylase Agmatinase
→alpha-ketoglutarate→TCA	Glutamate dehydrogenase
Other	cysteine+glutamate→glutathione: Gamma-glutamylcysteine synthetase Glutathione synthetase Gamma-glutamyl transpeptidase glutamate→glutamine: Glutamine synthetase Glutaminase

G→propionyl-CoA→
succinyl-CoA

VALINE→	Branched-chain amino acid aminotransferase Branched-chain alpha-keto acid dehydrogenase complex Enoyl-CoA hydratase 3-hydroxyisobutyryl-CoA hydrolase 3-hydroxyisobutyrate dehydrogenase Methylmalonate semialdehyde dehydrogenase
ISOLEUCINE→	Branched-chain amino acid aminotransferase Branched-chain alpha-keto acid dehydrogenase complex 3-hydroxy-2-methylbutyryl-CoA dehydrogenase
METHIONINE→	generation of homocysteine: Methionine adenosyltransferase Adenosylhomocysteinase regeneration of methionine: Methionine synthase/Homocysteine methyltransferase Betaine-homocysteine methyltransferase conversion to cysteine: Cystathionine beta synthase Cystathionine gamma-lyase
THREONINE→	Threonine aldolase
→succinyl-CoA→TCA	Propionyl-CoA carboxylase Methylmalonyl CoA epimerase Methylmalonyl-CoA mutase

G→fumarate

PHENYLALANINE→tyrosine→

tyrosine→melanin: Tyrosinase

G→oxaloacetate

asparagine→aspartate→	Asparaginase/Asparagine synthetase Aspartate transaminase

v t e Transferase: nitrogenous groups (EC 2.6)
2.6.1: Transaminases	Aspartate transaminase GOT1 GOT2 Alanine transaminase GABA transaminase Tyrosine aminotransferase Kynurenine—oxoglutarate transaminase Ornithine aminotransferase Branched-chain amino acid aminotransferase Alanine—glyoxylate transaminase AGXT
2.6.3: Oximinotransferases	Oximinotransferase
2.6.99: Other	Pyridoxine 5'-phosphate synthase

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

Portal:

Biology

Categories:

Structure

Function

Clinical significance

See also

References

External links