Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter.
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Identified ORNT1 (SLC25A15) by orthology to fungal mitochondrial ornithine carriers, showed it restores ornithine metabolism in HHH patient fibroblasts, and established that its mutations cause HHH syndrome.
"ORNT1 encodes the mitochondrial ornithine transporter involved in UC function and is defective in HHH syndrome."
The mitochondrial ornithine transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms.
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Reconstituted, purified ORNT1 (ORC1) transports L-ornithine, L-lysine, L-arginine and L-citrulline by exchange and unidirectional mechanisms; ORNT2 (ORC2) has broader specificity; both are most highly expressed in liver.
"Both transport L-isomers of ornithine, lysine, arginine, and citrulline by exchange and by unidirectional mechanisms, and they are inactivated by the same inhibitors."
Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder.
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ORNT2 (SLC25A2) is a paralog ~88% identical to ORNT1 that targets to mitochondria and rescues deficient ornithine metabolism in HHH patient fibroblasts, explaining partial functional redundancy.
"When ORNT2 is overexpressed transiently in cultured fibroblasts from HHH patients, it rescues the deficient ornithine metabolism in these cells."
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
Substrate specificity of the two mitochondrial ornithine carriers can be swapped by single mutation in substrate binding site.
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Mutagenesis of substrate-binding residues (R179, E180, W224) in ORNT1 shifts relative ornithine versus arginine/lysine transport, defining the substrate-specificity determinants of the carrier.
ornithine (cytosolic) + citrulline (mitochondrial) => ornithine (mitochondrial) + citrulline (cytosolic)
SLC25A15 variants don't translocate ornithine and citrulline