The mitochondrial ornithine transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms.
Two isoforms of the human ornithine carrier, ORC1 and ORC2, have been identified by overexpression of the proteins in bacteria and by study of the transport properties of the purified proteins reconstituted into liposomes. Both transport L-isomers of ornithine, lysine, arginine, and citrulline by exchange and by unidirectional mechanisms, and they are inactivated by the same inhibitors. ORC2 has a broader specificity than ORC1, and L- and D-histidine, L-homoarginine, and D-isomers of ornithine, lysine, and ornithine are all substrates. Both proteins are expressed in a wide range of human tissues, but ORC1 is the predominant form. The highest levels of expression of both isoforms are in the liver. Five mutant forms of ORC1 associated with the human disease hyperornithinemia-hyperammonemia-homocitrullinuria were also made. The mutations abolish the transport properties of the protein. In patients with hyperornithinemia-hyperammonemia-homocitrullinuria, isoform ORC2 is unmodified, and its presence compensates partially for defective ORC1.
Fiermonte
Giuseppe
G
Laboratory of Biochemistry and Molecular Biology, Department of Pharmaco-Biology, University of Bari, Via Orabona 4, 70125 Bari, Italy.
Dolce
Vincenza
V
David
Laura
L
Santorelli
Filippo Maria
FM
Dionisi-Vici
Carlo
C
Palmieri
Ferdinando
F
Walker
John E
JE
D026923:Amino Acid Transport Systems, Basic; D001120:Arginine / Q000737:chemistry; D001692:Biological Transport; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000737:chemistry* / Q000235:genetics; D002956:Citrulline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000652:urine; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D022124:Hyperammonemia / Q000235:genetics; D007700:Kinetics; D008081:Liposomes / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008239:Lysine / Q000737:chemistry; D008293:Malates / Q000737:chemistry; D026901:Membrane Transport Proteins; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009952:Ornithine / Q000737:chemistry / Q000378:metabolism; D010710:Phosphates / Q000737:chemistry; D017510:Protein Folding; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic
D026923:Amino Acid Transport Systems, Basic; D002352:Carrier Proteins; D018076:DNA, Complementary; D008081:Liposomes; D008293:Malates; D026901:Membrane Transport Proteins; D010710:Phosphates; D020033:Protein Isoforms; D011994:Recombinant Proteins; C488998:SLC25A2 protein, human; C041356:ornithine transporter; C001352:homocitrulline; D002956:Citrulline; C030298:malic acid; D001120:Arginine; D009952:Ornithine; D008239:Lysine