title: 3-Hydroxyglutaric acid is transported via the sodium-dependent dicarboxylate transporter NaDC3.
abstract: Patients with glutaryl-CoA dehydrogenase (GCDH) deficiency accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3OH-GA) in their blood and urine. To identify the transporter mediating the translocation of 3OH-GA through membranes, kidney tissue of Gcdh-/- mice have been investigated because of its central role in urinary excretion of this metabolite. Using microarray analyses of kidney-expressed genes in Gcdh-/- mice, several differentially expressed genes encoding transporter proteins were identified. Real-time polymerase chain reaction analysis confirmed the upregulation of the sodium-dependent dicarboxylate cotransporter 3 (NaDC3) and the organic cation transporter 2 (OCT2). Expression analysis of NaDC3 in Xenopus laevis oocytes by the two-electrode-voltage-clamp technique demonstrated the sodium-dependent translocation of 3OH-GA with a K (M) value of 0.95 mM. Furthermore, tracer flux measurements in Chinese hamster ovary cells overexpressing OCT2 showed that 3OH-GA inhibited significantly the uptake of methyl-4-phenylpyridinium, whereas 3OH-GA is not transported by OCT2. The data demonstrate for the first time the membrane translocation of 3OH-GA mediated by NaDC3 and the cis-inhibitory effect on OCT2-mediated transport of cations.
authors.affiliation: Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Stellmer
authors.forename: Britta
authors.initials: B
authors.lastname: Keyser
authors.forename: Birgitta C
authors.initials: BC
authors.lastname: Burckhardt
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.forename: Sabrina
authors.initials: S
authors.lastname: Jabs
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiem
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Herdering
authors.forename: David M
authors.initials: DM
authors.lastname: Koeller
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Goodman
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Lukacs
authors.forename: Kurt
authors.initials: K
authors.lastname: Ullrich
authors.forename: Gerhard
authors.initials: G
authors.lastname: Burckhardt
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
authors.forename: Chris
authors.initials: C
authors.lastname: Mühlhausen
mesh_terms: D000818:Animals; D001692:Biological Transport; D006224:Cricetinae; D003412:Cricetulus; D029382:Dicarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D005260:Female; D020869:Gene Expression Profiling; D005977:Glutarates / Q000378:metabolism*; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency*; D007668:Kidney / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D009865:Oocytes; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D010053:Ovary; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: C108959:3-hydroxyglutaric acid; D029382:Dicarboxylic Acid Transporters; D005977:Glutarates; D029363:Organic Anion Transporters, Sodium-Dependent; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C490479:Slc13a2 protein, mouse; C491012:Slc22a2 protein, mouse; D027981:Symporters; D050770:Glutaryl-CoA Dehydrogenase