3-Hydroxyglutaric acid is transported via the sodium-dependent dicarboxylate transporter NaDC3.
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.
Stellmer
Franziska
F
Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
Keyser
Britta
B
Burckhardt
Birgitta C
BC
Koepsell
Hermann
H
Streichert
Thomas
T
Glatzel
Markus
M
Jabs
Sabrina
S
Thiem
Joachim
J
Herdering
Wilhelm
W
Koeller
David M
DM
Goodman
Stephen I
SI
Lukacs
Zoltan
Z
Ullrich
Kurt
K
Burckhardt
Gerhard
G
Braulke
Thomas
T
Mühlhausen
Chris
C
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
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