title: Functional identification of SLC43A3 as an equilibrative nucleobase transporter involved in purine salvage in mammals.
abstract: The purine salvage pathway plays a major role in the nucleotide production, relying on the supply of nucleobases and nucleosides from extracellular sources. Although specific transporters have been suggested to be involved in facilitating their transport across the plasma membrane in mammals, those which are specifically responsible for utilization of extracellular nucleobases remain unknown. Here we present the molecular and functional characterization of SLC43A3, an orphan transporter belonging to an amino acid transporter family, as a purine-selective nucleobase transporter. SLC43A3 was highly expressed in the liver, where it was localized to the sinusoidal membrane of hepatocytes, and the lung. In addition, SLC43A3 expressed in MDCKII cells mediated the uptake of purine nucleobases such as adenine, guanine, and hypoxanthine without requiring typical driving ions such as Na(+) and H(+), but it did not mediate the uptake of nucleosides. When SLC43A3 was expressed in APRT/HPRT1-deficient A9 cells, adenine uptake was found to be low. However, it was markedly enhanced by the introduction of SLC43A3 with APRT. In HeLa cells, knock-down of SLC43A3 markedly decreased adenine uptake. These data suggest that SLC43A3 is a facilitative and purine-selective nucleobase transporter that mediates the cellular uptake of extracellular purine nucleobases in cooperation with salvage enzymes.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Furukawa
authors.affiliation: Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Maeda
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yasujima
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Kinya
authors.initials: K
authors.lastname: Ohta
authors.affiliation: Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Department of Pharmacy, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Tappei
authors.initials: T
authors.lastname: Takada
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsuo
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yuasa
mesh_terms: D000225:Adenine / Q000378:metabolism; D000228:Adenine Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D004285:Dogs; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014529:Uridine / Q000378:metabolism
chemical_list: D026905:Amino Acid Transport Systems; D033721:Equilibrative Nucleoside Transporter 1; D020033:Protein Isoforms; D011687:Purines; D034741:RNA, Small Interfering; C000605140:SLC43A3 protein, human; D019271:Hypoxanthine; D000228:Adenine Phosphoribosyltransferase; D000225:Adenine; D000241:Adenosine; D013936:Thymidine; D014529:Uridine