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.
Highlights
Nucleotides play vital roles in all living organisms both by forming the nucleic acids DNA and RNA, which store and implement genetic information, and as individual monomers involved in biological signaling and energy cycling
SLC43A3 is an orphan transporter belonging to an amino acid transporter family comprising three members, along with LAT3/SLC43A114 and LAT4/SLC43A215, both of which mediate the uptake of neutral amino acids such as leucine
SLC43A3 was originally identified as embryonic epithelia gene 1 (EEG1), a gene upregulated in a cell culture model of kidney development[20]
Summary
Nucleotides play vital roles in all living organisms both by forming the nucleic acids DNA and RNA, which store and implement genetic information, and as individual monomers involved in biological signaling and energy cycling. Similar purine nucleobase-selective transport systems have been suggested to be present in several types of cells, such as the cell lines L9298, CHO8, and COR-L239, as well as in rabbit cornea epithelial cells[10] and human cardiac microvascular endothelial cells[11] These transport systems, such as those in red blood cells, are sodium independent, highly nucleobase selective in substrate recognition, and insensitive to specific inhibitors of ENTs. the facilitative uptake of hypoxanthine and adenine has been observed even in cell lines that lack nucleoside transport systems[12]. A detailed functional analysis has shown that salvage enzymes cooperate in the cellular uptake of purine nucleobases mediated by ENBT1
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