Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane

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R-HSA-83936
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Homo sapiens
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Two families of transport proteins mediate the movement of nucleosides and free purine and pyrimidine bases across the plasma membrane. Equilibrative nucleoside transporters allow the movement of these molecules along concentration gradients into or out of cells (Baldwin et al. 2003); concentrative nucleoside transporters actively transport nucleosides into cells by coupling their transport to the inward movement of sodium ions (Gray et al. 2003).

Of the four human equilibrative nucleoside transporters, two are well characterized. SLC29A1 (solute carrier family 29 (nucleoside transporters), member 1) mediates the transport of nucleosides across the plasma membrane. SLC29A2 (solute carrier family 29 (nucleoside transporters), member 2) mediates the transport of both nucleosides and free bases. Transporter specificities were determined by expressing cloned human genes in Xenopus oocytes or in mammalian cultured cell lines whose own nucleotide transporters had been disrupted by mutation. These studies establish that the transport processes are specific and saturable, and that the multiple nucleotides and bases compete for a single binding site on each transporter. Some features of SLC29A2 specificity are complex. For example, in the Xenopus oocyte system, radiolabeled uracil and adenine are taken up, and an excess of either molecule inhibits uptake of radiolabeled hypoxanthine, while in the cultured mammalian cell system, neither adenine nor uracil can inhibit uptake of radiolabeled uridine. If these results reflect ENT2 function in vivo, they indicate that the net movement of a nucleoside or base across the cell membrane is determined not only by its own concentrations in the extracellular space and the cytosol, but also by the concentrations of the other nucleosides and bases competing for access to the transporter.

The human genome encodes three concentrative transporters, SLC28A1, 2, and 3 (solute carrier family 28 (sodium-coupled nucleoside transporter), member 1, 2, and 3). All three genes have been cloned, and expression of the human proteins in Xenopus oocytes has allowed their transport properties to be determined. SLC28A1 mediates the uptake of pyrimidine nucleosides and adenosine (Ritzel et al. 1997); SLC28A2 the uptake of purine nucleosides and uridine (Wang et al. 1997); and SLC28A3 the uptake of purine and pyrimidine nucleosides (Ritzel et al. 2001). Amino acid sequence motifs that determine the specificities of these transporters have been identified in studies of chimeric and mutant proteins (Loewen et al. 1999). SLC28A3 protein co-transports two sodium ions per nucleoside; SLC28A1 and 2 transport one sodium per nucleoside (Ritzel et al. 2001).

Physiological roles for nucleoside and base transport include provision of nucleosides to cells with little capacity to synthesize these molecules de novo, and regulation of extracellular levels of adenosine, which is released from muscle during intense exercise and has signaling properties. In kidney and intestinal epithelia, the combination of apically localized CNT transporters and basolaterally localized ENT transporters provides a mechanism for net transport of nucleosides (Mangravite et al. 2003). These transporters also mediate the uptake of nucleoside analogs used clinically as anti-viral and anti-tumor drugs.

Orthologs of human concentrative and equilibrative transporter proteins have been identified in many eukaryotes, but functional studies of transporters even from organisms closely related to humans (e.g. rat, Gerstin et al. 2002) have revealed differences in substrate specificities. Prediction of drug uptake and other functions of these molecules by human - model organism orthology is thus risky.

Literature References
PubMed ID Title Journal Year
9124315 Molecular cloning and functional expression of cDNAs encoding a human Na+-nucleoside cotransporter (hCNT1)

Ritzel, MW, Yao, SY, Huang, MY, Elliott, JF, Cass, CE, Young, JD

Am J Physiol Cell Physiol 1997
11032837 Molecular identification and characterization of novel human and mouse concentrative Na+-nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib)

Ritzel, MW, Ng, AM, Yao, SY, Graham, K, Loewen, SK, Smith, KM, Ritzel, RG, Mowles, DA, Carpenter, P, Chen, XZ, Karpinski, E, Hyde, RJ, Baldwin, SA, Cass, CE, Young, JD

J Biol Chem 2001
12527552 Localization of human equilibrative nucleoside transporters, hENT1 and hENT2, in renal epithelial cells

Mangravite, LM, Xiao, G, Giacomini, KM

Am J Physiol Renal Physiol 2003
12856181 The concentrative nucleoside transporter family, SLC28

Gray, JH, Owen, RP, Giacomini, KM

Pflugers Arch 2003
10455109 Identification of amino acid residues responsible for the pyrimidine and purine nucleoside specificities of human concentrative Na+ nucleoside cotransporters hCNT1 and hCNT2

Loewen, SK, Ng, AM, Yao, SY, Cass, CE, Baldwin, SA, Young, JD

J Biol Chem 1999
9435697 Na+-dependent purine nucleoside transporter from human kidney: cloning and functional characterization

Wang, J, Su, SF, Dresser, MJ, Schaner, ME, Washington, CB, Giacomini, KM

Am J Physiol Renal Physiol 1997
12838422 The equilibrative nucleoside transporter family, SLC29

Baldwin, SA, Beal, PR, Yao, SY, King, AE, Cass, CE, Young, JD

Pflugers Arch 2003
12110519 Specificty of human and rat orthologs of the concentrative nucleoside transporter, SPNT

Gerstin, KM, Dresser, MJ, Giacomini, KM

Am J Physiol Renal Physiol 2002
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