Influence of sugar ring conformation on the transportability of nucleosides by human nucleoside transporters.

The conformational preference of human nucleoside transporters (hNTs) with respect to sugar ring was examined using conformationally fixed purine and pyrimidine nucleosides built on a bicyclo[3.1.0]hexane template. These fixed-conformation nucleosides, methanocarba-deoxyadenosine or methanocarba-deoxycytidine in North (C3'-endo, N-MCdA and N-MCdC) or South (C2'-endo, S-MCdA and S-MCdC) conformations, were used to study inhibition of equilibrative (hENT1-4) and concentrative (hCNT1-3) nucleoside transport by individual recombinant hNTs produced in Saccharomyces cerevisiae cells or Xenopus laevis oocytes. Our results indicated that nucleosides in the North conformation were potent inhibitors of transport mediated by hCNTs whereas South nucleosides were inhibitors of hENTs, thus showing differences in the interaction with the hNTs. In summary, hCNTs exhibited strong preferences for North nucleosides whereas hENTs exhibited slight preferences for South nucleosides, demonstrating for the first time different conformational preferences among members of the two families of hNTs.