Equilibrative nucleoside transporters-A review

Abstract

Equilibrative nucleoside transporters (ENTs) are polytopic integral membrane proteins that mediate the transport of nucleosides, nucleobases, and therapeutic analogs. The best-characterized ENTs are the human transporters hENT1 and hENT2. However, non-mammalian eukaryotic ENTs have also been studied (e.g., yeast, parasitic protozoa). ENTs are major pharmaceutical targets responsible for modulating the efficacy of more than 30 approved drugs. However, the molecular mechanisms and chemical determinants of ENT-mediated substrate recognition, binding, inhibition, and transport are poorly understood. This review highlights findings on the characterization of ENTs by surveying studies on genetics, permeant and inhibitor interactions, mutagenesis, and structural models of ENT function.

Keywords: Nucleoside transport; equilibrative nucleoside transporter; membrane protein; nucleobase transport.

FIGURE 1. ENTs are diverse transporters and serve as major pharmaceutical targets

ENTs regulate the flux of pyrimidine and purine nucleosides, nucleobases, and therapeutic analogs. ENTs also modulate therapeutic efficacy by mediating the transport of medications across cellular membranes to their ultimate site of action (orange “1”) or serve as the direct target for drug binding (red “2”) resulting in transporter inhibition.

FIGURE 2. Human ENT1 expression levels correlate to increased patient survival

Multiple studies have shown that higher levels of hENT1 expression results in increased patient survival for pancreatic cancer patients receiving gemcitabine treatment. Data was compiled from multiple previously published works (–49), red bars indicate high hENT1 expression levels, while blue bars represent low hENT1 expression levels.