Nucleoside Transport Mechanisms in Human Physiology

Nucleoside transport across cellular membranes constitutes a fundamental process in human physiology, underpinning nucleic acid synthesis, cellular signalling and the efficacy of nucleoside-derived therapeutics. Two principal protein families mediate this transport: the concentrative nucleoside transporters (CNTs; gene family SLC28) and the equilibrative nucleoside transporters (ENTs; gene family SLC29). CNTs harness the transmembrane sodium gradient to drive active uptake of nucleosides against their concentration gradient, typically exhibiting high substrate specificity and electrogenicity. By contrast, ENTs support bidirectional, facilitative diffusion, equilibrating nucleoside concentrations across the plasma membrane. Tissue-specific expression patterns of these transporters reflect their distinct physiological roles. CNT1, CNT2 and CNT3 predominate in epithelia engaged in nutrient absorption, renal reabsorption and hepatic salvage, whereas ENT1, ENT2, ENT3 and ENT4 distribute widely to regulate extracellular nucleoside pools and purinergic signalling. Beyond their canonical transport functions, emerging evidence indicates that certain CNTs may act as transceptors, coupling substrate recognition to intracellular signalling cascades. Aberrant expression or function of CNTs and ENTs has been linked to inherited metabolic disorders, impaired antineoplastic drug uptake and altered inflammatory responses. Understanding the molecular properties, regulation and interplay of these transporter families thus carries global significance, informing strategies to modulate nucleoside availability in disease and to enhance delivery of antiviral and anticancer agents.

Research from Nature Portfolio

Recent studies have elucidated the in vivo role of CNT1 in renal nucleoside handling and chemotherapeutic efficacy. In a murine model lacking CNT1, researchers observed markedly increased urinary excretion of pyrimidine nucleosides alongside compensatory shifts in purine metabolism. Loss of CNT1 also accelerated renal clearance of the nucleoside analogue gemcitabine, reducing antitumour efficacy in pancreatic cancer grafts; pharmacokinetic adjustment to mimic wild-type exposure restored therapeutic effect. These findings underscore CNT1 as a key determinant of systemic nucleoside homeostasis and drug disposition. Separately, functional characterisation of the orphan transporter SLC43A3 revealed its identity as a facilitative, purine-selective nucleobase transporter. Localised to hepatocyte basolateral membranes, SLC43A3 cooperates with salvage enzymes to drive adenine and guanine uptake, thus reinforcing the purine salvage pathway. Together, these works highlight novel components of nucleoside and nucleobase transport that shape both physiological regulation and pharmacological response.

Nucleoside Transport Mechanisms in Human Physiology publication trend

The graph below shows the total number of articles in nucleoside transport mechanisms in human physiology across all publications each year (not limited to Nature Index journals).

Technical terms

Concentrative nucleoside transporter (CNT): A sodium-coupled membrane protein that actively imports nucleosides against their concentration gradient.

Equilibrative nucleoside transporter (ENT): A facilitative diffusion carrier that mediates bidirectional nucleoside flux in response to concentration gradients.

Purine salvage pathway: A metabolic route recycling free purine bases and nucleosides into nucleotide pools for DNA/RNA synthesis.

Transceptor: A transporter protein that also functions as a receptor, coupling substrate binding to intracellular signalling events.

References

1. Increased renal elimination of endogenous and synthetic pyrimidine nucleosides in concentrative nucleoside transporter 1 deficient mice. Nature Communications (2023).
2. Functional identification of SLC43A3 as an equilibrative nucleobase transporter involved in purine salvage in mammals. Scientific Reports (2015).
3. H syndrome treated with Tocilizumab: two case reports and literature review. Frontiers in Immunology (2023).
4. Emerging Roles of Nucleoside Transporters. Frontiers in Pharmacology (2018).
5. Kinetic and Pharmacological Properties of Cloned Human Equilibrative Nucleoside Transporters, ENT1 and ENT2, Stably Expressed in Nucleoside Transporter-deficient PK15 Cells ENT2 EXHIBITS A LOW AFFINITY FOR GUANOSINE AND CYTIDINE BUT A HIGH AFFINITY FOR INOSINE*. Journal of Biological Chemistry (2000).