Equilibrative nucleoside transporters—A review

Boswell-Casteel, Rebba C.; Hays, Franklin A.

doi:10.1080/15257770.2016.1210805

Cited by 173 publications

(158 citation statements)

References 178 publications

(232 reference statements)

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“…ENT1 and ENT2 have a fairly ubiquitous cell surface expression and are capable of mediating adenine (and hypoxanthine) transport across the blood brain barrier [126][127][128][129]. It is also likely that allopurinol enters the brain in this way, given its closely related structure to hypoxanthine (Fig.…”

Section: Penetration Into the Brainmentioning

confidence: 99%

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Frenguelli

2017

Neurochem Res

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Brain slices have been the workhorse for many neuroscience labs since the pioneering work of Henry McIlwain in the 1950s. Their utility is undisputed and their acceptance as appropriate models for the central nervous system is widespread, if not universal. However, the skeleton in the closet is that ATP levels in brain slices are lower than those found in vivo, which may have important implications for cellular physiology and plasticity. Far from this being a disadvantage, the ATP-impoverished slice can serve as a useful and experimentally-tractable surrogate for the injured brain, which experiences similar depletion of cellular ATP. We have shown that the restoration of cellular ATP in brain slices to in vivo values is possible with a simple combination of d-ribose and adenine (RibAde), two substrates for ATP synthesis. Restoration of ATP in slices to physiological levels has implications for synaptic transmission and plasticity, whilst in the injured brain in vivo RibAde shows encouraging positive results. Given that ribose, adenine, and a third compound, allopurinol, are all separately in use in man, their combined application after acute brain injury, in accelerating ATP synthesis and increasing the reservoir of the neuroprotective metabolite, adenosine, may help reduce the morbidity associated with stroke and traumatic brain injury.

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Section: Penetration Into the Brainmentioning

confidence: 99%

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Frenguelli

2017

Neurochem Res

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“…hENT1 and hENT2 are known to transport a broad range of purine and pyrimidine nucleosides (Ward et al, 2000; Baldwin et al, 2004; Boswell-Casteel and Hays, 2016; Young, 2016) (Fig. 3A and Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional characterization of human equilibrative nucleoside transporter 1

et al. 2016

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Equilibrative nucleoside transporters (ENTs), which facilitate cross-membrane transport of nucleosides and nucleoside-derived drugs, play an important role in the salvage pathways of nucleotide synthesis, cancer chemotherapy, and treatment for virus infections. Functional characterization of ENTs at the molecular level remains technically challenging and hence scant. In this study, we report successful purification and biochemical characterization of human equilibrative nucleoside transporter 1 (hENT1) in vitro. The HEK293F-derived, recombinant hENT1 is homogenous and functionally active in proteoliposome-based counter flow assays. hENT1 transports the substrate adenosine with a Km of 215 ± 34 µmol/L and a Vmax of 578 ± 23.4 nmol mg−1 min−1. Adenosine uptake by hENT1 is competitively inhibited by nitrobenzylmercaptopurine ribonucleoside (NBMPR), nucleosides, deoxynucleosides, and nucleoside-derived anti-cancer and anti-viral drugs. Binding of hENT1 to adenosine, deoxyadenosine, and adenine by isothermal titration calorimetry is in general agreement with results of the competitive inhibition assays. These results validate hENT1 as a bona fide target for potential drug target and serve as a useful basis for future biophysical and structural studies.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-016-0350-x) contains supplementary material, which is available to authorized users.

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“…29) (Detailed information on the physiology and function of ENTs as nucleoside transporters can be found elsewhere. 30,31) ) Recently, Yao et al have demonstrated that, in the Xenopus laevis oocyte expression system, ENT1 has the capability to transport not only nucleosides but also nucleobases such as adenine, hypoxanthine, guanine, thymine, and uracil 8) (Table 1). Although the affinity and efficiency values of ENT1 for nucleobases are much lower than those for nucleosides, 9,32) the transport activities are obvious.…”

Section: Facilitative Transport Systemsmentioning

confidence: 99%

Molecular Basis of Nucleobase Transport Systems in Mammals

Inoue

2017

Biological & Pharmaceutical Bulletin

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Nucleobases are water-soluble compounds that need specific transporters to cross biological membranes. Cumulative evidence based on studies using animal tissues and cells indicates that the carrier-mediated transport systems for purine and pyrimidine nucleobases can be classified into the following two types: concentrative transport systems that mediate nucleobase transport depending on the sodium ion concentration gradient; and other systems that mediate facilitated diffusion depending on the concentration gradient of the substrate. Recently, several molecular transporters that are involved in both transport systems have been identified. The function and activity of these transporters could be of pharmacological significance considering the roles that they play not only in nucleotide synthesis and metabolism but also in the pharmacokinetics and delivery of a variety of nucleobase analogues used in anticancer and antiviral drug therapy. The present review provides an overview of the recent advances in our understanding of the molecular basis of nucleobase transport systems, focusing on the transporters that mediate purine nucleobases, and discusses the involvement of intracellular metabolism in purine nucleobase transport and chemotherapy using ganciclovir.Key words purine nucleobase; transporter; salvage enzyme; equilibrative nucleoside transporter 1 (ENT1)/ solute carrier (SLC)29A1; ENT2/SLC29A2; equilibrative nucleobase transporter 1 (ENBT1)/ SLC43A3

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Equilibrative nucleoside transporters—A review

Cited by 173 publications

References 178 publications

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Functional characterization of human equilibrative nucleoside transporter 1

Molecular Basis of Nucleobase Transport Systems in Mammals

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