Chapter 9 Molecular mechanisms of nucleoside and nucleoside drug transport

Conserved Glutamate Residues Glu-343 and Glu-519 Provide Mechanistic Insights into Cation/Nucleoside Cotransport by Human Concentrative Nucleoside Transporter hCNT3

“…Physiologic nucleosides and the majority of synthetic nucleoside analogs with antineoplastic and/or antiviral activity are hydrophilic molecules that require specialized plasma membrane nucleoside transporter (NT) 3 proteins for transport into or out of cells (1)(2)(3)(4). NT-mediated transport is required for nucleoside metabolism by salvage pathways and is a critical determinant of the pharmacologic actions of nucleoside drugs (3)(4)(5)(6).…”

Topology of a Human Equilibrative, Nitrobenzylthioinosine (NBMPR)-sensitive Nucleoside Transporter (hENT1) Implicated in the Cellular Uptake of Adenosine and Anti-cancer Drugs

“…Uptake of exogenous nucleosides, for example, is a critical first step of nucleotide synthesis in tissues such as bone marrow and intestinal epithelium and certain parasitic organisms that lack de novo pathways for purine biosynthesis (2,3). The same transport mechanisms function as drug transporters and mediate uptake of many synthetic nucleoside analogs used in cancer (and viral) chemotherapy (2).…”

“…Uptake of exogenous nucleosides, for example, is a critical first step of nucleotide synthesis in tissues such as bone marrow and intestinal epithelium and certain parasitic organisms that lack de novo pathways for purine biosynthesis (2,3). The same transport mechanisms function as drug transporters and mediate uptake of many synthetic nucleoside analogs used in cancer (and viral) chemotherapy (2). Nucleoside transporters also control the extracellular concentration of adenosine in the vicinity of its cell surface receptors and regulate processes such as neurotransmission and cardiovascular activity (1)(2)(3).…”

“…The same transport mechanisms function as drug transporters and mediate uptake of many synthetic nucleoside analogs used in cancer (and viral) chemotherapy (2). Nucleoside transporters also control the extracellular concentration of adenosine in the vicinity of its cell surface receptors and regulate processes such as neurotransmission and cardiovascular activity (1)(2)(3). Adenosine itself is used clinically to treat cardiac arrhythmias, and nucleoside transport inhibitors such as dipyridamole, dilazep, and draflazine function as coronary vasodilators.…”

“…Adenosine itself is used clinically to treat cardiac arrhythmias, and nucleoside transport inhibitors such as dipyridamole, dilazep, and draflazine function as coronary vasodilators. In mammals, plasma membrane transport of nucleosides is brought about by members of the concentrative, Na ϩ -dependent (CNT) 1 and equilibrative, Na ϩ -independent (ENT) nucleoside transporter families (1)(2)(3). CNTs are expressed in a tissue-specific fashion; ENTs are present in most, possibly all, cell types.…”