Nucleosides are the ribosylated precursors of purine and pyrimidine nucleotides, and in addition to their biological importance with respect to cellular energy and signal transduction in the form of their phosphorylated analogs (e.g., ATP and cAMP, respectively), their importance to cellular function and physiology is profound. For instance, adenosine alone has been shown to exhibit cardiac and vascular effects (Ely and Berne, 1992), act as a neuromodulator (Dunwiddie, 1985;
Phillis and Wu, 1981), inhibit lipolysis in fat cells (Fain and Malbon, 1979), and act as an anti-inflammatory (Cronstein, 1994; Griffiths and Jarvis, 1996). In accordance with their overall physiological importance, the cellular transport of nucleosides is mediated by two distinct families of transporter proteins: the high-affinity, concentrative nucleoside transporters (CNT; SLC28) and the low affinity, equilibrative nucleoside transporters (ENT; SLC29). These transporter families are distinguished not only by their structural features, but also by their different transport mechanisms. In short, the SLC28 family is sodium dependent and works through an active symport mechanism, while the SLC29 family functions by a facilitated diffusion mechanism. On the cellular level, it is thought that ENTs and CNTs asymmetrically localize between the apical and basolateral membranes to mediate the vectorial transepithelial flux of nucleosides (Lai et al., 2002; Kong et al., 2004). However, given the broad and overlapping substrate specificities of each individual transporter family, coupled with their differential regulation, it has been surmised that these transporters may not only be key modulators of intracel-lular nucleoside availability, but may also fulfill various metabolic needs through selective and complementary activation (Pastor-Anglada et al., 2001). Regardless, given the widespread tissue localization, in concert with those items mentioned above, nucleoside transporters should be attractive pharmaceutical targets for therapeutic nucleoside analogs.
220.127.116.11 The Molecular and Structural Characteristics of Nucleoside Transporters CNT (SLC28A)
The human SLC28 family consists of three subtypes of sodium-dependent, con-centrative nucleoside transporters, hCNT1 (SLC28A1), hCNT2 (SLC28A2; also termed SPNT for sodium-dependent purine nucleoside transporter), and hCNT3 (SLC28A3), although five functionally distinct sodium dependent concentrative nucleoside activities have been reported, as N1 (system cif), N2 (sytem cit), N3 (sytem cib), N4, and N5 (Griffiths and Jarvis, 1996). In summary, N1 transport has been shown to be selective for purine nucleosides, as well as the nucleobase, uridine; N2 transport is characterized by pyrimidine selectivity and adenosine; N3 transport exhibits broad substrate specificity, transporting both purine and pyrim-idines alike; N4 transport is characterized by pyrimidine selectivity, guanosine and adenosine; and N5 is characterized by transport of formycin B and cladribine (Griffiths and Jarvis, 1996).
The current topological model for the SLC28 family is based on rCNT1, which is hypothesized to be comprised of 13 putative TMD, although a 15 transmembrane domain model cannot be ruled out (Hamilton et al., 2001). SLC28A1 is chromosomally localized to 15q25-26 and encodes a protein, CNT1, of approximately 649 amino acids in length that exhibits approximately 83% identity with its rat homologue (Ritzel et al., 1997). SLC28A2 is chromosomally localized to 15q13-14, and encodes a protein of approximately 658 amino acids with a molecular weight of approximately 72 kDa and exhibits several putative protein kinase C phosphorylation sites (Wang et al., 1997). hCNT3 is approximately 48 and 47%
identical to hCNTl and hCNT2, respectively (Ritzel et al., 2001). The SLC28A3 gene is localized to 9q22.2 and encodes a protein that is approximately 691 amino acids (Ritzel et al., 2001).
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