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Gene Review

SLC29A2  -  solute carrier family 29 (equilibrative...

Homo sapiens

Synonyms: 36 kDa nucleolar protein HNP36, DER12, Delayed-early response protein 12, ENT2, Equilibrative NBMPR-insensitive nucleoside transporter, ...
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Disease relevance of SLC29A2


High impact information on SLC29A2

  • Examination of expressional levels of the equilibrative nucleoside transporter (ENT)1 and ENT2 revealed a transcriptionally dependent decrease in mRNA, protein, and function in endothelia and epithelia [6].
  • Despite a huge individual variability in the mRNA amounts for every transporter gene expressed in CLL cells (CNT2, CNT3, ENT1, and ENT2), no relationship between mRNA levels and in vitro fludarabine cytotoxicity was observed [7].
  • The first mammalian examples of the equilibrative nucleoside transporter family to be characterized, hENT1 and hENT2, were passive transporters located predominantly in the plasma membranes of human cells [8].
  • To verify the roles of these residues in dipyridamole interactions, hENT2, which naturally exhibits low dipyridamole sensitivity, was mutated to contain side chains favorable for high affinity dipyridamole binding (i.e. a Met at the TM 1 and/or an Ile at the TM 11 positions) [9].
  • The single mutants exhibited increased hENT2 sensitivity to inhibition by dipyridamole, and the double mutant was the most sensitive, with an IC50 value that was only 2% of that of wild type [9].

Chemical compound and disease context of SLC29A2

  • Competition studies with HPX and thymidine transport via ENT2 indicated an overlap between nucleoside and nucleobase transport transporters in the breast cancer cell lines (MCF7 and T-47D) [10].

Biological context of SLC29A2


Anatomical context of SLC29A2

  • In hENT1- and hENT2-containing HeLa cells, initial rates of uptake (10 microM; picomoles per cell per second) of [3H]TaraC, [3H]araC, and [3H]deoxycytidine were low (0.30 +/- 0.003, 0.42 +/- 0.03, and 0.51 +/- 0.11, respectively) and mediated primarily by hENT1 (approximately 74, approximately 65, and approximately 61%, respectively) [16].
  • We now report the molecular cloning and functional expression in Xenopus oocytes of a cDNA from the same tissue encoding a homologous ei-type transporter, which we designate hENT2 [12].
  • Uptake studies demonstrated that the majority of adenosine transport was mediated by hENT1, which was localized to both apical and basolateral membranes, with a smaller hENT2-mediated component in basolateral membranes [17].
  • Human hepatocytes express hCNT1, hCNT2, hENT1, and hENT2 [18].
  • All four isoforms are widely distributed in mammalian tissues, although their relative abundance varies: ENT2 is particularly abundant in skeletal muscle [13].

Associations of SLC29A2 with chemical compounds

  • Like hENT1, hENT2 mediates saturable transport of the pyrimidine nucleoside uridine (Km 0.2+/-0.03 mM) and also transports the purine nucleoside adenosine [12].
  • These results suggest that ribavirin is taken up by BeWo cells via both the high-affinity Na(+)-dependent transporter hCNT3 and the low-affinity Na(+)-independent transporters hENT1 and hENT2 [19].
  • Transient expression studies with the full-length ENT2 and a 5'-truncated construct that lacks the first start codon (predicted protein 99% identical to HNP36) demonstrated that only the full-length construct conferred uridine transport activity to the cells [14].
  • The human (h) and rat (r) equilibrative (Na(+)-independent) nucleoside transporters (ENTs) hENT1, rENT1, hENT2, and rENT2 belong to a family of integral membrane proteins with 11 transmembrane domains (TMs) and are distinguished functionally by differences in sensitivity to inhibition by nitrobenzylthioinosine and coronary vasoactive drugs [20].
  • In contrast, the affinity of hENT2 for inosine is 4-fold higher than hENT1 [21].

Other interactions of SLC29A2


Analytical, diagnostic and therapeutic context of SLC29A2

  • Moreover, analysis by RT-PCR showed that BeWo cells express mRNA of hCNT3, hENT1 and hENT2 [19].
  • Quantitative PCR showed a transient decrease in the expression of both hENT1 (human ENT1) and hENT2 mRNAs within 4-12 h of induction of the inactive CK2alpha' subunit, but both transcripts had returned to control levels by 24 h [24].
  • In this study, using polyclonal monospecific antibodies we have observed a significant correlation between the expression of hENT2 by Western blot and fludarabine uptake via hENT carriers and also with ex vivo sensitivity of CLL cells to fludarabine [1].
  • To determine whether the reciprocal mutation in hENT2 (Ile33 to Met) also altered sensitivity to dilazep and dipyridamole, hENT2-I33M was created by site-directed mutagenesis [25].
  • The primary goal of this study was to localize these transporters in polarized renal epithelia. hENT1 and hENT2 were tagged with green fluorescence protein, stably expressed in renal epithelial cells, and localized by immunofluorescence and functional analysis [26].


  1. Equilibrative nucleoside transporter-2 (hENT2) protein expression correlates with ex vivo sensitivity to fludarabine in chronic lymphocytic leukemia (CLL) cells. Molina-Arcas, M., Marcé, S., Villamor, N., Huber-Ruano, I., Casado, F.J., Bellosillo, B., Montserrat, E., Gil, J., Colomer, D., Pastor-Anglada, M. Leukemia (2005) [Pubmed]
  2. Expression of the nucleoside-derived drug transporters hCNT1, hENT1 and hENT2 in gynecologic tumors. Farré, X., Guillén-Gómez, E., Sánchez, L., Hardisson, D., Plaza, Y., Lloberas, J., Casado, F.J., Palacios, J., Pastor-Anglada, M. Int. J. Cancer (2004) [Pubmed]
  3. Demonstration of equilibrative nucleoside transporters (hENT1 and hENT2) in nuclear envelopes of cultured human choriocarcinoma (BeWo) cells by functional reconstitution in proteoliposomes. Mani, R.S., Hammond, J.R., Marjan, J.M., Graham, K.A., Young, J.D., Baldwin, S.A., Cass, C.E. J. Biol. Chem. (1998) [Pubmed]
  4. Transport of antiviral 3'-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitrobenzylthioinosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in Xenopus oocytes. Yao, S.Y., Ng, A.M., Sundaram, M., Cass, C.E., Baldwin, S.A., Young, J.D. Mol. Membr. Biol. (2001) [Pubmed]
  5. The human HNP36 gene is localized to chromosome 11q13 and produces alternative transcripts that are not mutated in multiple endocrine neoplasia, type 1 (MEN I) syndrome. Williams, J.B., Rexer, B., Sirripurapu, S., John, S., Goldstein, R., Phillips, J.A., Haley, L.L., Sait, S.N., Shows, T.B., Smith, C.M., Gerhard, D.S. Genomics (1997) [Pubmed]
  6. HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. Eltzschig, H.K., Abdulla, P., Hoffman, E., Hamilton, K.E., Daniels, D., Schönfeld, C., Löffler, M., Reyes, G., Duszenko, M., Karhausen, J., Robinson, A., Westerman, K.A., Coe, I.R., Colgan, S.P. J. Exp. Med. (2005) [Pubmed]
  7. Fludarabine uptake mechanisms in B-cell chronic lymphocytic leukemia. Molina-Arcas, M., Bellosillo, B., Casado, F.J., Montserrat, E., Gil, J., Colomer, D., Pastor-Anglada, M. Blood (2003) [Pubmed]
  8. Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membranes. Baldwin, S.A., Yao, S.Y., Hyde, R.J., Ng, A.M., Foppolo, S., Barnes, K., Ritzel, M.W., Cass, C.E., Young, J.D. J. Biol. Chem. (2005) [Pubmed]
  9. Identification and mutational analysis of amino acid residues involved in dipyridamole interactions with human and Caenorhabditis elegans equilibrative nucleoside transporters. Visser, F., Baldwin, S.A., Isaac, R.E., Young, J.D., Cass, C.E. J. Biol. Chem. (2005) [Pubmed]
  10. Hypoxanthine transport in human tumour cell lines: relationship to the inhibition of hypoxanthine rescue by dipyridamole. Marshman, E., Taylor, G.A., Thomas, H.D., Newell, D.R., Curtin, N.J. Biochem. Pharmacol. (2001) [Pubmed]
  11. Functional characterization and haplotype analysis of polymorphisms in the human equilibrative nucleoside transporter, ENT2. Owen, R.P., Lagpacan, L.L., Taylor, T.R., De La Cruz, M., Huang, C.C., Kawamoto, M., Johns, S.J., Stryke, D., Ferrin, T.E., Giacomini, K.M. Drug Metab. Dispos. (2006) [Pubmed]
  12. Molecular cloning and characterization of a nitrobenzylthioinosine-insensitive (ei) equilibrative nucleoside transporter from human placenta. Griffiths, M., Yao, S.Y., Abidi, F., Phillips, S.E., Cass, C.E., Young, J.D., Baldwin, S.A. Biochem. J. (1997) [Pubmed]
  13. The equilibrative nucleoside transporter family, SLC29. Baldwin, S.A., Beal, P.R., Yao, S.Y., King, A.E., Cass, C.E., Young, J.D. Pflugers Arch. (2004) [Pubmed]
  14. Cloning of the human equilibrative, nitrobenzylmercaptopurine riboside (NBMPR)-insensitive nucleoside transporter ei by functional expression in a transport-deficient cell line. Crawford, C.R., Patel, D.H., Naeve, C., Belt, J.A. J. Biol. Chem. (1998) [Pubmed]
  15. Residue 33 of human equilibrative nucleoside transporter 2 is a functionally important component of both the dipyridamole and nucleoside binding sites. Visser, F., Zhang, J., Raborn, R.T., Baldwin, S.A., Young, J.D., Cass, C.E. Mol. Pharmacol. (2005) [Pubmed]
  16. The role of human nucleoside transporters in cellular uptake of 4'-thio-beta-D-arabinofuranosylcytosine and beta-D-arabinosylcytosine. Clarke, M.L., Damaraju, V.L., Zhang, J., Mowles, D., Tackaberry, T., Lang, T., Smith, K.M., Young, J.D., Tomkinson, B., Cass, C.E. Mol. Pharmacol. (2006) [Pubmed]
  17. Coupling of CFTR-mediated anion secretion to nucleoside transporters and adenosine homeostasis in Calu-3 cells. Szkotak, A.J., Ng, A.M., Man, S.F., Baldwin, S.A., Cass, C.E., Young, J.D., Duszyk, M. J. Membr. Biol. (2003) [Pubmed]
  18. Transcription factors involved in the expression of SLC28 genes in human liver parenchymal cells. Fern??ndez-Veledo, S., Jover, R., Casado, F.J., G??mez-Lech??n, M.J., Pastor-Anglada, M. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  19. Ribavirin uptake by cultured human choriocarcinoma (BeWo) cells and Xenopus laevis oocytes expressing recombinant plasma membrane human nucleoside transporters. Yamamoto, T., Kuniki, K., Takekuma, Y., Hirano, T., Iseki, K., Sugawara, M. Eur. J. Pharmacol. (2007) [Pubmed]
  20. Functional and molecular characterization of nucleobase transport by recombinant human and rat equilibrative nucleoside transporters 1 and 2. Chimeric constructs reveal a role for the ENT2 helix 5-6 region in nucleobase translocation. Yao, S.Y., Ng, A.M., Vickers, M.F., Sundaram, M., Cass, C.E., Baldwin, S.A., Young, J.D. J. Biol. Chem. (2002) [Pubmed]
  21. 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. Ward, J.L., Sherali, A., Mo, Z.P., Tse, C.M. J. Biol. Chem. (2000) [Pubmed]
  22. Role of human nucleoside transporters in the cellular uptake of two inhibitors of IMP dehydrogenase, tiazofurin and benzamide riboside. Damaraju, V.L., Visser, F., Zhang, J., Mowles, D., Ng, A.M., Young, J.D., Jayaram, H.N., Cass, C.E. Mol. Pharmacol. (2005) [Pubmed]
  23. Expression of human equilibrative nucleoside transporter 1 (hENT1) and its correlation with gemcitabine uptake and cytotoxicity in mantle cell lymphoma. Marcé, S., Molina-Arcas, M., Villamor, N., Casado, F.J., Campo, E., Pastor-Anglada, M., Colomer, D. Haematologica (2006) [Pubmed]
  24. Subtype-specific regulation of equilibrative nucleoside transporters by protein kinase CK2. Stolk, M., Cooper, E., Vilk, G., Litchfield, D.W., Hammond, J.R. Biochem. J. (2005) [Pubmed]
  25. Mutation of residue 33 of human equilibrative nucleoside transporters 1 and 2 alters sensitivity to inhibition of transport by dilazep and dipyridamole. Visser, F., Vickers, M.F., Ng, A.M., Baldwin, S.A., Young, J.D., Cass, C.E. J. Biol. Chem. (2002) [Pubmed]
  26. Localization of human equilibrative nucleoside transporters, hENT1 and hENT2, in renal epithelial cells. Mangravite, L.M., Xiao, G., Giacomini, K.M. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
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