Equilibrative nucleoside transporter

Activity Protein Gene Human gene locus Protein length Homology respect ENTl Substrates 

Activity Protein Gene gene locus length respect CNT1 Substrates 

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Figure 12.2 Adenosine metabolism. Intracellular adenosine concentrations depend on the balance between energy storage and breakdown. The most important enzymes catalyzing the reactions are indicated. SAH, S-adenosyl-homocysteine ENTs equilibrative nucleoside transporters CNTs, concentrating nucleoside transporters.

Adenosine metabolism (Fig. 12.2) is reviewed in Dunwiddie Masino (2001) and Ribeiro et al. (2002). The phosphorylation of intracellular adenosine to AMP is catalyzed by adenosine kinase. Intracellularly, adenosine can also be deami-nated to inosine by adenosine deaminase. Free intracellular adenosine is normally low. Excess adenosine, which cannot be regenerated to ATP, is extruded to the extracellular space by equilibrative nucleoside transporters (ENTs) in the cell membrane. During electrical stimulation or energy depletion, adenosine is... 

Yao, S. Y., Ng, A. M., Muzyka, W. R. et al. (1997). Molecular cloning and functional characterization of nitrobenzylthioinosine (NBMPR)-sensitive (es) and NBMPR-insensitive (ei) equilibrative nucleoside transporter proteins (rENTl and rENT2) from rat tissues. /. Biol. Chem. 272 (45), 28423-30. 

Fig.n.2. Human duodenal expression variability of nucleoside, organic cation ion, and anion transporters (unpublished data). Shaded box indicates 25-75% of expression range, the line within the box marks the median, and error bars indicate 10-90% of expression range. ENT2, equilibrative nucleoside transporter CNT1, concentrative pyrimidine nucleoside transporter CNT2, concentrative purine nucleoside transporter ... 

Griffiths, M., et al. Molecular cloning and characterization of a nitrobenzylfhioinosine-insensitive (ei) equilibrative nucleoside transporter from human placenta. Biochem. J. 1997, 328, 739-743. 

Immunohistochemical study ND not determined GLUT1 facilitative glucose transporter MCT1 monocarboxylate transporter CRT creatine transporter LAT1 L-type amino acid transporter TAUT taurine transporter ENT equilibrative nucleoside transporter Oatp organic anion-transporting polypeptide PAH p-aminohippuric acid RUI retinal uptake index TR-iBRB rat retinal capillary endothelial cells. 

Lee, E.-W., Lai, Y, Zhang, H. and Unadkat, J.D. (2006) Identification of the mitochondrial targeting signal of the human equilibrative nucleoside transporter 1 (hENTl) Implications for interspecies differences in mitochondrial toxicity of fialuridine. The Journal of Biologiccd Chemistry, 281 (24), 16700-16706. 

F]-FLT is not or only marginally incorporated into DNA (<2%) and therefore not a direct measure of proliferation [122]. In vitro studies indicated that [ F]-FLT uptake is closely related to thymidine kinase 1 (TK1) activity and respective protein levels [117,118]. p F]-FLT is therefore considered to reflect TK1 activity and hence, S-phase fraction rather than DNA synthesis. Although being a poor substrate for type 1 equilibrative nucleoside transporters (ENT), cellular uptake of [ F]-FLT is further facilitated by redistribution of nucleoside transporters to the cellular membrane after inhibition of endogenous synthesis of thymidylate (TMP) de novo synthesis of TMP) [125]. However, the detailed uptake mechanism of [ F]-FLT is yet unknown and the influence of membrane transporters and various nucleoside metabolizing enzymes remains to be determined. 

An increase of intracellular adenosine levels can also be achieved by inhibition of nucleoside transport proteins. Mammalian nucleoside transport processes can be classified into two types on the basis of their thermodynamic properties. These classes are the concentrative, Na+-dependent transport processes and the equilibrative, Na+-independent processes. The corresponding transporters are called CNTs (concentrative nucleoside transporters) and ENTs (equilibrative nucleoside transporters) (Pastor-Anglada and Baldwin, 2001). 

Eltzschig HK, Abdulla P, Hoffman E, Hamilton KE, Daniels D, Schonfeld C, Loffler M, Reyes G, Duszenko M, Karhausen J, Robinson A, Westerman KA, Coe IR, Colgan SP (2005) HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J Exp Med 202(11) 1493—1505... 

Iqbal N, Akula MR, Vo D et al (1998) Synthesis, rotamer orientation, and calcium channel modulation activities of alkyl and 2-phenethyl 1, 4-dihydro-2, 6-dlmethyl-3-nltro-4-(3- or 6-substltuted-2-pyrldyl)-5-pyridinecarboxylates. J Med Chem 41 1827-1837 LI RWS, Tse CM, Man RYK et al (2007) Inhibition of human equilibrative nucleoside transporters by dihydropyridine-type calcium channel antagonists. Eur J Pharmacol 568 75-82 Cosconatl S, Marlnelli L, Lavecchia A et al (2007) Characterizing the 1,4-dlhydropyrldlnes... 

In conclusion, the equilibrative nucleoside transporters are particularly widely expressed in mammalians, whereas until now, the concentrative transporter (CNT2) has been identified at the BBB. Although nucleosides play a role in many biological processes and various diseases, their role at the BBB in relation to brain diseases is not clear. 

ABC ATP CDX CNT ENT EMT GIT GO NCE PEPT1 PMT QSAR SAR SLC ATP-binding cassette Adenosine 5 -triphosphate Caudal-type homeobox transcription factor Concentrative nucleoside transporter Equilibrative nucleoside transporter Epithelial-mesenchymal transition Gastrointestinal tract Gene ontology New chemical entity Di/tri-peptide transporter 1 Pharmacogenetics of Membrane Transporters Project Quantitative structure-activity relationship Structure-activity relationship Solute carriers (SLCs)... 

Owen, R.P., Lagpacan, L.L., Taylor, T.R., De LaCruz, M., Huang, C.C., Kawamoto, M., Johns, S.J., Stryke, D., Ferrin, T.E. and Giacomini, KM. (2006) Functional characterization and haplotype analysis of polymorphisms in the human equilibrative nucleoside transporter, ENT2. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34 (1), 12-15. 

Zhu, Z. and Buolamwini, J.K. (2008) Constrained NBMPR analogue synthesis, pharmacophore mapping and 3D-QSAR modeling of equilibrative nucleoside transporter 1 (ENT1) inhibitory activity. Bioorganic and Medicinal Chemistry, 16 (7), 3848-3865. 

Osses, N., Pearson, J.D., Yudilevich. D.L., and Jarvis, S.M. (1996) Hypoxanthine enters human vascular endothelial cells (ECV 304) via the nitrobenzylthioinosine-insensitive equilibrative nucleoside transporter. The Biochemical Journal. 

Yao, S.Y., Ng, A.M., Vickers, M.F, Sundaram, M., Cass, C.F., Baldwin, S.A., and Young, J.D. (2002) Functional and molecular characterization of nucieobase transport by recombinant human and rat equilibrative nucleoside transporters 1 and 2. Chimeric constructs reveal a role for the FNT2 helix 5-6 region in nucieobase translocation. The Journal of Biological Chemistry, "m (28), 24938-24948. 

Griffiths, M., Yao, S.Y., Abidi, F., Phillips, S.E., Cass, C.E., Young, J.D., and Baldwin, S.A. (1997) Molecular cloning and characterization of a niti obenzylthioinosine-insensitive (ei) equilibrative nucleoside transporter from human placenta. The Biochemical Journal, 328 (Pt 3), 739-743. 

King, A.E.. Cass. C.F, and Young, J.D, (2004) The equilibrative nucleoside transporter family, SLC29. Pflugers Archives, 447 (5), 735-743. 

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