Equilibrative nucleoside transporter ENT

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... 

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. 

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... 

In addition to these transporters, specific transporters for hexoses (GLUT-1), amino acids (EAATl-3, LATl), and nucleosides (concentrative nucleoside transporters - CNT (SLC28 family) and equilibrative nucleoside transporters - ENT (SLC29 family) were reported as being present at the BBB. 

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.

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. 

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). 

Equilibrative-type nucleoside transporters (ENTs) were also characterized in rice451 and Arabidopsis370 in reference to cytokinin nucleoside transport using the yeast system. One of the four rice ENT gene products, OsENT2, mediates the uptake of cytokinin nucleoside as well as that of adenosine451 with higher affinity to iPR... 

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)... 

Figure 9.6 Nucleoside transporters in renal proximal tubule cells. Basolateral uptake proceeds by facilitated transport (bidirectional) via equilibrative nucleoside transporters (nENT 1, hENT2). At the luminal membrane, concentrative nucleoside transporters (CNT1-3) mediate nucleoside reabsorption via cotransport with sodium. Additionally, a role of ENTs at the brush border membrane has been proposed. Reprinted from Biochemistry and Cell Biology, Volume 84, A.N. EIwi, V.L. Damaraju, S.A. Baldwin, S.D. Young, M.B. Sawyer, and C.E. Cass, Renal nucleoside transporters Physiological and clinical implications, pp. 844 58, Copyright 2006, with permission from the NRC Research Press.

Molecular cloning studies in Leishmania and trypanosomes have revealed that all known purine transporters in these parasites are members of the ENT family described above. These proteins have 11 predicted transmembrane domains with the NH2- and COOH termini located on the inside and outside of the plasma membrane respectively (Fig. 4), and this topological model has been tested for the human equilibrative nucleoside transporter hENTl. Four Leishmania ENT permeases have been characterized, NTl (represented by two isoforms, NTl.l and NTl.2), NT2, NT3 and NT4, with the majority of the work on jqjj 6,57-59 Jjeing performed using the genes from L. donovani and the... 

Nucleoside analogues are widely used for the treatment of cancers and viral infections. Although there have been considerable advances in the development of new nucleoside analogs, little is known about the transport mechanisms involved in the intestinal absorption of these compounds. Nucleoside transporters have been subdivided into two major classes by Na+-independent equilibrative transporters (ENT family) and Na+-dependent concentrative transporters (CNT family) [77,100-103],... 

Nucleoside transporters (ENT1 -2, SLC28A CNT1 -3, SLC29A) Equilibrative (ENTs) and... 

The brain needs the influx of nucleosides because the brain is deficient in de novo nucleotide synthesis (102). Purine and pyrimidine nucleosides are necessary for the synthesis of DNA and RNA, but nucleosides also influence many other biological processes. In addition, nucleosides play an important role in the treatment of diseases, such as cardiac diseases, brain cancers, and infections [parasitic and viral (103)]. Nucleosides are hydrophilic compounds, and the influx and efflux of these compounds is therefore mediated by a number of distinct transporters (104). Nucleoside transporters are membrane-fixed transporters and are classified by their transport mechanisms (e = equilibrative, c = concentrative), their sensitivity to the transport inhibitor nitrobenzylmercaptopurine riboside (NBMPR s = sensitive, i = insensitive), and their substrates. Presently, there are two equilibrative transporters (ENTs es and ei) and six concentrative nucleoside transporters [CNTs cif (concentrative, NBMPR insensitive, broad specificity Nl), cit (concentrative, NBMPR insensitive, common permeant thymidine N2), cib (concentrative, NBMPR insensitive, broad specificity N3), cib (concentrative, MBMPR insensitive, broad specificity N4), cs (concentrative, NBMPR sensitive N5), and csg (concentrative, NBMPR sensitive, accepts guanosine as permeant N6) (104)]. The equilibrative es and ei nucleoside transporters are widely expressed in mammalian cells and are present at cultured endothelial cells and brain capillaries (105). In these cells, the expression of concentrative transporter cit (N2) was demonstrated also. In other parts of the rat brain, ei and es nucleoside transport systems have... 

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