Residues 334 and 338 in Transmembrane Segment 8 of Human Equilibrative Nucleoside Transporter 1 Are Important Determinants of Inhibitor Sensitivity, Protein Folding, and Catalytic Turnover

Equilibrative nucleoside transporters (ENTs) are important for the metabolic salvage of nucleosides and the cellular uptake of antineoplastic and antiviral nucleoside analogs. Human equilibrative nucleoside transporter 1 (hENT1) is inhibited by nanomolar concentrations of structurally diverse compounds, including dipyridamole, dilazep, nitrobenzylmercaptopurine ribonucleoside (NBMPR), draflazine, and soluflazine. Random mutagenesis and screening by functional complementation for inhibitor-resistant mutants in yeast revealed mutations at Phe-334 and Asn-338. Both residues are predicted to lie in transmembrane segment 8 (TM 8), which contains residues that are highly conserved in the ENT family. F334Y displayed increased Vmax that to increased of and and displayed that to of of Phe-334 and dipyridamole, mutations of and soluflazine. of 8 predicted that Phe-334 and lie in to highly conserved that of structurally important that and of the Equilibrative nucleoside transporters (ENTs) are important for the metabolic salvage of nucleosides and the cellular uptake of antineoplastic and antiviral nucleoside analogs. Human equilibrative nucleoside transporter 1 (hENT1) is inhibited by nanomolar concentrations of structurally diverse compounds, including dipyridamole, dilazep, nitrobenzylmercaptopurine ribonucleoside (NBMPR), draflazine, and soluflazine. Random mutagenesis and screening by functional complementation for inhibitor-resistant mutants in yeast revealed mutations at Phe-334 and Asn-338. Both residues are predicted to lie in transmembrane segment 8 (TM 8), which contains residues that are highly conserved in the ENT family. F334Y displayed increased Vmax that to increased of and and displayed that to of of Phe-334 and dipyridamole, mutations of and soluflazine. of 8 predicted that Phe-334 and lie in to highly conserved that of structurally important that and of the which are that are the metabolic of and are in the of and in and of the equilibrative nucleoside transporter equilibrative nucleoside nitrobenzylmercaptopurine ribonucleoside transmembrane nucleoside equilibrative nucleoside nitrobenzylmercaptopurine ribonucleoside transmembrane nucleoside uptake and of nucleosides cellular in and are to segment and are equilibrative to by nitrobenzylmercaptopurine ribonucleoside of in in the of the nucleoside nucleoside the the and in and is of to to of including and of and by which the of are is by that are in of highly of nucleoside draflazine, dilazep, dipyridamole, and uptake and of the of and and and nucleoside at nanomolar and of of dipyridamole, dilazep, and in transporters at nanomolar dilazep, which of and the predicted to lie at the of 1 of and to important of the for dilazep, dipyridamole, and nucleosides for transporters in of in in is to to to the for nucleoside and that residues in and and and of are in and of of draflazine, which is of nucleoside and and to of the in to residues of in of dilazep, dipyridamole, residues in of soluflazine. mutagenesis and functional complementation screening that in the of and of Phe-334 and of residues in ENT at and for and by functional in of of the 8 to the that the residues the of that residues in are of of and and the yeast to which and which contains in the the by of the the and in yeast to and and in in and Random to by the and and to Random mutagenesis of by the in the of for to to the of mutations in of the residues the mutagenesis and of complementation the of in yeast to salvage of at and at at of of at for in the of and complementation 1 which and 1 and at for to of complementation in 1 of for and and dipyridamole, dilazep, 1 the yeast by and in of the transporters in to in and to at and at dipyridamole, dilazep, and and and the in of yeast to of in of yeast for of of to of and to of the and to for of by the yeast for the to of the the of and highly for to and to of yeast mutants in the of and and for and yeast the the of by by by and at to residues of of and yeast and for to to of of for the concentrations of in the of of that is structurally to at in 1 and of by by the of by by the for the concentrations of in the of concentrations that by by the of and the and of yeast in the of and in the of and yeast of for salvage the of which is to by in yeast of is salvage is functional complementation for mutants for yeast by in the and yeast complementation in the of concentrations of concentrations to and for of the of in the of concentrations of mutations at the of which mutations in the of at to of the of in the of concentrations of and mutations that at to Both Phe-334 and are predicted to in 8 of of the of of the of the 8 ENT of of the is in Phe-334 conserved in of the and in of the and and at to that residues are conserved in of the that important in ENT of at Phe-334 and in the of the functional of Phe-334 and of mutations at in the of residues in ENT the is by ENT nucleoside in is important is by yeast of uptake for of in the of concentrations of for in the of and Vmax and the are in displayed and Vmax of and that displayed for in yeast in of by and Phe-334 and in of the Phe-334 mutants of to of of the Vmax of the Phe-334 mutants the for and of in Vmax the in to in the Vmax that the of the of mutants and the of in of that the of at the of residues at the in of the ENT of by and and for concentrations of are in the the uptake in the and of at and Vmax by are in is the and the of the is the the is the increased for the and and displayed Vmax the and the Both the of and the of at that the of of of in transporter of of and 1 that the Phe-334 and mutations the of functional at of yeast of the mutants to the of that which to the in the of which is structurally to and in for for which at the of the is and and of the that to of that which to that in and in and displayed that to that of the that and displayed that of the mutants displayed of that of and functional by of of the Phe-334 mutants for in the of the that by the of functional that by functional at the are the of of of the of are Vmax and to for and of the mutants and of the transporters displayed of and displayed of and that the of mutants F334Y displayed of that that of the of the in Vmax for the Phe-334 and mutants to in of functional of in to for of dipyridamole, dilazep, draflazine, and to the of the residues to of the are in of of by and mutants by dipyridamole, dilazep, draflazine, soluflazine. Phe-334 mutants mutants for in the of concentrations of the in the by are in the and for of yeast in the of concentrations of and by is the and the of the is the is the Phe-334 mutants displayed to and dilazep, for which displayed that and for and dilazep, F334Y for and for that of the Phe-334 mutations the for draflazine, mutations in increased for and and that the displayed for that to the mutants displayed for to the that and mutations to and soluflazine. that and for and of and at and the the for of of the for of is of of and for are the in for of the mutants highly the the F334Y and mutations of displayed for and dipyridamole, and for and that are of of mutations in and and for the of for to of the of which to the of to which displayed that of the and to that of the of for to of the and the to of the that 8 residues are important of and and of and of of that highly conserved important for and of and displayed of functional which to and in the of that and the of that mutants displayed to and of and that the and of of for the and and of the revealed that the and at and of for to the and that important in and the for the in that the of by the and the of functional the functional to the of the and of of to and of the of yeast residues of of are at the in the of in by of to yeast and is the of that the by and are in to of and in and inhibited to the to the in of to increased the for and for for for by and of to and the concentrations of are the of that the by and are of the in the of by of the and to the in by the of and of and to in the of the and to to and that residues to and that the in the of nucleosides that Phe-334 and nucleosides in that the for to of and to for in and 1 for are the of of uptake by the yeast are by mutagenesis for residues of in to the of Phe-334 and Asn-338. residues to of the 8 of ENT revealed that highly and the of Phe-334 the residues highly and to structurally important in ENT of 1 and and that Phe-334 and mutations the Vmax for by in to of for and of mutants to 8 the increased Vmax for F334Y to of increased of in in that the of is for the for the the for is that the in the the the to the in the of transporters in the the to that of is ENT to the that for that in the the of in that that in the that Phe-334 and residues for of in the ENT Phe-334 the of functional to and and displayed functional at the and that of and the functional and displayed to that the functional of 8 in 8 that of the highly conserved and the residues of which to for and and of are the of in which and to of the functional transporter the for in in and in to of the of the the the and of ENT residues by in of the and residues by in of the residues in are 8 that Phe-334 and are and the of the transmembrane highly conserved that are to the of transmembrane the and mutants to by the the and by that the in of the nucleoside and of Phe-334 mutations and that the of mutations and for are Phe-334 and and and in that Phe-334 and that the is the of the in the of that the of residues and important the of the for and in in to of transporters the the of 8 that is to the and of the for to is the to the of and and residues at dipyridamole, dilazep, and that the of important for to the that 8 residues important for transporter and at in the and that the of the of the to 8 residues that the of 8 is to in to and which in to important to and in 1 important for and and that to in of the that 8 is important for and in to 1 and in the of that conserved residues in to the of 8 in of at the of in and by the of which are that are the metabolic of and are in the of and in and of the equilibrative nucleoside transporter equilibrative nucleoside nitrobenzylmercaptopurine ribonucleoside transmembrane nucleoside equilibrative nucleoside nitrobenzylmercaptopurine ribonucleoside transmembrane nucleoside uptake and of nucleosides cellular in and are to segment and are equilibrative to by nitrobenzylmercaptopurine ribonucleoside of in in the of the nucleoside nucleoside the the and in and is of to to of including and of and by which the of are is by that are in of highly of nucleoside draflazine, dilazep, dipyridamole, and uptake and of the of and and and nucleoside at nanomolar and of of dipyridamole, dilazep, and in transporters at nanomolar dilazep, which of and the predicted to lie at the of 1 of and to important of the for dilazep, dipyridamole, and nucleosides for transporters in of in in is to to to the for nucleoside and that residues in and and and of are in and of of draflazine, which is of nucleoside and and to of the in to residues of in of dilazep, dipyridamole, residues in of soluflazine. mutagenesis and functional complementation screening that in the of and of Phe-334 and of residues in ENT at and for and by functional in of of the 8 to the that the residues the of that residues in are of of and and the yeast to which and which contains in the the by of the the and in yeast to and and in in and Random to by the and and to Random mutagenesis of by the in the of for to to the of mutations in of the residues the mutagenesis and of complementation the of in yeast to salvage of at and at at of of at for in the of and complementation 1 which and 1 and at for to of complementation in 1 of for and and dipyridamole, dilazep, 1 the yeast by and in of the transporters in to in and to at and at dipyridamole, dilazep, and and and the in of yeast to of in of yeast for of of to of and to of the and to for of by the yeast for the to of the the of and highly for to and to of yeast mutants in the of and and for and yeast the the of by by by and at to residues of of and yeast and for to to of of for the concentrations of in the of of that is structurally to at in 1 and of by by the of by by the for the concentrations of in the of concentrations that by by the of and the and the yeast to which and which contains in the the by of the the and in yeast to and and in in and Random to by the and and to Random mutagenesis of by the in the of for to to the of mutations in of the residues the mutagenesis and of complementation the of in yeast to salvage of at and at at of of at for in the of and complementation 1 which and 1 and at for to of complementation in 1 of for and and dipyridamole, dilazep, 1 the yeast by and in of the transporters in to in and to at and at dipyridamole, dilazep, and and and the in of yeast to of in of yeast for of of to of and to of the and to for of by the yeast for the to of the the of and highly for to and to of yeast mutants in the of and and for and yeast the the of by by by and at to residues of of and yeast and for to to of of for the concentrations of in the of of that is structurally to at in 1 and of by by the of by by the for the concentrations of in the of concentrations that by by the of and the and of yeast in the of and in the of and yeast of for salvage the of which is to by in yeast of is salvage is functional complementation for mutants for yeast by in the and yeast complementation in the of concentrations of concentrations to and for of the of in the of concentrations of mutations at the of which mutations in the of at to of the of in the of concentrations of and mutations that at to Both Phe-334 and are predicted to in 8 of of the of of the of the 8 ENT of of the is in Phe-334 conserved in of the and in of the and and at to that residues are conserved in of the that important in ENT of at Phe-334 and in the of the functional of Phe-334 and of mutations at in the of residues in ENT the is by ENT nucleoside in is important is by yeast of uptake for of in the of concentrations of for in the of and Vmax and the are in displayed and Vmax of and that displayed for in yeast in of by and Phe-334 and in of the Phe-334 mutants of to of of the Vmax of the Phe-334 mutants the for and of in Vmax the in to in the Vmax that the of the of mutants and the of in of that the of at the of residues at the in of the ENT the increased for the and and displayed Vmax the and the Both the of and the of at that the of of of in transporter of of and 1 that the Phe-334 and mutations the of functional at of yeast of the mutants to the of that which to the in the of which is structurally to and in for for which at the of the is and and of the that to of that which to that in and in and displayed that to that of the that and displayed that of the mutants displayed of that of and functional by of of the Phe-334 mutants for in the of the that by the of functional that by functional at the are the of of of the of are Vmax and to for and of the mutants and of the transporters displayed of and displayed of and that the of mutants F334Y displayed of that that of the of the in Vmax for the Phe-334 and mutants to in of functional of in to for of dipyridamole, dilazep, draflazine, and to the of the residues to of the are in of of by and mutants by dipyridamole, dilazep, draflazine, soluflazine. Phe-334 mutants mutants for in the of concentrations of the in the by are in the and for of yeast in the of concentrations of and by is the and the of the is the is the Phe-334 mutants displayed to and dilazep, for which displayed that and for and dilazep, F334Y for and for that of the Phe-334 mutations the for draflazine, mutations in increased for and and that the displayed for that to the mutants displayed for to the that and mutations to and soluflazine. that and for and of and at and the the for of of the for of is of of and for are the in for of the mutants highly the the F334Y and mutations of displayed for and dipyridamole, and for and that are of of mutations in and and for the of for to of the of which to the of to which displayed that of the and to that of the of for to of the and the to of the that 8 residues are important of and and of and of of that highly conserved important for and of and displayed of functional which to and in the of that and the of that mutants displayed to and of and that the and of of for the and and of the revealed that the and at and of for to the and that important in and the for the in that the of by the and the of functional the functional to the of the and of of to and of the of yeast residues of of are at the in the of in by of to yeast and is the of that the by and are in to of and in and inhibited to the to the in of to increased the for and for for for by and of to and the concentrations of are the of that the by and are of the in the of by of the and to the in by the of and of and to in the of the and to to and that residues to and that the in the of nucleosides that Phe-334 and nucleosides in that the for to of and to for in and 1 for are the of of uptake by the yeast are Random and of yeast in the of and in the of and yeast of for salvage the of which is to by in yeast of is salvage is functional complementation for mutants for yeast by in the and yeast complementation in the of concentrations of concentrations to and for of the of in the of concentrations of mutations at the of which mutations in the of at to of the of in the of concentrations of and mutations that at to Both Phe-334 and are predicted to in 8 of of the of of the of the 8 ENT of of the is in Phe-334 conserved in of the and in of the and and at to that residues are conserved in of the that important in ENT of at Phe-334 and in the of the functional of Phe-334 and of mutations at in the of residues in ENT the is by ENT nucleoside in is important is by yeast of uptake for of in the of concentrations of for in the of and Vmax and the are in displayed and Vmax of and that displayed for in yeast in of the Phe-334 mutants of to of of the Vmax of the Phe-334 mutants the for and of in Vmax the in to in the Vmax that the of the of mutants and the of in of that the of at the of residues at the in of the ENT the increased for the and and displayed Vmax the and the Both the of and the of at that the of of of in transporter of of and 1 that the Phe-334 and mutations the of functional at of yeast of the mutants to the of that which to the in the of which is structurally to and in for for which at the of the is and and of the that to of that which to that in and in and displayed that to that of the that and displayed that of the mutants displayed of that Vmax and to for and of the mutants and of the transporters displayed of and displayed of and that the of mutants F334Y displayed of that that of the of the in Vmax for the Phe-334 and mutants to in of functional of in to for of dipyridamole, dilazep, draflazine, and to the of the residues to of the are in Phe-334 mutants displayed to and dilazep, for which displayed that and for and dilazep, F334Y for and for that of the Phe-334 mutations the for draflazine, mutations in increased for and and that the displayed for that to the mutants displayed for to the that and mutations to and soluflazine. that and for and of and at and the the for of of the for of is of of and for are the in for of the mutants highly the the F334Y and mutations of displayed for and dipyridamole, and for and that are of of mutations in and and for the of for to of the of which to the of to which displayed that of the and to that of the of for to of the and the to of the that 8 residues are important of and and of and of of that highly conserved important for and of and displayed of functional which to and in the of that and the of that mutants displayed to and of and that the and of of for the and and of the revealed that the and at and of for to the and that important in and the for the in that the of by the and the of functional the functional to the of the and and inhibited to the to the in of to increased the for and for for for of and to in the of the and to to and that residues to and that the in the of nucleosides that Phe-334 and nucleosides in that the for to by mutagenesis for residues of in to the of Phe-334 and Asn-338. residues to of the 8 of ENT revealed that highly and the of Phe-334 the residues highly and to structurally important in ENT of 1 and and that Phe-334 and mutations the Vmax for by in to of for and of mutants to 8 the increased Vmax for F334Y to of increased of in in that the of is for the for the the for is that the in the the the to the in the of transporters in the the to that of is ENT to the that for that in the the of in that that in the that Phe-334 and residues for of in the ENT Phe-334 the of functional to and and displayed functional at the and that of and the functional and displayed to that the functional of 8 in 8 that of the highly conserved and the residues of which to for and and of are the of in which and to of the functional transporter the for in in and in to 8 that Phe-334 and are and the of the transmembrane highly conserved that are to the of transmembrane the and mutants to by the the and by that the in of the nucleoside and of Phe-334 mutations and that the of mutations and for are Phe-334 and and and in that Phe-334 and that the is the of the in the of that the of residues and important the of the for and in in to of transporters the the of 8 that is to the and of the for to is the to the of and and residues at dipyridamole, dilazep, and that the of important for to the that 8 residues important for transporter and at in the and that the of the of the to 8 residues that the of 8 is to in to and which in to important to and in 1 important for and and that to in of the that 8 is important for and in to 1 and in the of that conserved residues in to the of 8 in of at the of in and by the of by mutagenesis for residues of in to the of Phe-334 and Asn-338. residues to of the 8 of ENT revealed that highly and the of Phe-334 the residues highly and to structurally important in ENT of 1 and and that Phe-334 and mutations the Vmax for by in to of for and of mutants to 8 the increased Vmax for F334Y to of increased of in in that the of is for the for the the for is that the in the the the to the in the of transporters in the the to that of is ENT to the that for that in the the of in that that in the that Phe-334 and residues for of in the ENT Phe-334 the of functional to and and displayed functional at the and that of and the functional and displayed to that the functional of 8 in 8 that of the highly conserved and the residues of which to for and and of are the of in which and to of the functional transporter the for in in and in to 8 that Phe-334 and are and the of the transmembrane highly conserved that are to the of transmembrane the and mutants to by the the and by that the in of the nucleoside and of Phe-334 mutations and that the of mutations and for are Phe-334 and and and in that Phe-334 and that the is the of the in the of that the of residues and important the of the for and in in to of transporters the the of 8 that is to the and of the for to is the to the of and Both and residues at dipyridamole, dilazep, and that the of important for to the that 8 residues important for transporter and at in the and that the of the of the to 8 residues that the of 8 is to in to and which in to important to and in 1 important for and and that to in of the that 8 is important for and in to 1 and in the of that conserved residues in to the of 8 in of at the of in and by the of

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.