Affinage

SLC29A1

Equilibrative nucleoside transporter 1 · UniProt Q99808

Length
456 aa
Mass
50.2 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC29A1/ENT1 is a glycosylated, multi-pass integral membrane equilibrative nucleoside transporter that bidirectionally moves nucleosides and a range of nucleoside-analog drugs across cell membranes, thereby setting extracellular adenosine tone and supporting cellular nucleotide homeostasis (PMID:10722669, PMID:35042768). Functionally characterized in nucleoside-transporter-deficient cells, ENT1 binds the inhibitor NBMPR with high affinity and transports nucleosides such as uridine, with markedly greater sensitivity to NBMPR and dipyridamole than ENT2 (PMID:10722669). Crystal structures in complex with dilazep and NBMPR reveal two distinct inhibitory mechanisms and the residues underlying adenosine recognition and transport (PMID:31235912), and a Gly24 residue in transmembrane domain 1 is critical for transport activity, as its mutation abolishes uptake and NBMPR binding without disrupting plasma membrane localization (PMID:19116148). N-linked glycosylation at Asn48 is required for membrane abundance, transport activity, and self-oligomerization (PMID:27480168). Transport activity is regulated post-translationally by direct PKA and PKC phosphorylation of serine/threonine residues in the large intracellular loop (PMID:21809900) and by calcium-dependent calmodulin binding via a 1-5-10 motif, linking receptor-driven Ca2+ signals to nucleoside uptake (PMID:27009875). SLC29A1 expression is transcriptionally controlled through Sp1/MAZ promoter elements (PMID:11027664), repressed by JNK–c-Jun signaling at an AP-1 site (PMID:21145879), and modulated by NO-dependent hCHOP-C/EBPalpha and HIF-1alpha pathways in diabetic and oncogenic contexts (PMID:20032083, PMID:19853583). Physiologically, ENT1 governs purinergic signaling: knockout elevates circulating adenosine and reshapes adenosine-receptor-dependent cAMP signaling (PMID:21872611), astrocytic ENT1 controls extracellular adenosine that tonically inhibits dopamine release via A1 receptors (PMID:35042768), and ENT1-mediated adenosine and nicotinamide flux supports erythropoiesis, NAD+/metabolic homeostasis, and erythrocyte AMPK–BPGM–2,3-BPG-driven O2 delivery (PMID:39885119, PMID:33690842, PMID:37725437, PMID:32434995). In immunity and cancer, ENT1-mediated adenosine and uridine uptake suppresses anti-tumor T cell function through inhibition of PRPP synthetase-dependent pyrimidine synthesis and confers resistance to nucleoside-analog and DHODH-inhibitor therapies (PMID:40355731, PMID:36341997). Human SLC29A1-null mutations define the Augustine-negative blood type and cause periarticular and ectopic mineralization, establishing a role in mineral homeostasis (PMID:25896650).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Establishing ENT1 as a discrete, high-affinity nucleoside transporter required functional reconstitution in a transporter-null background; this defined its kinetics, inhibitor sensitivity, and biochemical identity distinct from ENT2.

    Evidence Stable expression in nucleoside-transporter-deficient PK15NTD cells with radiolabeled uptake, NBMPR binding, and deglycosylation assays

    PMID:10722669

    Open questions at the time
    • Did not resolve transport-cycle structural mechanism
    • Substrate range across all nucleoside analogs not exhaustively mapped
  2. 2000 Medium

    Defining the gene architecture and core promoter answered how baseline ENT1 expression is set, identifying Sp1 and MAZ as positive transcriptional regulators.

    Evidence Genomic cloning, primer extension, and luciferase reporter assays of the SLC29A1 promoter

    PMID:11027664

    Open questions at the time
    • Did not test these elements in the endogenous chromatin context
    • Tissue-specific regulation not addressed
  3. 2001 Medium

    Identification of an alternatively spliced isoform lacking a casein kinase II site raised the question of isoform-specific regulation, though transport pharmacology was unchanged.

    Evidence cDNA/genomic cloning and stable expression with adenosine uptake assays in mouse

    PMID:11179696

    Open questions at the time
    • Functional consequence of the missing phosphosite not demonstrated
    • Mouse isoform; human relevance unestablished
  4. 2008 High

    A point mutation found in Ara-C-resistant cells localized transport function to a specific residue, establishing Gly24 in TM1 as critical for the transport/binding pocket.

    Evidence Site-directed mutagenesis (G24R/E/A) with uridine/Ara-C uptake, NBMPR binding, and EGFP localization in CCRF-CEM cells

    PMID:19116148

    Open questions at the time
    • Atomic-level role of Gly24 not resolved until later structures
    • Did not address whether the mutation alters drug-specific selectivity
  5. 2011 High

    Direct phosphorylation mapping answered how kinase signaling tunes ENT1, showing PKA and PKC phosphorylate defined sites in the large intracellular loop.

    Evidence In vitro kinase assays on tagged intracellular-loop peptides with phosphoamino acid analysis and site-directed mutagenesis

    PMID:21809900

    Open questions at the time
    • Functional effect of each phosphosite on transport not quantified
    • In vivo phosphorylation stoichiometry unknown
  6. 2016 High

    Glycosylation and calmodulin studies established two distinct post-translational requirements—Asn48 glycosylation for trafficking/oligomerization and Ca2+/CaM binding for activity-coupling to receptor signals.

    Evidence Glycosylation-site mutagenesis with transport/co-IP and Ca2+/CaM functional uptake assays including NMDA receptor stimulation

    PMID:27009875 PMID:27480168

    Open questions at the time
    • CaM interaction is Medium-confidence single-lab Co-IP without reciprocal validation
    • Structural basis of glycosylation-dependent oligomerization unresolved
  7. 2010 High

    Multiple signaling-to-transcription studies answered how disease and metabolic states downregulate ENT1, converging on NO/eNOS–hCHOP-C/EBPalpha, Sp1, PKC-zeta/Raf/MEK/p38, JNK–c-Jun, and HIF-1alpha pathways.

    Evidence Luciferase reporters, ChIP, promoter mutagenesis, siRNA, and pharmacological kinase inhibition across HUVEC, cardiac fibroblast, and leukemia models

    PMID:16688763 PMID:17941087 PMID:18064606 PMID:19853583 PMID:20032083 PMID:21145879

    Open questions at the time
    • Several pathways tested in single labs/cell types
    • Cross-talk and hierarchy among these regulators not integrated
  8. 2012 Medium

    Knockout and tissue studies established ENT1 as the dominant nucleoside transporter controlling extracellular adenosine and adenosine-receptor-dependent cAMP signaling in vascular and cardiac tissue.

    Evidence ENT1-/- mouse endothelial/cardiomyocyte uptake, HPLC nucleoside quantification, and cAMP measurements with hypoxic challenge

    PMID:20543083 PMID:21872611

    Open questions at the time
    • Compensatory ADA/A2A upregulation complicates interpretation
    • Receptor-subtype-specific contributions not fully separated
  9. 2013 High

    Neural and platelet studies answered how ENT1 shapes purinergic signaling at synapses and in hemostasis, placing it upstream of A1/A2A receptor cascades.

    Evidence Electrophysiology with A1R antagonists in spinal cord, ENT1-/- × CREB epistasis in striatum, GRAB-Ado imaging/voltammetry, and platelet adenosine/cAMP/VASP assays

    PMID:12611914 PMID:21283641 PMID:23467349 PMID:24163005 PMID:25490964 PMID:27694321 PMID:35042768

    Open questions at the time
    • Astrocyte-specific overexpression strongest; some endpoints rely on pharmacology alone
    • Direct vs indirect contributions to behavior incompletely separated
  10. 2015 Medium

    Human genetics established physiological roles by linking SLC29A1-null status to the Augustine-negative blood type and to ectopic/periarticular mineralization.

    Evidence Genetic sequencing, blood-group serology, and clinical phenotyping of ENT1-null individuals

    PMID:25896650

    Open questions at the time
    • No in vitro reconstitution of the mineralization mechanism
    • Molecular link between ENT1 loss and mineral deposition not defined
  11. 2019 High

    High-resolution crystal structures with dilazep and NBMPR answered the structural basis of substrate recognition and revealed two distinct inhibitory mechanisms.

    Evidence X-ray crystallography with site-directed mutagenesis and transport assays

    PMID:31235912

    Open questions at the time
    • Captured limited conformational states of the transport cycle
    • Substrate-bound (vs inhibitor-bound) states not resolved here
  12. 2023 High

    Tissue-specific knockouts and metabolic flux defined ENT1 as a master regulator of erythroid and systemic metabolism—cAMP homeostasis, AMPK–BPGM–2,3-BPG O2 delivery, NAD+ maintenance, and placental nutrient supply.

    Evidence Erythrocyte-specific and global Ent1-/- mice with ABCC4/AMPD3 epistasis, isotopic flux, metabolomics, and nicotinamide/NAD+ assays

    PMID:32434995 PMID:33690842 PMID:37725437 PMID:39885119

    Open questions at the time
    • NAD+/senescence link is Medium-confidence single-lab
    • Relative tissue contributions to systemic phenotypes not fully apportioned
  13. 2025 High

    Cancer and immunology studies established ENT1 as a determinant of nucleoside-analog drug response and anti-tumor immunity via adenosine/uridine uptake and PRPPS-dependent pyrimidine synthesis.

    Evidence ENT1 knockout/inhibition with metabolomics, co-culture cytotoxicity, and in vivo tumor models including PD-1 combination; uridine-salvage and gemcitabine-resistance pathway studies

    PMID:22232287 PMID:30097436 PMID:31711924 PMID:36341997 PMID:40355731

    Open questions at the time
    • PRPPS-inhibition mechanism characterized in one major study
    • Combination-therapy efficacy in humans not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse post-translational (phosphorylation, Ca2+/CaM), transcriptional, and structural regulatory inputs are integrated to set ENT1 transport rate in specific tissues, and the molecular mechanism linking ENT1 loss to ectopic mineralization, remain unresolved.
  • No unified model connecting phosphosite occupancy to transport kinetics in vivo
  • Mechanism of mineralization phenotype undefined
  • Full substrate-bound transport-cycle structures lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0140104 molecular carrier activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-168256 Immune System 1
Partners
ABCC4CALM1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 Crystal structures of hENT1 in complex with two adenosine reuptake inhibitors (dilazep and NBMPR) were solved, revealing two distinct inhibitory mechanisms. Mutagenesis studies elucidated the molecular basis of adenosine recognition and transport, and identified key residues in the inhibitor binding sites. X-ray crystallography combined with site-directed mutagenesis and functional transport assays Nature structural & molecular biology High 31235912
2000 hENT1 stably expressed in nucleoside transporter-deficient PK15NTD cells is N-glycosylated (apparent MW 40 kDa; deglycosylated to 37 kDa by PNGase-F/Endo-H), binds [3H]NBMPR with high affinity (Kd 0.377 nM, ~34,000 sites/cell), and transports nucleosides with a turnover number of ~46 molecules/s for uridine. hENT1 shows markedly higher sensitivity to NBMPR (IC50 0.4 nM) and dipyridamole (IC50 5 nM) than hENT2, and lower affinity for inosine relative to hENT2. Stable transfection in nucleoside-transporter-deficient PK15NTD cells; radiolabeled uptake assays; [3H]NBMPR binding; peptide-N-glycosidase F and endoglycosidase H deglycosylation; SDS-PAGE The Journal of biological chemistry High 10722669
2016 N-linked glycosylation at Asn48 (in the first extracellular loop) is required for ENT1 function: N48Q substitution abolishes glycosylation, reduces plasma membrane abundance, eliminates nucleoside transport activity, and prevents ENT1 self-oligomerization as detected by co-immunoprecipitation. Site-directed mutagenesis of glycosylation sites; PNGase-F treatment; NBTI binding; chloroadenosine transport assay; co-immunoprecipitation; immunofluorescence microscopy Bioscience reports High 27480168
2011 ENT1 is a phosphoprotein directly phosphorylated at multiple serine residues in the large intracellular loop (between TM6 and TM7). PKA phosphorylates multiple sites within this loop; PKC specifically targets Ser279, Ser286, and Thr274. Affinity-purified overexpressed hENT1/mENT1; phosphoamino acid analysis; in vitro kinase assays with His/Ubiquitin-tagged intracellular loop peptides; site-directed mutagenesis Molecular membrane biology High 21809900
2016 Calmodulin (CaM) interacts with ENT1 via a conserved 1-5-10 CaM-binding motif in a calcium-dependent manner. Pharmacological chelation of Ca2+ reduces nucleoside and nucleoside analog drug uptake (~12% and ~39%, respectively), while increasing intracellular Ca2+ enhances uptake (~26%). NMDA receptor activation also increases nucleoside uptake in a CaM-dependent manner, establishing a receptor-stimulated Ca2+/CaM regulatory mechanism for ENT1. Co-immunoprecipitation; functional uptake assays with Ca2+-modulating pharmacological agents; NMDA receptor agonist/antagonist experiments; CaM antagonist W7 American journal of physiology. Cell physiology Medium 27009875
2001 An alternative splice isoform of mouse ENT1 (mENT1.2) lacks a 2-amino-acid segment including Ser254, a consensus casein kinase II phosphorylation site. Both isoforms show equivalent pharmacological sensitivity to NBMPR and dipyridamole and similar nucleoside selectivity, but mENT1.2 lacks a potential phosphorylation site. cDNA cloning; genomic DNA analysis; stable expression in CEM/C19 cells; [3H]adenosine uptake and inhibition assays; RT-PCR for tissue distribution Gene Medium 11179696
2000 The mouse ENT1 gene spans ~12 kb on chromosome 17C with 12 exons and 11 introns. The SLC29A1 promoter region between -652 and -111 bp contains cis-regulatory elements including two Sp1 binding sites (-296/-303, -307/-313) and two MAZ binding sites (-353/-359, -522/-528) that are positive regulators of transcription, as confirmed by luciferase reporter assays. Genomic cloning and sequencing; primer extension; luciferase reporter assays; electrophoretic mobility shift assay (inferred from binding site analysis) Biochemical and biophysical research communications Medium 11027664
2009 In HUVECs from gestational diabetes, nitric oxide (NO) reduces SLC29A1 promoter activity and hENT1-mediated adenosine transport through a hCHOP-C/EBPalpha transcription factor complex. The hCHOP-C/EBPalpha complex binds to a consensus site at -1845/-1844 of the SLC29A1 promoter; mutation of this site, eNOS siRNA knockdown, or NOS inhibition all block the NO-dependent reduction in hENT1 expression. Luciferase reporter assays; chromatin immunoprecipitation; overlap extension mutagenesis of promoter; eNOS siRNA knockdown (adenoviral); adenosine uptake assays; Western blotting Cardiovascular research High 20032083
2006 NO produced by eNOS reduces SLC29A1 promoter activity and hENT1-mediated adenosine transport in HUVECs from gestational diabetes. Adenoviral siRNA knockdown of eNOS increases hENT1 expression and transport activity in both normal and diabetic cells; SLC29A1 promoter activity is regulated differentially by the region between -2154 and -1114. Luciferase reporter assays (pGL3 constructs); eNOS siRNA adenoviral knockdown; adenosine uptake assays; real-time PCR; Western blotting Journal of cellular physiology Medium 16688763
2008 High D-glucose reduces hENT1-mediated adenosine transport by increasing Sp1 transcription factor binding to the SLC29A1 promoter, thereby downregulating hENT1 expression. This effect requires eNOS, MEK1/2, and PKC activity and is blocked by their respective inhibitors (L-NAME, PD-98059, calphostin C). Sp1 overexpression alone reduces SLC29A1 promoter activity under normal glucose conditions. Luciferase reporter assays; chromatin immunoprecipitation for Sp1 binding; pharmacological inhibition of eNOS/MEK/PKC; [3H]adenosine uptake; Western blotting Journal of cellular physiology Medium 18064606
2008 High glucose suppresses ENT1 expression in rat cardiac fibroblasts through a signaling cascade involving PKC-zeta, Raf-1 kinase, MEK, and p38 MAPK, independent of nitric oxide. Selective inhibitors of PKC-zeta (pseudosubstrate), Raf kinase (GW5074), MEK (PD98059), and p38 MAPK (SB203580) each blocked high-glucose-induced ENT1 suppression. Pharmacological inhibition; quantitative mRNA measurement; NBTI-sensitive [3H]adenosine uptake assay Journal of cellular physiology Medium 17941087
2010 JNK activation (but not p38 MAPK) causes rapid loss of mouse ENT1 function, mRNA expression, and promoter activity. c-Jun (but not the Ser63/73Ala mutant) decreases mENT1 promoter activity, and c-Jun binds to an AP-1 site at -1196 of the mENT1 promoter, establishing that the JNK-c-Jun pathway negatively regulates ENT1. JNK activation and inhibition assays; luciferase reporter assays with mENT1 promoter; chromatin immunoprecipitation for c-Jun; [3H]uridine uptake; dominant-negative c-Jun construct Biochemical and biophysical research communications Medium 21145879
2009 FLT3-ITD (an oncogenic kinase mutation in AML) reduces ENT1 promoter activity and ara-C uptake in leukemia cells through upregulation of HIF-1alpha. HIF-1alpha induction reduces SLC29A1 promoter activity; the FLT3 kinase inhibitor PKC412 rescues ENT1 promoter activity and ara-C cellular uptake. Luciferase reporter assays; FLT3 inhibitor (PKC412) treatment; [3H]ara-C uptake; mRNA expression analysis Biochemical and biophysical research communications Medium 19853583
2008 A point mutation G24R in transmembrane domain 1 of ENT1, identified in Ara-C-resistant CCRF-CEM cells, abolishes nucleoside uptake and NBMPR binding while preserving plasma membrane localization. Additional G24 mutants (G24E, G24A) also show reduced ENT1 activity, defining Gly24 as a critical residue for transport function. DNA sequencing; site-directed mutagenesis (G24R, G24E, G24A); [3H]uridine and [3H]Ara-C uptake assays; [3H]NBMPR binding; EGFP-tagged construct for localization FEBS letters High 19116148
2010 ENT1 regulates EAAT2 (glutamate transporter) expression and function in astrocytes. ENT1 inhibition or siRNA knockdown reduces EAAT2 mRNA and glutamate uptake activity, while ENT1 overexpression upregulates EAAT2 mRNA. ENT1 knockdown also blocks ethanol-induced EAAT2 upregulation. ENT1-specific antagonist and siRNA knockdown; ENT1 overexpression; quantitative real-time PCR; glutamate uptake assay Alcoholism, clinical and experimental research Medium 20374202
2013 ENT1 inhibition by ticagrelor on platelets leads to accumulation of extracellular adenosine and activation of Gs-coupled A2A receptors, increasing cAMP and VASP phosphorylation. Ticagrelor also acts as an inverse agonist at the P2Y12 receptor, blocking constitutive Gi signaling. These two mechanisms are distinct and together contribute to platelet inhibition. Platelet adenosine uptake assay; cAMP measurement; VASP-P (phosphorylation) assay; 1321N1 cells stably expressing P2Y12R; pharmacological inhibition; [3H]NBMPR competition Blood Medium 27694321
2012 ENT1 is the primary nucleoside transport mechanism in endothelial cells; in ENT1-/- microvascular endothelial cells, nucleoside uptake is severely reduced while nucleobase transport (ENBT1) is unchanged. Loss of ENT1 leads to compensatory increases in adenosine deaminase and A2a adenosine receptor expression at both transcript and protein levels in vascular endothelium. Radiolabeled nucleoside/nucleobase uptake in ENT1-/- and WT mouse microvascular endothelial cells; quantitative PCR; protein expression analysis American journal of physiology. Heart and circulatory physiology Medium 20543083
2011 Absence of ENT1 in knockout mice elevates circulating adenosine levels (~2-fold) and increases extracellular adenosine in isolated cardiomyocytes following hypoxic challenge. ENT1 modulates adenosine receptor (AR)-dependent cAMP signaling, as AR activation mimics hypoxia-induced cAMP increases in ENT1-null cells. ENT1-/- mouse model; HPLC nucleoside quantification; hypoxic challenge in isolated cardiomyocytes; PCR arrays; cAMP measurements Life sciences Medium 21872611
2013 ENT1 in striatal astrocytes controls extracellular adenosine tone, which tonically inhibits dopamine release in nucleus accumbens core via A1 receptors. Virally mediated astrocyte-specific ENT1 overexpression enhances dopamine release and relieves A1R-mediated inhibition. ENT1 inhibition elevates extracellular adenosine (directly imaged with GRAB-Ado fluorescent sensor), and ethanol promotes A1R-mediated inhibition of dopamine release by reducing adenosine uptake via ENT1. ENT1 inhibitor (NBTI); viral astrocyte-specific ENT1 overexpression; fast-scan cyclic voltammetry; optogenetic stimulation; GRAB-Ado fluorescent adenosine sensor imaging; gliotoxin fluorocitrate control The Journal of neuroscience High 35042768
2025 Adenosine uptake into activated T cells by ENT1 suppresses anti-cancer immune responses by inhibiting phosphoribosyl pyrophosphate synthetase (PRPPS), thereby reducing de novo pyrimidine nucleotide (UMP and derivatives) synthesis required for T cell proliferation and function. T cells upregulate ENT1 upon activation, and ENT1 deficiency or its pharmacological blockade restores pyrimidine levels and enhances tumor cell killing. ENT1 knockout mice; CD8+ T cell tumor-infiltrating analysis; pharmacological ENT1 inhibitor (EOS301984); co-culture cytotoxicity assay; metabolomics for pyrimidine levels; transcriptomic profiling; PD-1 combination in humanized mouse tumor model Nature immunology High 40355731
2025 ENT1 (SLC29A1) and ENT2 (SLC29A2) transport nicotinamide (NAM) across cell membranes and regulate cellular NAD+ levels, mitochondrial status, and cellular senescence. ENT1/2 knockdown reduces NAD+ pool and induces senescence, effects reversed by NMN supplementation. ENT1/2 knockdown; nicotinamide uptake assay; NAD+ metabolomics; cellular respiration measurements; senescence assays; NMN supplementation rescue Nature communications Medium 39885119
2021 ENT1-mediated adenosine transport is critical for cyclic AMP (cAMP) homeostasis in erythroid cells. Absence of ENT1 (Augustine-null blood type) causes defective erythropoiesis, macrocytosis, and abnormal nucleotide metabolome. Genetic loss-of-function of ABCC4 (a cAMP exporter) in Ent1-/- mice rescues erythropoiesis, and pharmacological ABCC4 inhibition in Ent1-/- mice also rescues erythropoiesis, establishing an ENT1-cAMP-erythroid transcription factor axis. ENT1-/- mouse model; shRNA knockdown of ENT1 in human CD34+ progenitors; metabolomics; genetic epistasis (ABCC4 loss-of-function); pharmacological ABCC4 inhibition; erythropoiesis assays Blood High 33690842
2023 In erythrocytes, ENT1-mediated adenosine uptake activates AMPK-alpha by raising intracellular AMP, which in turn activates bisphosphoglycerate mutase (BPGM) to increase 2,3-BPG and glutathione, enhancing O2 delivery and antioxidative capacity. Loss of erythrocyte-specific ENT1 impairs this pathway, activating AMPD3-mediated metabolic reprogramming and causing renal hypoxia. Genetic ablation of AMPD3 in Ent1-/- mice rescues AMPK-BPGM activation and O2 delivery. Erythrocyte-specific ENT1 knockout (eEnt1-/-) mice; Ampd3-/- mice; isotopic adenosine flux analysis; unbiased metabolomics; AMPK/BPGM/2,3-BPG biochemical measurements; CKD mouse models Journal of the American Society of Nephrology High 37725437
2020 Maternal erythrocyte ENT1-dependent adenosine uptake activates AMPK (by controlling AMP/ATP ratio) and downstream BPGM, increasing 2,3-BPG and O2 delivery to the placenta. Genetic ablation of ENT1 specifically in maternal erythrocytes (eENT1 KO) causes fetal growth restriction through placental hypoxia, elevated HIF-1alpha, and preferential reduction of LAT1 amino acid transporter expression/activity. Erythrocyte-specific eENT1-/- dams; isotopic labeled tracer metabolic flux; unbiased metabolomics; HIF-1alpha measurement; LAT1 functional assay; HIF-1alpha overexpression in human trophoblasts JCI insight High 32434995
2022 ENT1 mediates uptake of extracellular uridine as a salvage mechanism for pyrimidine nucleotide synthesis, conferring resistance to DHODH inhibitors (e.g., brequinar) in pancreatic cancer cells. CNX-774, a BTK inhibitor, inhibits ENT1 in a BTK-independent manner and sensitizes resistant cells to DHODH inhibition by blocking uridine uptake. Small molecule combination screen; ENT1 transport assay; [3H]uridine uptake; cell viability; metabolomics (pyrimidine nucleotide levels); in vivo mouse tumor model Cancer letters Medium 36341997
2019 ZIP4 overexpression in pancreatic cancer cells activates STAT3, inducing ZEB1, which in turn upregulates integrin α3β1. Subsequent integrin α3β1 signaling via JNK inhibits SLC29A1 (ENT1) expression and gemcitabine uptake, contributing to drug resistance. Knockdown/overexpression of ZIP4, ZEB1, ITGA3, ITGB1; chromatin immunoprecipitation; luciferase reporter assays; gemcitabine accumulation by LC-MS/MS; xenograft tumor models Gastroenterology Medium 31711924
2015 A nonsynonymous SNP in SLC29A1 (rs45458701, p.Glu391Lys) is responsible for the Augustine-negative blood type. Separately, homozygous null mutation (c.589+1G>C) in SLC29A1 causes absence of ENT1 protein and results in periarticular and ectopic mineralization in humans, establishing a role for ENT1 in bone/mineral homeostasis. Genetic sequencing; blood group serology; clinical phenotyping of ENT1-null individuals Blood Medium 25896650
2012 ENT1 (rENT1) is abundantly expressed in rat spinal cord dorsal horn (laminae I-III). The ENT1 inhibitor NBMPR attenuates synaptically evoked EPSCs onto lamina II neurons in a concentration-dependent and adenosine A1 receptor-dependent manner, reduces miniature EPSC frequency (but not amplitude), and increases paired-pulse ratio, demonstrating presynaptic modulation of glutamatergic transmission via adenosine accumulation. Immunohistochemistry; immunoblotting; whole-cell patch-clamp recording in spinal cord slices; A1 receptor antagonist (DPCPX); adenosine deaminase treatment The Journal of physiology Medium 12611914
2013 ENT1 deletion in mice reduces A2A receptor-mediated CREB activity in the dorsomedial striatum (DMS), enhancing goal-directed behavior and increasing vulnerability to excessive ethanol drinking. Dominant-negative CREB in the DMS reduces A2AR signaling and promotes ethanol drinking; A2AR antagonist promotes excessive ethanol drinking in wild-type but not ENT1-/- mice, placing ENT1 upstream of A2AR-CREB signaling in DMS. ENT1-/- mouse model; CRE-lacZ reporter mice crossed with ENT1-/- mice; dominant-negative CREB; A2AR antagonist (ZM241385); PKA activity measurement; operant conditioning The Journal of neuroscience Medium 23467349
2010 Ethanol (5–200 mM) reduces ENT1-dependent [3H]2-chloroadenosine uptake in cardiomyocytes (HL-1 cells) by up to ~27%. Ethanol sensitivity of adenosine uptake is altered by pharmacological activation of PKA and PKC; cardiomyocytes from PKCε-null mice show greater (~37%) sensitivity to ethanol-induced inhibition of ENT1. Radiolabeled adenosine uptake; PKA/PKC activators; primary cardiomyocytes from PKCε-null mice Purinergic signalling Medium 24163005
2018 ENT1 is the dominant transporter for abacavir uptake at the maternal face of the human syncytiotrophoblast (apical/microvillous plasma membrane), as demonstrated in BeWo cells, fresh villous fragments, MVM vesicles, and dually perfused rat term placentas. CNT-mediated transport of abacavir was only detected in BeWo cells. [3H]abacavir uptake in BeWo cells, villous fragments, MVM vesicles; ENT1 inhibitor (NBMPR) and dipyridamole; dually perfused rat placenta; quantitative SLC29A1/2 expression Drug metabolism and disposition Medium 30097436
2012 ENT1 is the primary ribavirin transporter in HCV-replicating OR6 cells. NBMPR and miRNA targeting ENT1 mRNA each reduce ribavirin uptake and proportionally reduce antiviral activity, demonstrating that ENT1-mediated ribavirin uptake determines drug efficacy against HCV replication. mRNA expression analysis; transport assays; NBMPR inhibition; miRNA-mediated ENT1 knockdown; HCV replication assay Antimicrobial agents and chemotherapy Medium 22232287
2022 Molecular dynamics simulations of hENT1 reveal that conformational transitions from outward-open to occluded states are mainly driven by TM1, TM2, TM7, and TM9. Dilazep occupies both the orthosteric adenosine-binding site (via one trimethoxyphenyl ring) and an opportunistic extracellular site (via the other ring, interacting with N30, M33, M84, P308, F334), blocking the transport cycle by preventing complete occlusion. Long-timescale unbiased molecular dynamics simulations; comparative analysis with crystal structures Current research in structural biology Low 35677775
2014 ENT1 inhibition in the spinal cord elevates extracellular adenosine and suppresses glutamatergic neurotransmission, attenuating seizure severity in rats. Intrahippocampal and intraperitoneal NBTI (ENT1 inhibitor) reduces seizure severity, prolongs onset latency, suppresses neuronal firing, reduces miniature EPSC frequency, and decreases phospho-CREB. NBTI administration (intrahippocampal and i.p.); EEG monitoring; patch-clamp recording; Western blotting for phospho-CREB Neuromolecular medicine Medium 25490964
2011 The ENT1 variant 647C (ENT1-216Thr) shows increased adenosine uptake after prolonged ethanol exposure compared to wild-type ENT1-216Ile in transfected cells, potentially reducing extracellular adenosine levels. ENT1-/- mice display increased propensity to ethanol withdrawal seizures. Transfected cell adenosine uptake assay; ENT1-/- mouse model; ethanol withdrawal seizure scoring PloS one Medium 21283641

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 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. The Journal of biological chemistry 272 10722669
2019 ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3β1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells. Gastroenterology 127 31711924
2003 The yeast Epsin Ent1 is recruited to membranes through multiple independent interactions. The Journal of biological chemistry 105 12529323
2019 Structures of human ENT1 in complex with adenosine reuptake inhibitors. Nature structural & molecular biology 90 31235912
2012 Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice. The Journal of clinical investigation 90 22269324
1999 Distribution of equilibrative, nitrobenzylthioinosine-sensitive nucleoside transporters (ENT1) in brain. Journal of neurochemistry 85 10428086
2013 Ceftriaxone treatment affects the levels of GLT1 and ENT1 as well as ethanol intake in alcohol-preferring rats. Journal of molecular neuroscience : MN 82 23893122
2013 Adenosine transporter ENT1 regulates the acquisition of goal-directed behavior and ethanol drinking through A2A receptor in the dorsomedial striatum. The Journal of neuroscience : the official journal of the Society for Neuroscience 81 23467349
2016 Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor. Blood 76 27694321
2003 Functional characterization in yeast of genetic variants in the human equilibrative nucleoside transporter, ENT1. Pharmacogenetics 62 12724623
2018 Adenosine Augmentation Evoked by an ENT1 Inhibitor Improves Memory Impairment and Neuronal Plasticity in the APP/PS1 Mouse Model of Alzheimer's Disease. Molecular neurobiology 52 29616397
2003 Control of glutamatergic neurotransmission in the rat spinal dorsal horn by the nucleoside transporter ENT1. The Journal of physiology 52 12611914
2010 Biodistribution and uptake of 3'-deoxy-3'-fluorothymidine in ENT1-knockout mice and in an ENT1-knockdown tumor model. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 45 20720035
2009 Nitric oxide reduces SLC29A1 promoter activity and adenosine transport involving transcription factor complex hCHOP-C/EBPalpha in human umbilical vein endothelial cells from gestational diabetes. Cardiovascular research 43 20032083
2010 ENT1 regulates ethanol-sensitive EAAT2 expression and function in astrocytes. Alcoholism, clinical and experimental research 40 20374202
2006 Nitric oxide reduces adenosine transporter ENT1 gene (SLC29A1) promoter activity in human fetal endothelium from gestational diabetes. Journal of cellular physiology 40 16688763
2017 Targeting ENT1 and adenosine tone for the treatment of Huntington's disease. Human molecular genetics 38 28069792
2015 Lack of the nucleoside transporter ENT1 results in the Augustine-null blood type and ectopic mineralization. Blood 38 25896650
2004 Distribution of CNT2 and ENT1 transcripts in rat brain: selective decrease of CNT2 mRNA in the cerebral cortex of sleep-deprived rats. Journal of neurochemistry 38 15287894
2009 FLT3-ITD induces ara-C resistance in myeloid leukemic cells through the repression of the ENT1 expression. Biochemical and biophysical research communications 35 19853583
2013 Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy. European journal of cancer (Oxford, England : 1990) 34 24361227
2011 Absence of equilibrative nucleoside transporter 1 in ENT1 knockout mice leads to altered nucleoside levels following hypoxic challenge. Life sciences 34 21872611
2021 The equilibrative nucleoside transporter ENT1 is critical for nucleotide homeostasis and optimal erythropoiesis. Blood 33 33690842
2011 Functional role of the polymorphic 647 T/C variant of ENT1 (SLC29A1) and its association with alcohol withdrawal seizures. PloS one 33 21283641
2006 Thirty novel genetic variations in the SLC29A1 gene encoding human equilibrative nucleoside transporter 1 (hENT1). Drug metabolism and pharmacokinetics 33 16858130
2001 Cloning of a novel isoform of the mouse NBMPR-sensitive equilibrative nucleoside transporter (ENT1) lacking a putative phosphorylation site. Gene 32 11179696
2012 Bone marrow stromal cells modulate mouse ENT1 activity and protect leukemia cells from cytarabine induced apoptosis. PloS one 31 22629369
2017 FBW7 increases the chemosensitivity of pancreatic cancer cells to gemcitabine through upregulation of ENT1. Oncology reports 30 28765935
2020 ENT1 inhibition attenuates apoptosis by activation of cAMP/pCREB/Bcl2 pathway after MCAO in rats. Experimental neurology 29 32445645
2012 ENT1, a ribavirin transporter, plays a pivotal role in antiviral efficacy of ribavirin in a hepatitis C virus replication cell system. Antimicrobial agents and chemotherapy 28 22232287
2018 Equilibrative Nucleoside Transporter 1 (ENT1, SLC29A1) Facilitates Transfer of the Antiretroviral Drug Abacavir across the Placenta. Drug metabolism and disposition: the biological fate of chemicals 27 30097436
2011 Role of nucleoside transporters SLC28A2/3 and SLC29A1/2 genetics in ribavirin therapy: protection against anemia in patients with chronic hepatitis C. Pharmacogenetics and genomics 27 21346688
2011 The Equilibrative Nucleoside Transporter (ENT1) can be phosphorylated at multiple sites by PKC and PKA. Molecular membrane biology 27 21809900
2004 Gene-expression profiling reveals down-regulation of equilibrative nucleoside transporter 1 (ENT1) in Ara-C-resistant CCRF-CEM-derived cells. Journal of biochemistry 27 15632314
2014 ENT1 inhibition attenuates epileptic seizure severity via regulation of glutamatergic neurotransmission. Neuromolecular medicine 26 25490964
2012 Characterization of the Salmonella bacteriophage vB_SenS-Ent1. The Journal of general virology 26 22694898
2017 Potential role of polymorphisms in the transporter genes ENT1 and MATE1/OCT2 in predicting TAS-102 efficacy and toxicity in patients with refractory metastatic colorectal cancer. European journal of cancer (Oxford, England : 1990) 25 28992563
2000 Genomic organization and expression of the mouse equilibrative, nitrobenzylthioinosine-sensitive nucleoside transporter 1 (ENT1) gene. Biochemical and biophysical research communications 25 11027664
2023 Erythrocyte ENT1-AMPD3 Axis is an Essential Purinergic Hypoxia Sensor and Energy Regulator Combating CKD in a Mouse Model. Journal of the American Society of Nephrology : JASN 24 37725437
2022 ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer. Cancer letters 24 36341997
2019 Affinity, binding kinetics and functional characterization of draflazine analogues for human equilibrative nucleoside transporter 1 (SLC29A1). Biochemical pharmacology 24 31830468
2008 High D-glucose reduces SLC29A1 promoter activity and adenosine transport involving specific protein 1 in human umbilical vein endothelium. Journal of cellular physiology 24 18064606
2025 Inhibition of ENT1 relieves intracellular adenosine-mediated T cell suppression in cancer. Nature immunology 23 40355731
2014 Aberrant bone density in aging mice lacking the adenosine transporter ENT1. PloS one 22 24586402
2022 Dopamine Release in Nucleus Accumbens Is under Tonic Inhibition by Adenosine A1 Receptors Regulated by Astrocytic ENT1 and Dysregulated by Ethanol. The Journal of neuroscience : the official journal of the Society for Neuroscience 21 35042768
2016 Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease. Neurobiology of disease 21 27567601
2010 Regulation of ENT1 expression and ENT1-dependent nucleoside transport by c-Jun N-terminal kinase. Biochemical and biophysical research communications 21 21145879
2008 Identification of a novel point mutation in ENT1 that confers resistance to Ara-C in human T cell leukemia CCRF-CEM cells. FEBS letters 21 19116148
2020 Decreased Equilibrative Nucleoside Transporter 1 (ENT1) Activity Contributes to the High Extracellular Adenosine Levels in Mesenchymal Glioblastoma Stem-Like Cells. Cells 20 32824670
2020 Maternal erythrocyte ENT1-mediated AMPK activation counteracts placental hypoxia and supports fetal growth. JCI insight 19 32434995
2016 Novel regulation of equlibrative nucleoside transporter 1 (ENT1) by receptor-stimulated Ca2+-dependent calmodulin binding. American journal of physiology. Cell physiology 19 27009875
2023 Targeting myocardial equilibrative nucleoside transporter ENT1 provides cardioprotection by enhancing myeloid Adora2b signaling. JCI insight 18 37288658
2003 Nitrobenzylthioinosine (NBMPR) binding and nucleoside transporter ENT1 mRNA expression after prolonged wakefulness and recovery sleep in the cortex and basal forebrain of rat. Journal of sleep research 18 14633241
2025 Adenosine Uptake through the Nucleoside Transporter ENT1 Suppresses Antitumor Immunity and T-cell Pyrimidine Synthesis. Cancer research 17 39652568
2022 Adenosine derivatives from Cordyceps exert antitumor effects against ovarian cancer cells through ENT1-mediated transport, induction of AMPK signaling, and consequent autophagic cell death. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 16 36076585
2019 Label-free detection of transporter activity via GPCR signalling in living cells: A case for SLC29A1, the equilibrative nucleoside transporter 1. Scientific reports 16 31551431
2014 Dilazep analogues for the study of equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2). Bioorganic & medicinal chemistry letters 16 25454272
2005 6-Benzylthioinosine analogues: promising anti-toxoplasmic agents as inhibitors of the mammalian nucleoside transporter ENT1 (es). Biochemical pharmacology 16 16310172
2016 SLC29A1 (ENT1) polymorphisms and outcome of complete remission in acute myeloid leukemia. Cancer chemotherapy and pharmacology 15 27422302
2013 The adenosine transporter, ENT1, in cardiomyocytes is sensitive to inhibition by ethanol in a kinase-dependent manner: implications for ethanol-dependent cardioprotection and nucleoside analog drug cytotoxicity. Purinergic signalling 15 24163005
2010 Reduced effect of NMDA glutamate receptor antagonist on ethanol-induced ataxia and striatal glutamate levels in mice lacking ENT1. Neuroscience letters 15 20570605
2025 SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters. Nature communications 14 39885119
2018 Identification of a Genomic Region between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance). Clinical cancer research : an official journal of the American Association for Cancer Research 14 29871907
2011 Sex-Specific Regulation of Depression, Anxiety-Like Behaviors and Alcohol Drinking in Mice Lacking ENT1. Journal of addiction research & therapy 14 23101030
2010 Nucleoside/nucleobase transport and metabolism by microvascular endothelial cells isolated from ENT1-/- mice. American journal of physiology. Heart and circulatory physiology 14 20543083
2010 Human erythrocyte nucleoside transporter ENT1 functions at ice-cold temperatures. Drug metabolism and pharmacokinetics 14 20814156
2022 PF-07321332 (Nirmatrelvir) does not interact with human ENT1 or ENT2: Implications for COVID-19 patients. Clinical and translational science 13 35505633
2019 Role of equilibrative nucleoside transporter 1 (ENT1) in the disposition of cytarabine in mice. Pharmacology research & perspectives 13 31832201
2016 Localization and Expression of Nucleoside Transporters ENT1 and ENT2 in Polar Cells of Intestinal Epithelium. Bulletin of experimental biology and medicine 12 27160886
2018 Nrf2-ARE signaling pathway regulates the expressions of A1R and ENT1 in the brain of epileptic rats. European review for medical and pharmacological sciences 11 30402855
2017 Curcumin and its cyclohexanone analogue inhibited human Equilibrative nucleoside transporter 1 (ENT1) in pancreatic cancer cells. European journal of pharmacology 11 28365185
2014 Contribution of CNT1 and ENT1 to ribavirin uptake in human hepatocytes. Archives of pharmacal research 11 25011570
2012 Impact of solute carrier family 29 member 1 (SLC29A1) single nucleotide polymorphisms on mRNA expression in peripheral blood mononuclear cells. Biological & pharmaceutical bulletin 11 23095574
2008 High glucose suppresses expression of equilibrative nucleoside transporter 1 (ENT1) in rat cardiac fibroblasts through a mechanism dependent on PKC-zeta and MAP kinases. Journal of cellular physiology 11 17941087
2005 Localization of the NBMPR-sensitive equilibrative nucleoside transporter, ENT1, in the rat dorsal root ganglion and lumbar spinal cord. Brain research 11 16226730
2021 Differential Inhibition of Equilibrative Nucleoside Transporter 1 (ENT1) Activity by Tyrosine Kinase Inhibitors. European journal of drug metabolism and pharmacokinetics 10 34275128
2019 Loss of ENT1 increases cell proliferation in the annulus fibrosus of the intervertebral disc. Journal of cellular physiology 10 31010267
2019 Quantification of ENT1 and ENT2 Proteins at the Placental Barrier and Contribution of These Transporters to Ribavirin Uptake. Journal of pharmaceutical sciences 10 31520644
2018 Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1). Diabetes, obesity & metabolism 10 29962100
2016 N-linked glycosylation of N48 is required for equilibrative nucleoside transporter 1 (ENT1) function. Bioscience reports 10 27480168
2015 SLC29A1 polymorphism and prediction of anaemia severity in patients with chronic hepatitis C receiving triple therapy with telaprevir. The Journal of antimicrobial chemotherapy 10 25583751
2015 Effect of Hypoxanthine on Functional Activity of Nucleoside Transporters ENT1 and ENT2 in Caco-2 Polar Epithelial Intestinal Cells. Bulletin of experimental biology and medicine 10 26593410
2024 Deep Brain Stimulation Inhibits Epileptic Seizures via Increase of Adenosine Release and Inhibition of ENT1, CD39, and CD73 Expression. Molecular neurobiology 9 39042219
2019 Type 1 equilibrative nucleoside transporter (ENT1) regulates sex-specific ethanol drinking during disruption of circadian rhythms. Addiction biology 9 31267611
2016 Interleukin-1β Suppresses the Transporter Genes Ank and Ent1 Expression in Stromal Progenitor Cells Retaining Mineralization. Calcified tissue international 9 27086348
2021 NBTI attenuates neuroinflammation and apoptosis partly by ENT1/NLRP3/Bcl2 pathway after subarachnoid hemorrhage in rats. Neuroreport 8 34718248
2002 Complex effects of sulfhydryl reagents on ligand interactions with nucleoside transporters: evidence for multiple populations of ENT1 transporters with differential sensitivities to N-ethylmaleimide. Archives of biochemistry and biophysics 8 12061806
2012 On-pump inhibition of es-ENT1 nucleoside transporter and adenosine deaminase during aortic crossclamping entraps intracellular adenosine and protects against reperfusion injury: role of adenosine A1 receptor. The Journal of thoracic and cardiovascular surgery 7 22325325
2011 Analysis of recombinant tagged equilibrative nucleoside transporter 1 (ENT1) expressed in E. coli. Biochemistry and cell biology = Biochimie et biologie cellulaire 7 21455275
2021 miR-33-3p Regulates PC12 Cell Proliferation and Differentiation In Vitro by Targeting Slc29a1. Neurochemical research 6 34152551
2021 Influence of FPGS, ABCC4, SLC29A1, and MTHFR genes on the pharmacogenomics of fluoropyrimidines in patients with gastrointestinal cancer from the Brazilian Amazon. Cancer chemotherapy and pharmacology 6 34331561
2024 The JNK Signaling Pathway Regulates Seizures Through ENT1 in Pilocarpine-Induced Epilepsy Rat Model. CNS neuroscience & therapeutics 5 39722194
2022 Insight into the nucleoside transport and inhibition of human ENT1. Current research in structural biology 5 35677775
2021 Potential role of CMPK1, SLC29A1, and TLE4 polymorphisms in gemcitabine-based chemotherapy in HER2-negative metastatic breast cancer patients: pharmacogenetic study results from the prospective randomized phase II study of eribulin plus gemcitabine versus paclitaxel plus gemcitabine (KCSG-BR-13-11). ESMO open 4 34438242
2018 Changes in aortic reactivity associated with the loss of equilibrative nucleoside transporter 1 (ENT1) in mice. PloS one 4 30408123
2012 Purification and crystallization of yeast Ent1 ENTH domain. Acta crystallographica. Section F, Structural biology and crystallization communications 4 22750874
2024 Development of a Novel HEK293 Cell Model Lacking SLC29A1 to Study the Pharmacology of Endogenous SLC29A2-Encoded Equilibrative Nucleoside Transporter Subtype 2. Drug metabolism and disposition: the biological fate of chemicals 3 39054074
2020 Adaptative mechanism of the equilibrative nucleoside transporter 1 (ENT-1) and blood adenosine levels in elite freedivers. European journal of applied physiology 3 33052430
2019 Numerical analysis of apparent decitabine uptake in HCT116 cells: Incorporation of a bidirectional first-order kinetic parameter for ENT1 transport and Michaelis-Menten parameters for subsequent phosphorylation. Drug metabolism and pharmacokinetics 2 31964620
2024 Frequency Distributions of Alleles and Genotypes and Lung Cancer Risk of Polymorphisms DCK, SLC29A1, and SLC29A3 in South Indian Healthy Population. Cureus 1 39564037

Missed literature

Know a paper Affinage missed for SLC29A1? Flag it for the maintainers and the community.

No submissions yet.