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SLC29A1

Official Full Name
solute carrier family 29 member 1 (Augustine blood group)
Organism
Homo sapiens
GeneID
2030
Background
This gene is a member of the equilibrative nucleoside transporter family. The gene encodes a transmembrane glycoprotein that localizes to the plasma and mitochondrial membranes and mediates the cellular uptake of nucleosides from the surrounding medium. The protein is categorized as an equilibrative (as opposed to concentrative) transporter that is sensitive to inhibition by nitrobenzylthioinosine (NBMPR). Nucleoside transporters are required for nucleotide synthesis in cells that lack de novo nucleoside synthesis pathways, and are also necessary for the uptake of cytotoxic nucleosides used for cancer and viral chemotherapies. Multiple alternatively spliced variants, encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]
Synonyms
AUG; ENT1; hENT1;
Protein Sequence
MTTSHQPQDRYKAVWLIFFMLGLGTLLPWNFFMTATQYFTNRLDMSQNVSLVTAELSKDAQASAAPAAPLPERNSLSAIFNNVMTLCAMLPLLLFTYLNSFLHQRIPQSVRILGSLVAILLVFLITAILVKVQLDALPFFVITMIKIVLINSFGAILQGSLFGLAGLLPASYTAPIMSGQGLAGFFASVAMICAIASGSELSESAFGYFITACAVIILTIICYLGLPRLEFYRYYQQLKLEGPGEQETKLDLISKGEEPRAGKEESGVSVSNSQPTNESHSIKAILKNISVLAFSVCFIFTITIGMFPAVTVEVKSSIAGSSTWERYFIPVSCFLTFNIFDWLGRSLTAVFMWPGKDSRWLPSLVLARLVFVPLLLLCNIKPRRYLTVVFEHDAWFIFFMAAFAFSNGYLASLCMCFGPKKVKPAEAETAGAIMAFFLCLGLALGAVFSFLFRAIV
Open
Disease
Angina pectoris
Approved Drug
1 +
Clinical Trial Drug
0
Discontinued Drug
0

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Detailed Information

The SLC29A1 gene is located on human chromosome 6p21.1, spanning approximately 27 kb and consisting of 11 exons and 10 introns. Alternative promoter usage and differential splicing generate multiple transcript variants, but all encode the same protein of 499 amino acids. The gene encodes equilibrative nucleoside transporter 1 (ENT1), a glycoprotein of about 50 kDa with 11 predicted transmembrane domains. The N-terminus is oriented toward the cytoplasm, while the C-terminus faces the extracellular space. ENT1 belongs to the solute carrier family 29 (SLC29). Its functional core lies in a substrate-binding pocket formed by transmembrane helices (TMHs) 1, 4, 5, and 10, where His33 and Phe88 play key roles in nucleoside recognition. ENT1 localizes to both the plasma membrane and mitochondrial membrane, where it functions as a homooligomer. Its expression is widespread, with high abundance in erythrocytes, blood–brain barrier endothelial cells, hepatocytes, cardiomyocytes, and neurons, consistent with its diverse physiological roles.

Figure 1. Simplified scheme of hNT protein functions.Figure 1. Simplified scheme of hNT protein functions. (Pastor-Anglada M, et al., 2018)

Gene Regulation and Evolution

ENT1 expression is regulated by multiple factors. Under hypoxic conditions, HIF-1α represses promoter activity, whereas p53 enhances expression through binding to enhancer elements. Promoter analysis reveals conserved GC-boxes and E-boxes that interact with transcription factors such as Sp1 and c-Myc. Epigenetic regulation, including promoter methylation, has been linked to expression silencing in hematologic disorders. Evolutionary studies indicate that ENT1 is highly conserved across vertebrates, with key substrate-binding residues identical in humans, mice, and zebrafish.

Biological Function and Physiological Roles

ENT1 mediates sodium-independent, equilibrative nucleoside transport based on bidirectional diffusion, with transport direction determined by substrate gradients. Its substrate profile includes purine nucleosides (adenosine, inosine, guanosine), pyrimidine nucleosides (uridine, thymidine, cytidine), and purine/pyrimidine bases. Among these, adenosine is the preferred substrate, consistent with ENT1's role in regulating adenosine signaling. ENT1 maintains intracellular nucleoside pools, which is particularly important for cells lacking de novo nucleotide synthesis, such as mature erythrocytes and lymphocytes.

ENT1 also modulates extracellular adenosine concentration and participates in diverse physiological processes:

  • Cardioprotection: During ischemia, ENT1 uptake of adenosine prevents excessive receptor activation.
  • Neuroregulation: In the brain, ENT1 influences synaptic adenosine levels, thereby modulating excitability via A1 and A2A receptors.
  • Immunoregulation: Macrophage ENT1 clears adenosine from inflamed tissues, limiting A2A receptor–mediated anti-inflammatory responses.

Mitochondrial ENT1 (mtENT1) has emerged as a focus of interest. Located in the inner mitochondrial membrane, it transports cytosolic nucleosides into the mitochondrial matrix, supplying precursors for mtDNA synthesis. This function is particularly important in highly replicative cells such as hematopoietic stem cells and intestinal epithelial cells. Inhibition of mtENT1 can lead to mtDNA depletion and mitochondrial dysfunction. In addition, mtENT1 contributes to mitochondrial salvage pathways that maintain the nucleotide triphosphate pool.

Clinical Associations and Therapeutic Relevance

Dysfunction of SLC29A1 is associated with several conditions:

  • Augustine blood group system: Missense mutations in SLC29A1 can generate new antigens, leading to hemolytic disease of the fetus or transfusion reactions.
  • Myeloproliferative neoplasms: ENT1 silencing disrupts nucleoside balance in hematopoietic stem cells, promoting clonal expansion.

Altered ENT1 expression has also been observed in neurological and metabolic disorders. Reduced ENT1 in the prefrontal cortex has been linked to alcohol dependence, while compensatory upregulation occurs after ischemic injury, potentially serving as a protective mechanism.

In oncology, ENT1 is a key transporter of nucleoside-based chemotherapeutics such as cytarabine, gemcitabine, and capecitabine. Its expression level influences cellular drug uptake and therapeutic response, making it a valuable biomarker for treatment planning.

ENT1 is also relevant in antiviral and neuroprotective therapies. Inhibition of ENT1 can disrupt viral RNA synthesis by limiting nucleoside availability, and ENT1 inhibitors enhance extracellular adenosine signaling, offering neuroprotection in models of neurodegenerative disease.

Research Challenges and Future Directions

A central challenge in ENT1 research is balancing its broad substrate specificity with the need for selective modulation. Potential strategies include developing allosteric modulators to influence specific substrates, using tissue-specific promoters for targeted gene therapy, and designing prodrugs that bypass ENT1-dependent uptake.

Another unresolved question concerns the dynamic regulation of ENT1 subcellular localization. Stress-induced relocalization from the plasma membrane to mitochondria, regulated by the PINK1/Parkin pathway, suggests a role in mitochondrial DNA maintenance and related disorders.

Future work will likely focus on:

  1. Structural studies at atomic resolution to guide drug design.
  2. Development of imaging probes for in vivo visualization of ENT1 activity.
  3. Exploration of ENT1's role in immune regulation, particularly its interaction with adenosine and immune checkpoint pathways.

These directions highlight the potential of ENT1 as both a fundamental research subject and a therapeutic target across multiple disease contexts.

Reference

  1. Rosenbrier Ribeiro L, Ian Storer R. A semi-quantitative translational pharmacology analysis to understand the relationship between in vitro ENT1 inhibition and the clinical incidence of dyspnoea and bronchospasm. Toxicol Appl Pharmacol. 2017 Feb 15;317:41-50.

  2. Smith SM, Smith CJ. Capturing the mechanics of clathrin-mediated endocytosis. Curr Opin Struct Biol. 2022 Aug;75:102427.

  3. Bicket A, Mehrabi P, Naydenova Z, et al. Novel regulation of equlibrative nucleoside transporter 1 (ENT1) by receptor-stimulated Ca2+-dependent calmodulin binding. Am J Physiol Cell Physiol. 2016 May 15;310(10):C808-20.

  4. Pastor-Anglada M, Pérez-Torras S. Emerging Roles of Nucleoside Transporters. Front Pharmacol. 2018 Jun 6;9:606.

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