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TCID	Name	Domain	Kingdom/Phylum	Protein(s)
2.A.57.1.1	Equilibrative nucleoside transporter (ENT1) (present in the membranes surrounding the cell as well as eukaryotic organelles) (Lee et al., 2006). Residues 334 and 338 in TMS8 determine the inhibitor sensitivity, protein folding and catalytic turnover (Visser et al., 2007). The porter is inhibited by nanomolar concentrations of various structurally distinct coronary vasodilator drugs, including dipyridamole, dilazep, draflazine, soluflazine and nitrobenzylmercaptopurine ribonucleoside (NBMPR) (Paproski et al., 2008). It transports the A1 adenosine receptor agonist, tecadenoson (Lepist et al. 2013) and mediates gemcitabine (GEM) and folfirinox uptake, chemotheraputic agents for patients with metastatic pancreatic cancer (Orlandi et al. 2016). The matricellular protein, cysteine-rich angiogenic inducer 61 (CYR61), negatively regulates synthesis of the nucleoside transporters hENT1 and hCNT3, both of which transport gemcitabine (Hesler et al. 2016). These two transporters as well as ENT2 (TC# 2.A.57.1.8) are able to take up the adenosine analogue, fludarabine (AraFA), used to treat cancer (lymphomas and leukemia) (Gorzkiewicz et al. 2018). NEM modification of Cys(416), which is located at the inner extremity of TM10, results in inhibition of hENT1 uridine transport and NBMPR binding by constraining the protein in its inward-facing conformation (Yao et al. 2018). Ent1 transports nucleosides and bases, like Ent2, but Ent1 is more important than Ent2 or CNT3 in determining plasma adenosine concentrations (Altaweraqi et al. 2020). The Thr residue at position 336 may help determine inhibitor and substrate sensitivity (Boakes et al. 2022).	Eukaryota	Metazoa	SLC29A1 or Ent1 of Homo sapiens
2.A.57.1.2	Equilibrative nitrobenzylmercaptopurine riboside (NBMPR)-insensitive nucleoside transporter of 456 aas, ENT2 (Slc29a2). In humans, the same gene product is the nucleolar protein, HNP36 (function unknown).	Eukaryota	Metazoa	ENT2 (HNP36) of Mus musculus (Q61672)
2.A.57.1.3	Equilibrative high affinity nucleoside transporter (nitrobenzyl-thioinosine-sensitive) (transports thymidine, adenosine, cytosine, and guanosine; inosine and hypoxanthine are poorly transported). Uridine uptake in the basolateral membrane of sertoli cells is selectively inhibited by 100 nM nitrobenzylmercaptopurine riboside (NBMPR, 6-S-[(4-nitrophenyl)methyl]-6-thioinosine) (Klein et al. 2013).	Eukaryota	Metazoa	rENT1 of Rattus norvegicus
2.A.57.1.4	Equilibrative low affinity nucleoside transporter (nitrobenzyl-thioinosine-insensitive) (transports adenosine, inosine and hypoxanthine with high affinity; other nucleosides are transported with lower affinity)	Eukaryota	Metazoa	rENT2 of Rattus norvegicus
2.A.57.1.5	The brain plasma membrane monoamine transporter, PMAT, Slc29A4 or ENT4, a polyspecific orgnaocation transporter. (transports serotonin [Km=110 μM), dopamine (Km=330 μM), metformin (Km=1.3 mM) and the neurotoxin, 1-methyl-4-phenylpyridinium (Km=33 μM)) (Nucleosides and nucleobases are not transported; transport is sensitive to the membrane potential, but is Na⁺ and Cl^- independent.) (Engel et al., 2004). Also expressed in kidney apical membranes where it transports MPP⁺ by a ΔΨ-dependent process (Xia et al., 2007). TMSs 1 - 6 bear the substrate recognition site, and Glu206 in TMS5 determines the catioin specificiity. An E206Q mutant lost cation selectivity and transported uridine (Zhou et al. 2007). Residues Ile89 and thr220 influence its organic cation transport activity and sensitivity to inhibition by dilazep (Ho et al., 2012). May play a role in insulin secretion in β-cells (Kobayashi et al. 2016).	Eukaryota	Metazoa	SLC29A4 of Homo sapiens
2.A.57.1.6	Equilibrative (Na⁺-independent) low affinity nucleoside transporter, hENT3 or SLC29A3 (transports nucleosides with broad selectivity and low affinity; also transports adenine). Relatively low sensitivity to classical nucleoside transport inhibitors, nitrobenzylthioinosine, dipyridamole, and dilazep. pH optimum=5.5; present in acidic intracellular compartments (Baldwin et al., 2005). (Present largely in the lysosomes). May cause histiocytosis, perturb lysosome function and upset macrophage homeostasis when defective (Hsu et al., 2012; Farooq et al., 2012). A single nucleotide polymorphism (SNP) in ENT3 may be a risk factor for squamous cell carcioma (Li et al. 2010). Mutations cause H syndrome, an autosomal recessive genodermatosis characterized by hyperpigmented and hypertrichotic skin (Liu et al. 2015).	Eukaryota	Metazoa	SLC29A3 of Homo sapiens
2.A.57.1.7	The fluorouridine insensitive 1 (Fur1) or Ent3 pyrimidine nucleoside transporter (Traub et al., 2007). AtENT4, AtENT6 and AtENT7). Three paralogs, Ent4, Ent6 and Ent7, exhibited broad substrate specificity and transported the purine nucleosides adenosine and guanosine, as well as the pyrimidine nucleosides cytidine and uridine (Wormit et al. 2004). The apparent K_m values were in the range 3-94 μM, and transport was inhibited strongly by deoxynucleosides, and to a smaller extent by nucleobases.	Eukaryota	Viridiplantae	Ent3 of Arabidopsis thaliana (Q9M0Y3)
2.A.57.1.8	Equilibrative nucleoside transporter 2 (36 kDa nucleolar protein HNP36) (Delayed-early response protein 12) (Equilibrative nitrobenzylmercaptopurine riboside-insensitive nucleoside transporter) (Equilibrative NBMPR-insensitive nucleoside transporter) (Hydrophobic nucleolar protein, 36 kDa) (Nucleoside transporter, ei-type) (Solute carrier family 29 member 2). Takes up the adenosine analogue, fludarabine (AraFA), used to treat cancer (lymphomas and leukemia) (Gorzkiewicz et al. 2018).	Eukaryota	Metazoa	SLC29A2 of Homo sapiens
2.A.57.1.9	Uncharacterized protein of 359 aas and 9 TMSs.	Eukaryota	Florideophyceae	UP of Chondrus crispus
2.A.57.1.10	ENT7 of 417 aas and 11 TMSs, an equilibrative nucleoside transporter in contrast to most plant ENT proteins which are concentrative, functioning by H⁺ symport (Girke et al. 2015). Binding of purine and pyrimidine nucleosides to the purified recombinant protein, and binding of nucleobases has been demonstrated (Girke et al. 2015).	Eukaryota	Viridiplantae	ENT7 of Arabidopsis thaliana (Mouse-ear cress)
2.A.57.1.12	Putative equilibrative nucleoside transporter 1 isoform X1 of 432 aas and 11 TMSs.	Viruses	Herpesvirales	ENT of Harp seal herpesvirus
2.A.57.1.13	Uncharacterized protein of 379 aas and 10 TMSs in a 5 + 5 TMS arrangement.	Eukaryota	Entamoebidae	UP of Entamoeba histolytica
2.A.57.1.14	Putative nucleoside transporter of 481 aas and 12 TMSs.	Eukaryota	Entamoebidae	UP of Entamoeba histolytica
2.A.57.1.15	Equilabrative nucleoside transporter of 445 aas and 11 TMSs. This system and the human isoforms are inhibited by nanomolar concentrations of dipyridamole, and residues involved in the binding have been identified (Visser et al. 2005).	Eukaryota	Metazoa	Ent of Caenorhabditis elegans
2.A.57.1.16	Equilibrative nucleoside transporter, ENT1 of 423 aas and 11 TMSs.	Eukaryota	Viridiplantae	ENT1 of Oryza sativa subsp. japonica (Rice)
2.A.57.1.17	Equilibrative nuceloside transporter 2, ENT2, of 418 aas and 11 TMSs. OsENT2 transports adenosine and uridine with high affinity (adenosine, K_m = 3.0 μM; uridine, K_m = 0.7 μm) (Hirose et al. 2005). Purine or pyrimidine nucleosides and 2'-deoxynucleosides strongly inhibit adenosine transport via OsENT2, suggesting that it possesses broad substrate specificity. OsENT2-mediated adenosine transport is resistant to the typical inhibitors of mammalian ENTs, nitrobenzylmercaptopurine ribonucleoside, dilazep, and dipyridamole. Transport activity is maximal at pH 5.0. In competition experiments with various cytokinins, adenosine transport is inhibited by isopentenyladenine riboside (iPR). Direct measurements with radiolabeled cytokinins demonstrated that OsENT2 mediated uptake of iPR (K(m) = 32 microm) and trans-zeatin riboside (K(m) = 660 microm), suggesting that OsENT2 participates in iPR transport in planta. In mature plants, OsENT2 is predominantly expressed in roots. The OsENT2 promoter drives expression in the scutellum during germination and in vascular tissues in germinated plants, suggesting participation in the retrieval of endosperm-derived nucleosides by the germinating embryo and in the long-distance transport of nucleosides in growing plants, respectively (Hirose et al. 2005). Three other ENTs have been partially characterized, Ent4, Ent6 and Ent7; all three proteins exhibit broad substrate specificity and transport the purine nucleosides adenosine and guanosine, as well as the pyrimidine nucleosides cytidine and uridine. The apparent K_m values were in the range 3-94 μM, and transport was inhibited most strongly by deoxynucleosides, and to a lesser extent by nucleobases. Ent6 is in the plasma membrane (Wormit et al. 2004). Ent2 transports both nucleosides and bases, and is less important than Ent1 (Altaweraqi et al. 2020).	Eukaryota	Viridiplantae	ENT2 of Oryza sativa, Japonica group
2.A.57.2.1	Concentrative nucleoside (adenosine, uridine, cytosine, tubercidin):H⁺ symporter, NT1.1 (The Leishmania major orthologue, NT1.1 (Q4QF58), also transports tubercidin) (Stein et al., 2003). TMS 5 is an amphipathic helix that forms part of the nucleoside translocation pathway (Valdés et al. 2004). The intracellular and extracellular gates have been defined by modeling FucP (Valdés et al. 2012; Valdés et al. 2014).	Eukaryota	Kinetoplastida	NT1.1 of Leishmania donovani
2.A.57.2.2	Nucleoside (nucleobase, drug) transporter of 463 aas, AT1 or P2. Transports adenosine and adenine as well as the drugs, eflornithine, melarsoprol, pentamidine, diminazene and cordycepin (Schmidt et al. 2018; Zhang et al. 2022); Kasozi et al. 2022).	Eukaryota	Kinetoplastida	TbAT1 of Trypanosoma brucei
2.A.57.2.3	High affinity, concentrative nucleoside (inosine, formycin, guanosine):H⁺ symporter, NT2 (Stein et al., 2003). Mutations confer drug (formycin) resistance and drug transport deficiency (Galazka et al. 2006). Asp₃₈₉ is critical for transporter function without affecting ligand affinity or plasma membrane targeting, but Asn₁₇₅ and Asp₃₈₉ (when mutated as a second site mutation) lie in close proximity to each other; second-site suppressor mutations cluster to one region of the transporter, suggested that Asp₁₇₅is conformationally sensitive (Arastu-Kapur et al. 2005). Development of glutamatergic/cholinergic postmitotic human neurons is induced by short-term treatment with nucleoside analogues such as cytosine β-D-arabinofuranoside, 2'-O-methyl substituted 2-deoxy-β-D-ribofuranosyl residues as glyconic moieties, and cladribine (Raasch et al. 2015; González-Burguera et al. 2016).	Eukaryota	Kinetoplastida	NT2 of Leishmania donovani
2.A.57.2.4	High-affinity (<5 μM) adenosine/inosine transporter, NT2	Eukaryota	Kinetoplastida	NT2 of Trypanosoma brucei
2.A.57.2.5	High-affinity nucleobase transporter (transports adenine, hypoxanthine, xanthine, guanine, guanosine, allopurinol, and inosine) (Burchmore et al., 2003)	Eukaryota	Kinetoplastida	NBT1 of Trypanosoma brucei brucei (AAO60071)
2.A.57.2.6	High affinity purine nucleobase (hypoxanthine, guanine, xanthine, adenine, allopurinol) transporter, NT3 (Ortiz et al., 2007)	Eukaryota	Kinetoplastida	NT3 of Leishmania major (Q4QG33)
2.A.57.2.7	Low affinity adenine transporter, NT4 (Ortiz et al., 2007)	Eukaryota	Kinetoplastida	NT4 of Leishmania major (Q4QH25)
2.A.57.2.8	Nucleotide transporter 2, NT2, specific for inosine and guanosine, but mutations in TMS 4 which may line the channel allow uptake of adenosine (Arendt & Ullman et al., 2010). (Most similar to 2.A.57.2.3).	Eukaryota	Kinetoplastida	NT2 of Crithidia fasciculata (Q9GTP4)
2.A.57.2.9	High affinity adenosine-specific nucleoside transporter (Arendt 2013). Similar to 2.A.547.2.1. A lysine residue in TMS4 plays an important role in substrate affinity.	Eukaryota	Kinetoplastida	Adenosine transporter of Crithidia fasciculata
2.A.57.2.10	Nucleoside/nucleobase transporter 1, AT-A or NT11.1, of 482 aas and 11 TMSs. Transports adenine, xanthine and hypoxanthine as well as the drug, pentamidine (Schmidt et al. 2018; Zhang et al. 2022).	Eukaryota	Kinetoplastida	AT-A of Trypanosoma brucei
2.A.57.2.11	Putative nucleoside transporter, NT3 or ENT3, of 437 aas and 11 TMSs in a 6 + 5 TMS arrangement.	Eukaryota	Sar	NT3 or Plasmodium falciparum
2.A.57.3.1	Nucleoside (uridine, adenosine, cytidine) transporter, Fun26p (intraorganellar)	Eukaryota	Fungi	Fun26p of Saccharomyces cerevisiae
2.A.57.3.2	Uncharacterized protein of 436 aas and 11 TMSs	Eukaryota	Fungi	UP of Meliniomyces bicolor
2.A.57.3.3	Uncharacterized protein of 746 aas and 7 TMSs. This protein has its TMSs in the N-terminal half of the protein, and the C-terminal hydrophilic half shows statistically meaningful seqence similarity with cytochrome P450 isoforms (e.g., P10632) (Mustafa et al. 2020); M Saier, unpublished observation.	Eukaryota	Fungi	UP of Aspergillus fumigatus
2.A.57.4.1	The parasite plasma membrane equilibrative nucleoside transporter, PfNT1 or PfENT1, of 422 aas and 11 or 12 TMSs in a 6 + 5 TMS arrangement. Both L- and D-nucleosides of both purines and pyrimidines are transported; L-nucleosides are transported with low affinity (transports adenosine, inosine and thymidine (K_M values=1-2mM) (Downie et al., 2006)). ENT1 is the primary uptake transporter for purines, and transmembrane segments 2, 10 and 11 appear to line the purine permeation pathway (Riegelhaupt et al., 2010, Nishtala et al. 2018).	Eukaryota	Apicomplexa	PfNT1 of Plasmodium falciparum
2.A.57.4.2	The intracellular (endoplasmic reticulum) nucleoside transporter, NT2, of 585 aas and 11 TMSs in a 6 + 5 TMS arrangement. Transports purine nucleosides and 5-fluorouridine (PfNT-2; Downie et al., 2010)	Eukaryota	Apicomplexa	PfNT2 of Plasmodium falciparum (Q8IB78)
2.A.57.4.3	Uncharacterized protein of 443 aas and 11 TMSs.	Eukaryota	Apicomplexa	UP of Eimeria maxima
2.A.57.4.4	Adenine/adenosine uptake porter, NT4 or ENT4, of 434 aas and 11 TMSs in a 6 + 5 TMS arrangement.	Eukaryota	Sar	Nucleobase/nucleoside porter of Plasmodium falciparum
2.A.57.4.5	Vacuolar protein sorting-associated protein 51, putative (VPS51) protein with two transmembrane domains of 6 and 5 TMSs, respectively, homologous to the transmembrane domains of 2.A.57.4.4 (NT4).	Eukaryota	Sar	NT5 of Plasmodium ovale curtisi
2.A.57.5.1	Battenin (BTN) or ceroid lipofuscinosis neuronal-3 (CLN3), with 6 TMSs and the N- and C-termini in the cytoplasm (Nugent et al. 2008). May function in trafficking from the Golgi to the plasma membrane (Tecedor et al. 2013). Mutations give rise to the disease, juvenile neuronal ceroid lipofuscinosis (JNCL) or Batten disease in humans, a fatal childhood-onset neurodegenerative disorder caused by mutations in CLN3. May indirectly regulate activity of the Na⁺,K⁺-ATPase (Uusi-Rauva et al. 2008).	Eukaryota	Metazoa	Cln3 of Mus musculus
2.A.57.5.2	Protein BTN1	Eukaryota	Fungi	YHC3 of Saccharomyces cerevisiae
2.A.57.5.3	Protein BTN1	Eukaryota	Fungi	BTN1 of Candida albicans
2.A.57.5.4	10 TMS homologue	Eukaryota	Trichomonadida	10 TMS homologue of Trichomonas vaginalis
2.A.57.5.5	Cln3 family protein of 513 aas and 11 putative TMSs.	Eukaryota	Intramacronucleata	Cln3 family protein of Oxytricha trifallax
2.A.57.5.6	Uncharacterized protein of 5432 aas	Eukaryota	Kinetoplastida	UP of Trypanosoma cruzi
2.A.57.5.7	Battenin homologue of 439 aas and 10 or 11 TMSs.	Eukaryota	Longamoebia	Battenin of Acanthamoeba castellanii
2.A.57.5.8	Battenin or Cln3, of 438 aas and 11 TMSs, is phosphorylated on both serine and threonine residues by three protein kinases (Michalewski et al. 1998). The N-terminus of Battenin is a protein interaction domain (Moroziewicz et al. 2006). Cln3 is involved in microtubule-dependent, anterograde transport of late endosomes and lysosomes. CLN3 interacts directly with active, guanosine-5'-triphosphate (GTP)-bound Rab7 and with the Rab7-interacting lysosomal protein (RILP) that anchors the dynein motor (Uusi-Rauva et al. 2012). Loss-of-function mutations in CLN3 are responsible for juvenile-onset neuronal ceroid lipofuscinosis (JNCL), or Batten disease, which is an incurable lysosomal disease that manifests with vision loss, followed by seizures and progressive neurodegeneration, robbing children of motor skills, speech and cognition, and eventually leading to death in the second or third decade of life. A current understanding of CLN3 structure, function and dysfunction in JNCL can be found in (Cotman and Staropoli 2012). Mutational variability in CLN3 gives rise to JNCL (Sher et al. 2019). The N-terminus of Battenin is a protein interaction domain (Moroziewicz et al. 2006). Dysregulation of intracellular calcium homeostasis results from the absence of a functional CLN3 protein. and has been linked to synaptic dysfunction and accelerated apoptosis in vulnerable neuronal cells. Prolonged increased intracellular calcium may be a trigger for neuronal apoptosis and cellular loss in JNCL (An Haack et al. 2011).	Eukaryota	Metazoa	Cln3 of Homo sapiens
2.A.57.6.1	Uncharacterized protein of 418 aas and 10 - 11 TMSs	Eukaryota	Fungi	UP of Mycosphaerella pini (Red band needle blight fungus) (Dothistroma septosporum)
2.A.57.6.2	Uncharacterized protein of 467 aas and 10 TMSs.	Eukaryota	Fungi	UP of Phialocephala scopiformis