2.A.57 The Equilibrative Nucleoside Transporter (ENT) Family

Several members of the ENT family (Pfam CLN3) have been functionally characterized (Engel et al., 2004Griffiths et al., 1997b; Mäser et al., 1999; Sundaram et al., 1998; Vasudevan et al., 1998). The hENT1 is of human placental origin, is 456 amino acyl residues long and possesses 11 TMSs. It has an N-terminal mitochondrial targetting sequence and is expressed in the mitochondria and other organelles of many human tissues. Homologues have been sequenced from yeast, protozoa, plants, nematodes and mammals.  Most characterized plant (and probably lower eukaryotic) ENTs act in a concentrative manner, defying their name (Girke et al. 2015). C. elegans possesses at least five such homologues. Among these are the two smaller nucleolar ''''delayed early response'''' gene products, HNP36, sequenced from humans and mice (Williams and Lanahan, 1995). The hENT1 and rENT1 proteins appear to exhibit broad specificity for purine and pyrimidine nucleosides and cytotoxic nucleoside analogues used in cancer and viral chemotherapy. Some are sensitive and others are insensitive to inhibition by nitrobenzyl thioinosine. hENT2 has higher affinity for adenosine, inosine and hypoxanthine than hENT1 but lower affinity for other nucleosides. Both human and rat isoforms of hENT1 are cell surface and organellar localized being found in mitochondria, nuclear envelopes and lysosomes. One, PMAT (TC #2.A.57.1.5), transports monoamines, probably by an H+ symport mechanism. Nucleoside drug analogues and inhibitors used in cancer chemotherapy include docetaxel, uridine-furane and S-(4-nitrobenzyl)-6-thioinosine (Drápela et al. 2018).

Nucleoside transporters have been identified in Trypanosoma brucei and Leishmania donovani. They transport adenosine and probably other nucleosides and nucleobases as well as several drugs. When reconstituted in yeast, one (called TbAT1) catalyzes adenosine uptake and confers susceptibility to melaminophenyl arsenicals. Tyrpanocide drug-resistant tyrpanosomes have a mutated TbAT1 gene. These protozoan proteins are 460-500 residues long and exhibit 10 putative TMSs. The three Leishmania donovani paralogues (NT1.1, NT1.2 and NT2) are all electrogenic proton symporters (Stein et al., 2003).

The 7 known human nucleosides transporters (hNTs) exhibit varying permeant selectivities and are found into 2 protein families: the solute carrier (SLC) 29 (SLC29A1, SLC29A2, SLC29A3, SLC29A4) and SLC28 (SLC28A1, SLC28A2, SLC28A3) proteins, otherwise known, respectively, as the human equilibrative NTs (hENTs, hENT1, hENT2, hENT3, hENT4) and human concentrative NTs (hCNTs, hCNT1, hCNT2, hCNT3) (Elwi et al., 2006). The well characterized hENTs (hENT1 and hENT2) are bidirectional facilitative diffusion transporters in plasma membranes; hENT3 and hENT4 are much less well known, although hENT3, found in lysosomal membranes, transports nucleosides and is pH dependent.  hENT4-PMAT is a H+/adenosine cotransporter as well as a monoamine-organic cation transporter. The 3 hCNTs are unidirectional secondary active Na+/nucleoside cotransporters. In renal epithelial cells, hCNT1, hCNT2, and hCNT3, at apical membranes, and hENT1 and hENT2 at basolateral membranes, apparently work in concert to mediate reabsorption of nucleosides from lumen to blood, driven by Na+ gradients. Secretion of some physiological nucleosides, therapeutic nucleoside analog drugs, and nucleotide metabolites of therapeutic nucleoside and nucleobase drugs likely occurs through various xenobiotic transporters in renal epithelia, including organic cation transporters, organic anion transporters, multidrug resistance related proteins, and multidrug resistance proteins. Mounting evidence suggests that hENT1 may have a presence at both apical and basolateral membranes of renal epithelia, and thus may participate in both selective secretory and reabsorptive fluxes of nucleosides (Elwi et al., 2006).

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal childhood-onset neurodegenerative disorder caused by mutations in ceroid lipofuscinosis neuronal-3 (CLN3), a transmembrane protein of unresolved function. There may be blood-brain barrier (BBB) defects in JNCL. Cln3 is expressed in mouse brain endothelium. Tecedor et al. 2013 showed that CLN3 is necessary for normal trafficking of the microdomain-associated proteins caveolin-1, syntaxin-6, and multidrug resistance protein 1 (MDR1) in brain endothelial cells. CLN3-null cells have reduced caveolae, and impaired caveolae- and MDR1-related functions including endocytosis, drug efflux, and cell volume regulation. They also detected an abnormal blood-brain barrier response to osmotic stress in vivo and proposed that CLN3 facilitates golgi-to-plasma membrane transport of microdomain-associated proteins. 

The best-characterized members of the human Ent family, hENT1 and hENT2, possess similar broad permeant selectivities for purine and pyrimidine nucleosides, but hENT2 also efficiently transports nucleobases. hENT3 has a similar broad permeant selectivity for nucleosides and nucleobases and appears to function in intracellular membranes, including lysosomes. hENT4 is uniquely selective for adenosine, and also transports a variety of organic cations. hENT3 and hENT4 are pH sensitive and optimally active under acidic conditions. ENTs, including those in parasitic protozoa, function in nucleoside and nucleobase uptake for salvage pathways of nucleotide synthesis and, in humans, are also responsible for the cellular uptake of nucleoside analogues used in the treatment of cancers and viral diseases. By regulating the concentration of adenosine available to cell surface receptors, mammalian ENTs additionally influence physiological processes ranging from cardiovascular activity to neurotransmission (Young et al. 2008).

The generalized transport reaction catalyzed by well characterized ENT family members is:

Nucleoside (out) → Nucleoside (in)



This family belongs to the MFS Superfamily.

 

References:

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Girke C., Arutyunova E., Syed M., Traub M., Mohlmann T. and Lemieux MJ. (2015). High yield expression and purification of equilibrative nucleoside transporter 7 (ENT7) from Arabidopsis thaliana. Biochim Biophys Acta. 1850(9):1921-9.

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Griffiths, M., S.Y.M. Yao, F. Abidi, S.E.V. Phillips, C.E. Cass, J.D. Young, and S.A. Baldwin. (1997b). Molecular cloning and characterization of a nitrobenzylthioinosine-insensitive (ei) equilibrative nucleoside transporter from human placenta. Biochem. J. 328: 739-743.

Ho HT., Xia L. and Wang J. (2012). Residue Ile89 in human plasma membrane monoamine transporter influences its organic cation transport activity and sensitivity to inhibition by dilazep. Biochem Pharmacol. 84(3):383-90.

Hsu, C.L., W. Lin, D. Seshasayee, Y.H. Chen, X. Ding, Z. Lin, E. Suto, Z. Huang, W.P. Lee, H. Park, M. Xu, M. Sun, L. Rangell, J.L. Lutman, S. Ulufatu, E. Stefanich, C. Chalouni, M. Sagolla, L. Diehl, P. Fielder, B. Dean, M. Balazs, and F. Martin. (2012). Equilibrative nucleoside transporter 3 deficiency perturbs lysosome function and macrophage homeostasis. Science 335: 89-92.

Klein, D.M., K.K. Evans, R.N. Hardwick, W.H. Dantzler, S.H. Wright, and N.J. Cherrington. (2013). Basolateral uptake of nucleosides by Sertoli cells is mediated primarily by equilibrative nucleoside transporter 1. J Pharmacol Exp Ther 346: 121-129.

Kobayashi, M., E. Yamato, K. Tanabe, F. Tashiro, S. Miyazaki, and J. Miyazaki. (2016). Functional Analysis of Novel Candidate Regulators of Insulin Secretion in the MIN6 Mouse Pancreatic β Cell Line. PLoS One 11: e0151927.

Lee, E.W., Y. Lai, H. Zhang, and J.D. Unadkat. (2006). Identification of the mitochondrial targeting signal of the human equilibrative nucleoside transporter 1 (hENT1): implications for interspecies differences in mitochondrial toxicity of fialuridine. J. Biol. Chem. 281: 16700-16706.

Lepist, E.I., V.L. Damaraju, J. Zhang, W.P. Gati, S.Y. Yao, K.M. Smith, E. Karpinski, J.D. Young, K.H. Leung, and C.E. Cass. (2013). Transport of A1 adenosine receptor agonist tecadenoson by human and mouse nucleoside transporters: evidence for blood-brain barrier transport by murine equilibrative nucleoside transporter 1 mENT1. Drug Metab Dispos 41: 916-922.

Li, X., J. Zhang, Z. Zhang, and C. Zhou. (2010). [Relationship between single nucleotide polymorphism of the equilibrative nucleoside transporter ENT3 and susceptibility to lung cancer]. Zhongguo Fei Ai Za Zhi 13: 458-463.

Liu, J.W., N. Si, L.Q. Wang, T. Shen, X.J. Zeng, X. Zhang, and D.L. Ma. (2015). Identification of a novel mutation in solute carrier family 29, member 3 in a Chinese patient with H syndrome. Chin Med J (Engl) 128: 1336-1339.

Mäser, P., C. Sütterlin, A. Kralli, and R. Kaminsky. (1999). A nucleoside transporter from Tyrpanosoma brucei involved in drug resistance. Science 285: 242-244.

Nishtala, S.N., A. Arora, J. Reyes, and M.H. Akabas. (2018). Accessibility of substituted cysteines in TM2 and TM10 transmembrane segments in the equilibrative nucleoside transporter PfENT1. J. Biol. Chem. [Epub: Ahead of Print]

Nugent, T., S.E. Mole, and D.T. Jones. (2008). The transmembrane topology of Batten disease protein CLN3 determined by consensus computational prediction constrained by experimental data. FEBS Lett. 582: 1019-1024.

Orlandi, A., M.A. Calegari, M. Martini, A. Cocomazzi, C. Bagalà, G. Indellicati, V. Zurlo, M. Basso, A. Cassano, L.M. Larocca, and C. Barone. (2016). Gemcitabine versus FOLFIRINOX in patients with advanced pancreatic adenocarcinoma hENT1-positive: everything was not too bad back when everything seemed worse. Clin Transl Oncol. [Epub: Ahead of Print]

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Paproski, R.J., F. Visser, J. Zhang, T. Tackaberry, V. Damaraju, S.A. Baldwin, J.D. Young, and C.E. Cass. (2008). Mutation of Trp(29) of human equilibrative nucleoside transporter 1 alters affinity for coronary vasodilator drugs and nucleoside selectivity. Biochem. J. 414: 291-300.

Rager, N., C. Ben Mamoun, N.S. Carter, D.E. Goldberg, and B. Ullman. (2001). Localization of the Plasmodium falciparum PfNT1 nucleoside transporter to the parasite plasma membrane. J. Biol. Chem. 276: 41095-41099.

Riegelhaupt, P.M., I.J. Frame, and M.H. Akabas. (2010). Transmembrane segment 11 appears to line the purine permeation pathway of the Plasmodium falciparum equilibrative nucleoside transporter 1 (PfENT1). J. Biol. Chem. 285: 17001-17010.

Sanchez, M.A., R. Tryon, J. Green, I. Boor, and S.M. Landfear. (2002). Six related nucleoside/nucleobase transporters from Trypanosoma brucei exhibit distinct biochemical functions. J. Biol. Chem. 277: 21499-21504.

Schmidt, R.S., J.P. Macêdo, M.E. Steinmann, A.G. Salgado, P. Bütikofer, E. Sigel, D. Rentsch, and P. Mäser. (2018). Transporters of Trypanosoma brucei-phylogeny, physiology, pharmacology. FEBS J. 285: 1012-1023.

Sher, M., M. Farooq, U. Abdullah, Z. Ali, S. Faryal, M. Zakaria, F. Ullah, H. Bukhari, R.S. Møller, N. Tommerup, and S.M. Baig. (2019). A novel in-frame mutation in CLN3 leads to Juvenile neuronal ceroid lipofuscinosis in a large Pakistani family. Int J. Neurosci. 1-6. [Epub: Ahead of Print]

Stein, A., G. Vaseduvan, N.S. Carter, B. Ullman, S.M. Landfear, and M.P. Kavanaugh. (2003). Equilibrative nucleoside transporter family members from Leishmania donovani are electrogenic proton symporters. J. Biol. Chem. 278: 35127-35134.

Sundaram, M., S.Y. Yao, A.M. Ng, M. Griffiths, C.E. Cass, S.A. Baldwin, and J.D. Young. (1998). Chimeric constructs between human and rat equilibrative nucleoside transporters (hENT1 and rENT1) reveal hENT1 structural domains interacting with coronary vasoactive drugs. J. Biol. Chem. 273: 21519-21525.

Tecedor, L., C.S. Stein, M.L. Schultz, H. Farwanah, K. Sandhoff, and B.L. Davidson. (2013). CLN3 Loss Disturbs Membrane Microdomain Properties and Protein Transport in Brain Endothelial Cells. J. Neurosci. 33: 18065-18079.

Traub, M., M. Flörchinger, J. Piecuch, H.H. Kunz, A. Weise-Steinmetz, J.W. Deitmer, H. Ekkehard Neuhaus, and T. Möhlmann. (2007). The fluorouridine insensitive 1 (fur1) mutant is defective in equilibrative nucleoside transporter 3 (ENT3), and thus represents an important pyrimidine nucleoside uptake system in Arabidopsis thaliana. Plant J. 49: 855-864.

Uusi-Rauva, K., A. Kyttälä, R. van der Kant, J. Vesa, K. Tanhuanpää, J. Neefjes, V.M. Olkkonen, and A. Jalanko. (2012). Neuron.al ceroid lipofuscinosis protein CLN3 interacts with motor proteins and modifies location of late endosomal compartments. Cell Mol Life Sci 69: 2075-2089.

Uusi-Rauva, K., K. Luiro, K. Tanhuanpää, O. Kopra, P. Martín-Vasallo, A. Kyttälä, and A. Jalanko. (2008). Novel interactions of CLN3 protein link Batten disease to dysregulation of fodrin-Na+, K+ ATPase complex. Exp Cell Res 314: 2895-2905.

Valdés, R., J. Elferich, U. Shinde, and S.M. Landfear. (2014). Identification of the Intracellular Gate for a Member of the Equilibrative Nucleoside Transporter (ENT) Family. J. Biol. Chem. 289: 8799-8809.

Valdés, R., U. Shinde, and S.M. Landfear. (2012). Cysteine Cross-linking Defines the Extracellular Gate for the Leishmania donovani Nucleoside Transporter 1.1 (LdNT1.1). J. Biol. Chem. 287: 44036-44045.

Valdés, R., W. Liu, B. Ullman, and S.M. Landfear. (2006). Comprehensive examination of charged intramembrane residues in a nucleoside transporter. J. Biol. Chem. 281: 22647-22655.

Vasudevan, G., N.S. Carter, M.E. Drew, S.M. Beverley, M.A. Sanchez, A. Seyfang, B. Ullman, and S.M. Landfear. (1998). Cloning of Leishmania nucleoside transporter genes by rescue of a transport-deficient mutant. Proc. Natl. Acad. Sci. USA 95: 9873-9878.

Vickers, M.F., S.Y.M. Yao, S.A. Baldwin, J.D. Young, and C.E. Cass. (2000). Nucleoside transporter proteins of Saccharomyces cerevisiae: demonstration of a transporter (FUI1) with high uridine selectivity in plasma membranes and a transporter (FUN26) with broad nucleoside selectivity in intracellular membranes. J. Biol. Chem. 275: 25931-25938.

Visser, F., L. Sun, V. Damaraju, T. Tackaberry, Y. Peng, M.J. Robins, S.A. Baldwin, J.D. Young, C.E. Cass. (2007). 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. J. Biol. Chem. 282: 14148-14157.

Ward, J.L., A. Sherali, Z. Mo, and C. Tse. (2000). Kinetic and pharmacological properties of cloned human equilibrative nucleoside transporters, ENT1 and ENT2, stably expressed in nucleoside transporter-deficient PK15 cells. J. Biol. Chem. 275: 8375-8381.

Williams, J.B. and A.A. Lanahan. (1995). A mammalian delayed early response gene encodes HNP36, a novel conserved nucleolar protein. Biochem. Biophys. Res. Commun. 213: 325-333.

Xia, L., K. Engel, M. Zhou, and J. Wang. (2007). Membrane localization and pH-dependent transport of a newly cloned organic cation transporter (PMAT) in kidney cells. Am. J. Physiol. Renal Physiol 292: F682-690.

Yao, S.Y.M., A.M.L. Ng, C.E. Cass, and J.D. Young. (2018). Role of Cysteine 416 in -ethylmaleimide Sensitivity of Human Equilibrative Nucleoside Transporter 1 (hENT1). Biochem. J. [Epub: Ahead of Print]

Yao, S.Y.M., A.M.L. Ng, W.R. Muzyka, M. Griffiths, C.E. Cass, S.A. Baldwin, and J.D. Young. (1997). Molecular cloning and functional characterization of nitrobenzylthioinosine (NBMPR)-sensitive (es) and NBMPR-insensitive (ei) equilibrative nucleoside transporter proteins (rENT1 and rENT2) from rat tissues. J. Biol. Chem. 272: 28423-28430.

Young, J.D., S.Y. Yao, L. Sun, C.E. Cass, and S.A. Baldwin. (2008). Human equilibrative nucleoside transporter (ENT) family of nucleoside and nucleobase transporter proteins. Xenobiotica 38: 995-1021.

Zhou, M., L. Xia, K. Engel, and J. Wang. (2007). Molecular determinants of substrate selectivity of a novel organic cation transporter (PMAT) in the SLC29 family. J. Biol. Chem. 282: 3188-3195.

Examples:

TC#NameOrganismal TypeExample
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).

Animals

SLC29A1 or Ent1 of Homo sapiens

 
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).

Plants

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.

ENT of Harp seal herpesvirus

 
2.A.57.1.13

Uncharacterized protein of 379 aas and 10 TMSs in a 5 + 5 TMS arrangement.

UP of Entamoeba histolytica

 
2.A.57.1.14

Putative nucleoside transporter of 481 aas and 12 TMSs.

UP of Entamoeba histolytica

 
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).

Mammals

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).

Mammals

rENT1 of Rattus norvegicus

 
2.A.57.1.4Equilibrative low affinity nucleoside transporter (nitrobenzyl-thioinosine-insensitive) (transports adenosine, inosine and hypoxanthine with high affinity; other nucleosides are transported with lower affinity) Mammals rENT2 of Rattus norvegicus
 
2.A.57.1.5

The brain plasma membrane monoamine transporter, PMAT 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).

Animals

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).

Animals

SLC29A3 of Homo sapiens

 
2.A.57.1.7The fluorouridine insensitive 1 (fur1) or Ent3 pyrimidine nucleoside transporter (Traub et al., 2007).PlantsEnt3 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).

Animals

SLC29A2 of Homo sapiens

 
2.A.57.1.9

Uncharacterized protein of 359 aas and 9 TMSs.

Rhodophyta

UP of Chondrus crispus

 
Examples:

TC#NameOrganismal TypeExample
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).  The intracellular and extracellular gates have been defined by modeling FucP (Valdés et al. 2012; Valdés et al. 2014).

Protozoa

NT1.1 of Leishmania donovani

 
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).

AT-A of Trypanosoma brucei

 
2.A.57.2.2

Nucleoside (nucleobase, drug) transporter of 463 aas, AT1 or P2.  Transports adenosine and adenine as well as the drugs, melarsoprol, pentamidine, diminazene and cordycepin (Schmidt et al. 2018).

Protozoa

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).

Protozoa

NT2 of Leishmania donovani

 
2.A.57.2.4High-affinity (<5 μM) adenosine/inosine transporter, NT2ProtozoaNT2 of Trypanosoma brucei
 
2.A.57.2.5High-affinity nucleobase transporter (transports adenine, hypoxanthine, xanthine, guanine, guanosine, allopurinol, and inosine) (Burchmore et al., 2003)ProtozoaNBT1 of Trypanosoma brucei brucei (AAO60071)
 
2.A.57.2.6High affinity purine nucleobase (hypoxanthine, guanine, xanthine, adenine, allopurinol) transporter, NT3 (Ortiz et al., 2007)ProtozoaNT3 of Leishmania major (Q4QG33)
 
2.A.57.2.7Low affinity adenine transporter, NT4 (Ortiz et al., 2007)ProtozoaNT4 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

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.

Protozoans

Adenosine transporter of Crithidia fasciculata

 
Examples:

TC#NameOrganismal TypeExample
2.A.57.3.1Nucleoside (uridine, adenosine, cytidine) transporter, Fun26p (intraorganellar) Yeast Fun26p of Saccharomyces cerevisiae
 
Examples:

TC#NameOrganismal TypeExample
2.A.57.4.1

The parasite plasma membrane equilibrative nucleoside transporter, PfNT1 or PfENT1, of 422 aas and 10 or 11 TMSs. Both L- and D-nucleosides of both purines and pyrimidines are transported; L-nucleosides are transported with low affinity (transports adenosine, inosine and thymidine (KM 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).

Protozoa

PfNT1 of Plasmodium falciparum

 
2.A.57.4.2

The intracellular (endoplasmic reticulum) nucleoside transporter. Transports purine nucleosides and 5-fluorouridine (PfNT-2; Downie et al., 2010)

Protozoa

PfNT2 of Plasmodium falciparum (Q8IB78)

 
Examples:

TC#NameOrganismal TypeExample
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).

Animals

Cln3 of Mus musculus

 
2.A.57.5.2Protein BTN1FungiYHC3 of Saccharomyces cerevisiae
 
2.A.57.5.3Protein BTN1YeastBTN1 of Candida albicans
 
2.A.57.5.4

10 TMS homologue

Parabasalia

10 TMS homologue of Trichomonas vaginalis

 
2.A.57.5.5

Cln3 family protein of 513 aas and 11 putative TMSs.

Alveolata

Cln3 family protein of Oxytricha trifallax

 
2.A.57.5.6

Uncharacterized protein of 5432 aas

Euglenozoa

UP of Trypanosoma cruzi

 
2.A.57.5.7

Battenin homologue of 439 aas and 10 or 11 TMSs.

Battenin of Acanthamoeba castellanii

 
2.A.57.5.8

Battenin or Cln3 of 438 aas and 11 TMSs. 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 Juvenile neuronal ceroid lipofuscinosis (Sher et al. 2019).

 

Cln3 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
2.A.57.6.1

Uncharacterized protein of 418 aas and 10 - 11 TMSs

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.

UP of Phialocephala scopiformis

 
Examples:

TC#NameOrganismal TypeExample
2.A.57.7.1

Uncharacterized protein of 192 aas and 4 TMSs.

UP of Amycolatopsis jejuensis

 
2.A.57.7.2

Uncharacterized protein of 234 aas and 3 or 4 TMSs.

UP of Mycobacterium europaeum

 
2.A.57.7.3

Uncharacterized protein of 200 aas and 4 TMSs.

UP of Rhodococcus rhodochrous

 
2.A.57.7.4

Uncharacterized protein of 154 aas and 4 TMSs.

UP of Pseudonocardiaceae bacterium