TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
2.A.41.1.1









Pyrimidine nucleoside:H+ symporter, NupC (Craig et al. 1994; Patching et al. 2005). Wild-type NupC had an apparent affinity for uridine of 22.2 +/- 3.7 muM and an apparent binding affinity of 1.8-2.6 mM, and various mutants with alterred properties were isolated and characterized (Sun et al. 2017). ADP-glucose is also a substrate of this system (Almagro et al. 2018).

Bacteria
Pseudomonadota
NupC of E. coli (P0AFF2)
2.A.41.1.2









Pyrimidine-specific nucleoside:H+ symporter, NupC
Bacteria
Bacillota
NupC of Bacillus subtilis
2.A.41.1.3









The purine nucleoside uptake transporter NupG (YxjA) (Johansen et al., 2003)
Bacteria
Bacillota
NupG of Bacillus subtilis (P42312)
2.A.41.2.1









Purine-specific nucleoside:Na+ symporter
Eukaryota
Metazoa, Chordata
The bile canalicular purine-specific nucleoside:Na+ symporter of Rattus norvegicus (Q62773)
2.A.41.2.2









Nonspecific nucleoside:Na+ symporter
Eukaryota
Metazoa, Chordata
The nucleoside:Na+ symporter of Rattus norvegicus (Q62674)
2.A.41.2.3









Pyrimidine-preferring nucleoside:Na+ symporter, CNT1 (Na+/nucleoside = 2)(transports uridine, gemcitabine and 5'-deoxy-5'-fluorouridine) (Larráyoz et al., 2004), but in addition to pyrimidine nucelosides, it transports adenosine (Altaweraqi et al. 2020).

Eukaryota
Metazoa, Chordata
SLC28A1 of Homo sapiens
2.A.41.2.4









Purine nucleoside, uridine, and 2'3'dideoxyinosine cladribrine:Na+ symporter, CNT2 (Na+/nucleoside = 1) (Owen et al., 2006; Altaweraqi et al. 2020).

Eukaryota
Metazoa, Chordata
SLC28A2 of Homo sapiens
2.A.41.2.5









Broadly selective nucleoside:Na+ cotransporter, hfCNT (transports uridine, thymidine, inosine, 3'-azido-3'deoxythymidine, 2'3'dideoxycytidine, and 2'3'dideoxyinosine) (Na+/uridine = 2)
Eukaryota
Metazoa, Chordata
hfCNT of Eptatretus stouti (Q9UA35)
2.A.41.2.6









Broad-specificity nucleoside:Na+, H+ and Li+ symporter, hCNT3 (Slc28a3) transports a broad range of both purine and pyrimidine nucleosides as well as anticancer and antiviral nucleoside drugs, but guanosine, 3'azido-3-deoxythymidine and 2',3'-dideoxycytidine, which are substrates with Na+, are not substrates with H+. Both of the two cation-binding sites can apparently bind Na+, but only one can bind H+, and the Na+ and H+ forms transport different ranges of substrates. (Note: Cnt1 and Cnt2 are Na+-specific.) (Smith et al., 2005).  (Na+/nucleoside = 2; Na+ + H+/nucleoside = 2; H+/nucleoside = 1).  The matricellular protein, cysteine-rich angiogenic inducer 61 (CYR61), negatively regulates synthesis of the nucleoside transporters hENT1 and hCNT3, both of which transport the anti-cancer agent, gemcitabine (Hesler et al. 2016). Also probably transports gemcitabine, 3'-azido-3'-deoxythymidine (AZT), ribavirin and 3-deazauridine. Modeling revealed mobility of selected binding site and homotrimer interface residues (Latek 2017). The 3-D structure has been solved at 3.6 Å resolution by cryoEM (Zhou et al. 2020). As for its bacterial homologs, hCNT3 presents a trimeric architecture with additional N-terminal transmembrane helices to stabilize the conserved central domains. The conserved binding sites for the substrate and sodium ions unravel the selective nucleoside transport and distinct coupling mechanism (Zhou et al. 2020). A multistep elevator-like transport mechanism for nucleoside transport has been proposed (Duan et al. 2021).

Eukaryota
Metazoa, Chordata
CNT3 of Homo sapiens (Q9ERH8)
2.A.41.2.7









Broad specificity nucleoside:H+ symporter (1:1 stoichiometry). Adenosine, uridine, inosine, and guanosine are transported but not cytidine, thymidine or the nucleobase hypoxanthine (Km range: 15-65 μM). Purine and uridine nucleoside drug analogues including cordycepin (3'-deoxyadenosine) are substrates.

Eukaryota
Fungi, Ascomycota
CNT of Candida albicans, (Q874I3)
2.A.41.2.8









Solute carrier family 28 member 3 (Concentrative Na+-nucleoside cotransporter 3) (CNT 3) (hCNT3).  This protein is distinct from TC# 2.A.41.2.6 (78% identity) although these two proteins are called Slc28a3 and CNT3 and have the same description in UniProt (see 2.A.41.2.6 for a more complete description).  hCNT3 can transport extracellular nucleosides and various nucleoside-derived anticancer drugs. Typical nucleoside anticancer drugs, including fludarabine, cladabine, decitabine, and clofarabine, are recognized by hCNT3 and then delivered to the lesion site for their therapeutic effects. hCNT3 is highly conserved during the evolution from lower to higher vertebrates, which contains scaffold and transport domains in structure and delivers substrates by coupling with Na+ and H+ ions in function. In the process of substrate delivery, the transport domain rises from the lower side of TMS9 in the inward conformation to the upper side of the outward conformation, accompanied by the collaborative motion of TMS7b/ TMS4b and hairpin 1b (HP1b)/HP2b. With the report of a series of three-dimensional structures of homologous CNTs, the structural characteristics and biological functions of hCNT3 hae become important. Yue et al. 2023 designed an anticancer lead compound with high hCNT3 transport potential based on the structure of 5-fluorouracil. The sequence evolution, conservation, molecular structure, cationic chelation, substrate recognition, elevator motion pattern and nucleoside derivative drugs of hCNT3 were reviewed, and the differences in hCNT3 transport mode and nucleoside anticancer drug modification were summarized (Yue et al. 2023).

Eukaryota
Metazoa, Chordata
SLC28A3 of Homo sapiens
2.A.41.2.9









Putative pseudouridine transporter, PsuT

Bacteria
Pseudomonadota
PsuT of Escherichia coli
2.A.41.2.10









Nucleoside permease NupX

Bacteria
Pseudomonadota
NupX of Escherichia coli
2.A.41.2.11









Concentrative nucleoside transporter, CNT, of 418 aas and 12 TMSs. A repeat-swapped model of VcCNT predicts that nucleoside transport occurs via a mechanism involving an elevator-like substrate binding domain movement across the membrane (Vergara-Jaque et al. 2015).

Bacteria
Pseudomonadota
CNT of Vibrio cholerae
2.A.41.2.12









Concentrative nucleotide transporter of 590 aas and 12 TMSs in a 1 + 4 + 1 + 1 + 4 + 1 TMS arrangement, DmCnt1.  Mutations in DmCnt1 alters spermatid maturation and mating behavior (Maaroufi et al. 2022).

Eukaryota
Metazoa, Arthropoda
Cnt1 of Drosophila melanogaster
2.A.41.2.13









Sodium-dependent and pyrimidine-selective transporter, CNT1 or SLC26A1, of 649 aas and 16 TMSs in an apparent 2 + 3 + 3 + 2 + 4 + 2  arrangement   (Cano-Soldado et al. 2012, Loewen et al. 1999).  It is selective for pyrimidine nucleosides and adenosine (Cano-Soldado et al. 2012). It transports uridine, cytidine, thymidine, and nucleoside-derived drugs (Yao et al. 2011), including the antiviral pyrimidine nucleoside analogs 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC). It may be involved in the intestinal absorption and renal handling of pyrimidine nucleoside analogs used to treat acquired immunodeficiency syndrome (AIDS) and has the following selective inhibition: adenosine, thymidine, cytidine, uridine >> guanosine, inosine (Ritzel et al. 1997).

Eukaryota
Metazoa, Chordata
CNT1 of Homo sapiens