Pantothenate:Na⁺ symporter, PanF (Vallari and Rock 1985; Jackowski and Alix 1990; Reizer et al. 1991).

Bacteria

PanF of E. coli

Proline:Na⁺ symporter, PutP (Jung et al., 2012).  Extracellular loop 4 (eL4) controls periplasmic entry of substrate to the binding site (Raba et al. 2014).  Interactions between the tip of eL4 and the peptide backbone at the end of TMS 10 participate in coordinating conformational alterations underlying the alternating access mechanism of transport (Bracher et al. 2016).  TMS 6 plays a central role in substrate (both Na⁺ and proline) binding and release on the inner side of the membrane, and functionally relevant amino acids have been identified (Bracher et al. 2016).

Bacteria

PutP of E. coli

PutP of Staphylococcus aureus

L-proline uptake porter, PutP.  Proline is used via this system as a carbon and nitrogen source.  Induced by proline (Johnson et al. 2008).

Proteobacteria

PutP of Pseudomonas aeruginoas

The high affinity nutritional proline uptake porter, PutP.  PutP is inducible by external (but not internal) proline in a poorly defined process dependent on PutR (Moses et al. 2012). 

Firmicutes

PutP of Bacillus subtilis

Proline uptake porter, OpuE (YerK) (von Blohn et al. 1997).  Regulated by osmotic stress (high osmolarity).  Induction involves σ^B and σ^A (Spiegelhalter and Bremer 1998).

Firmicutes

OpuE of Bacillus subtilis

High affinity proline-specific Na⁺:proline symporter, PutP (Rivera-Ordaz et al. 2013).  Proline is a preferred source of energy for this microaerophilic bacterium.  PutP is efficiently inhibited by the proline analogs, 3,4-dehydro-D,L-proline and L-azetidine-2-carboxylic acid.

Proteobacteria

PutP of Helicobacter pylori

Sodium:proline symporter of 428 aas and 11 TMSs

Proline uptake porter of Methanosarcina mazei (Methanosarcina frisia)

Glucose or galactose:Na⁺ symporter, SGLT1 (galactose > glucose > fucose). Cotransports water against an osmotic gradient (Naftalin, 2008). SGLT1 harbors a water channel (Barta et al. 2022). TMS IV of the high-affinity sodium-glucose cotransporter participates in sugar binding (Liu et al., 2008) and also participates in the uptake of resveratrol, an anti atherosclerosis polyphenol (Chen et al. 2013).  hSGLT1 is expressed as a disulfide bridged homodimer via C355; a portion of the intracellular 12-13 loop is re-entrant and readily accessible from the extracellular milieu (Sasseville et al. 2016). Possibly, the extracellular loop between TMS 12 and TMS 13 participates in the sugar transport of SGLT1 (Nagata and Hata 2006). SGLT1 also transports water efficiently. Calculation of the unitary water channel permeability, pf, yielded similar values for cell and proteoliposome experiments. The absence of glucose, Na⁺, a membrane potential in vesicles, or the directionality of water flow did not grossly altered the pf. Such a weak dependence on protein conformation indicates that a water-impermeable occluded state (glucose and Na⁺ in their binding pockets) lasts for only a minor fraction of the transport cycle or, alternatively, that occlusion of the substrate does not render the transporter water-impermeable (Erokhova et al. 2016). the ortholog from grass carp (Ctenopharyngodon idellus) of 465 aas and 12 putative TMSs is 80% identical and is found in the anterior and mid intestine (Liang et al. 2020). Sodium-dependent glucose transporter 1 and glucose transporter 2 mediate intestinal transport of quercetrin (Li et al. 2020). Cardiac SGLT1 does not contribute appreciably to overall glucose uptake (Ferté et al. 2021). Collective domain motion facilitates water transport in SGLT1 (Sever and Merzel 2023).  Ferulic acid-grafted chitosan (FA-g-CS) stimulates the transmembrane transport of anthocyanins by SGLT1 and GLUT2 (Ma et al. 2022). SLC5A1 and SLC5A3 are involved in glioblastoma cell migration, thereby complementing the migration-associated transportome, suggesting that SLC inhibition may be a promising approach for treatment (Brosch et al. 2022). SGLT1 mediates the absorption of water, yet the mechanism and the effect of inhibitors is not well defined.  Sever and Merzel 2023 determined the influence of the energetic and dynamic properties of SGLT1 as they are influenced by selected sugar uptake inhibitors on water permeation. variants of Slc5A1 give rise to Congenital Glucose-Galactose Malabsorption (Hoşnut et al. 2023). Soluble β-glucan fibers modulate blood glucose regulation and intestinal permeability (Marcobal et al. 2024). A small library of glycoderivative putative ligands of SGLT1 has been prepared, and a preliminary biological evaluation has been conducted (D'Orazio and La Ferla 2024). The effectiveness of sodium-glucose co-transporter 2 inhibitors on cardiorenal outcomes has been reviewed (Ali et al. 2024).

Animals

SLC5A1 of Homo sapiens

Na⁺-dependent, smf-driven, sialic acid transporter, STM1128 (NanP) (Severi et al., 2010). Also transports the related sialic acids, N-glycolylneuraminic acid (Neu5Gc) and 3-keto-3-deoxy-d-glycero-d-galactonononic acid (KDN) (Hopkins et al. 2013). 

Bacteria

STM1128 (NanP) of Salmonella enterica (Q8ZQ35)

The alginate oligosaccharide uptake porter, ToaA (Wargacki et al., 2012).

Bacteria

ToaA in Vibrio splendida (A3UWQ1) 

The alginate oligosaccharide uptake porter, ToaB (Wargacki et al., 2012).

Bacteria

ToaB in Vibrio splendida (A3UWQ9)

The alginate oligosaccharide uptake porter, ToaC (Wargacki et al., 2012).

Bacteria

ToaC in Vibrio splendida (A3UR54)

Sodium/glucose cotransporter 5 (Na⁺/glucose cotransporter 5) (Solute carrier family 5 member 10)

Animals

SLC5A10 of Homo sapiens

Sodium/glucose cotransporter 2 (Na⁺/glucose cotransporter 2; SGLT2) of 672 aas and 14 TMSs. It is a low affinity sodium-glucose cotransporter). It shows increased expression in human diabetic nephropathy. Inhibition causes decreased renal lipid accumulation, inflamation and disease symptoms (Wang et al. 2017). It has a Na⁺ to glucose coupling ratio of 1:1 (Brown et al. 2019). Efficient substrate transport in the mammalian kidney is provided by the concerted action of a low affinity high capacity and a high affinity low capacity Na⁺/glucose cotransporter arranged in series along kidney proximal tubules. Inhibitors are antidiabetic agents (Li 2019; Singh and Singh 2020). They are also useful as theraputic agents of non-alcoholic fatty liver disease and chronic kidney disease (Kanbay et al. 2021). Marein, an active component of the Coreopsis tinctoria Nutt plant, ameliorates diabetic nephropathy by inhibiting renal sodium glucose transporter 2 and activating the AMPK signaling pathway (Guo et al. 2020). NHE-3 (TC# 2.A.53.2.18) was markedly downregulated, while the Na⁺-HCO₃^--cotransporter (NBC-1; TC# 2.A.31.2.12) and SGLT2 were upregulated after kidney transplantation (Velic et al. 2004). Pharmacological inhibition of hSGLT2 by oral small-molecule inhibitors, such as empagliflozin, leads to enhanced excretion of glucose and is widely used in the clinic to manage blood glucose levels for the treatment of type 2 diabetes. Niu et al. 2022 determined the cryoEM structure of the hSGLT2-MAP17 complex in the empagliflozin-bound state to a resolution of 2.95 Å. MAP17 interacts with transmembrane helix 13 of hSGLT2. Empagliflozin occupies both the sugar-substrate-binding site and the external vestibule to lock hSGLT2 in an outward-open conformation, thus inhibiting the transport cycle (Niu et al. 2022 ). There is no upregulation regarding host factors potentially promoting SARS-CoV-2 virus entry into host cells when the SGLT2-blocker empagliflozin, telmisartan and the DPP4-inhibitor blocker, linagliptin, are used (Xiong et al. 2022).  The effectiveness of sodium-glucose co-transporter 2 inhibitors on cardiorenal outcomes has been described (Ali et al. 2024).

Animals

SLC5A2 of Homo sapiens

Sodium/glucose cotransporter 4 (Na⁺/glucose cotransporter 4) (hSGLT4) (Solute carrier family 5 member 9).  The involvement of aromatic residue pi interactions, especially with Na⁺ binding, has been examined (Jiang et al. 2012).

Animals

SLC5A9 of Homo sapiens

Low affinity sodium-glucose cotransporter (Sodium/glucose cotransporter 3) (Na⁺/glucose cotransporter 3) (Solute carrier family 5 member 4)

Animals

SLC5A4 of Homo sapiens

The putative arabinose porter, AraP (Rodionov D.A., personal communication). Regulated by arabinose regulon AraR.

Bacteroidetes

AraP (Q8AAV7) of Bacteroides thetaiotaomicron

Glucose or galactose:Na⁺ symporter, SglS or SglT of 543 aas and 14 TMSs (Turk et al. 2006). The 3.0 Å structure is known (Faham et al., 2008). Sodium exit causes a reorientation of transmembrane helix 1 that opens an inner gate required for substrate exit (Veenstra et al. 2004; Watanabe et al., 2010). The involvement of aromatic residue pi interactions, especially with Na⁺ binding, has been examined (Jiang et al. 2012).  Its function has been compared with that of LacZ of E. coli (Abramson and Wright 2021).

Bacteria

SglS of Vibrio parahaemolyticus

NanT sialic acid transporter of 500 aas (Anba-Mondoloni et al. 2013).

Firmicutes

NanT of Lactobacillus sakei

Putative sugar:sodium symporter of 571 aas and 15 TMSs, YidK

YidK of E. coli

Renal Na⁺:D-glucose symporter type 1 (Sglt1; Slc5a1) of 662 aas and 14 TMSs.  The distribution in renal tissues has been reported (Althoff et al. 2007). Loop 13, which is associated with phlorizin binding, is variable, as is the interaction with this inhibitor in various species. Immunoreaction was observed in the proximal tubular segments PIa and PIIa, the early distal tubule, and the collecting tubule. Thus, Leucoraja, in contrast to the mammalian kidney, employs only SGLT1 to reabsorb D-glucose in the early, as well as in the late segments of the proximal tubule and probably also in the late distal tubule. It differs from the kidney of the close relative, Squalus acanthias, which uses SGLT2 in more distal proximal tubular segments (Althoff et al. 2007). The ortholog in Squalus acanthias (Spiny dogfish), is 88% identical and has been characterized (Althoff et al. 2006).

Sglt1 of Leucoraja erinacea (Little skate) (Raja erinacea)

Kidney low affinity SGLT (Slc5a1) Na⁺:D-glucose symporter of 662 aas and 14 TMSs. Of the mammalian homologues, it most resembles SGLT2 (Althoff et al. 2006). 

SGLT of Squalus acanthias (spiny dogfish shark)

Putative Na⁺:Glucose symporter of 507 aas and 14 TMSs.

Sodium:Glucose symporter of Aeromonas virus 44RR2

Na+/Glucose (2:1) symporter, Sglt1, of 658 aas and 14 TMSs, in a 6 + 2 + 6 TMS arrangement (Liang et al. 2021). The mRNA levels of intestinal sglt1 had a positive correlation with dietary starch levels, but the mRNA levels of renal sglt1 were opposite to those of intestinal sglt1 (Liang et al. 2021).

Sglt1 of Megalobrama amblycephala (blunt snout bream)

Myoinositol:Na⁺ symporter, SMIT2 (also transports D-chiro-inositol, D-glucose and D-xylose) (Coady et al., 2002; Aouameur et al., 2007).  A 5-state model includes cooperative binding of Na⁺, strong apparent asymmetry of the energy barriers, a rate limiting step which is likely associated with the translocation of the empty transporter, and a turnover rate of 21 s-1 (Sasseville et al. 2014). The potential for modulation of plasma myoinositol by variation in SLC5A11 has been assessed (Weston et al. 2022).

Animals

SLC5A11 of Homo sapiens

The putative mannose porter, ManP^ll (Rodionov et al. 2010).

Proteobacteria

ManP^ll of Shewanella amazonensis (A1S2A8)

The putative galactose porter, GalP^ll (Rodionov et al., 2010).

Proteobacteria

GalP^ll of Shewanella pealeana (A8H019)

The monocarboxylate uptake (H⁺ symport?) permease, MctP (transports lactate (K_m = 4.4 μM), pyruvate (K_m = 3.8), propionate, butyrate (butanoic acid), α-hydroxybutyrate, L- and D-alanine (K_m = 0.5 mM), and possibly cysteine and histidine) (Hosie et al., 2002).

Bacteria

MctP of Rhizobium leguminosarum

Uncharacterized symporter YodF.  It is regulated by the global transcriptional regulator responding to nitrogen availablity, TnrA, suggesting the YodF transports a nitrogenous compound (Yoshida et al. 2003).

Bacilli

YodF of Bacillus subtilis

Sodium iodide symporter, NIS (I^-:Na⁺ = 1:2). It also transports other monovalent anions including: ClO₃^-, SCN^-, SeCN^-, NO₃^-, Br^-, BF₄^-, IO₄^- and BrO₃^-. It mediates electroneutral active transport of the environmental pollutant perchlorate (Dohan et al., 2007) and inhibits I^- uptake. The stoichometry of ClO₄^-:Na⁺ uptake is 1 to 1 as perchlorate binds both to the anion and one of the two cation binding sites (Llorente-Esteban et al. 2020). Five beta-OH group-containing residues (Thr-351, Ser-353, Thr-354, Ser-356, and Thr-357) and Asn-360, all of which putatively face the same side of the helix in TMS IX, plus Asp-369, located in the membrane/cytosol interface, play key roles in NIS function and seem to be involved in Na⁺ binding/translocation (De la Vieja et al. 2007). Thr-354 is essential for iodide uptake (Tatsumi et al., 2010). The G39R mutant (congenital) is inactive. G93 is a pivot for the inwardly to outwardly conformational change (Paroder-Belenitsky et al., 2011).  The protein is present as a dimer (Huc-Brandt et al. 2011).  Functionally equivalent systems have been reviewed (Darrouzet et al. 2014). Mutations cause congenital I^- transport defects (ITD; Li et al. 2013).  The physiological, medical and mechanistic features of NIS have been reviewed (Portulano et al. 2014). Mutations in TMS IX can give rise to hypothyroidism (Watanabe et al. 2018). NIS may also have a pump-independent, protumorigenic role in thyroid cancer via its cross-talk with PTEN signaling (Feng et al. 2018). Mutations in its gene gives rise to fetal goitrous hypothyroidism (Stoupa et al. 2020). Iodide transport across thyrocytes constitutes a critical step for thyroid hormone biosynthesis, mediated mainly by the basolateral NIS and the apical anion exchanger pendrin (PDS; SLC26A4; TC# 2.A.53.2.17) (Eleftheriadou et al. 2020). Autoimmunity against NIS for thyroid disease has been documented (Eleftheriadou et al. 2020). The iodide transport defect-causing Y348D mutation in the Na⁺/I^- symporter (NIS) renders the protein intrinsically inactive and impairs its targeting to the plasma membrane (Reyna-Neyra et al. 2021). Mutations in NIS can give rise to congenital hypothyroidism (Zhang et al. 2021). Iodide transport defect is a cause of dyshormonogenic congenital hypothyroidism due to homozygous or compound heterozygous pathogenic variants in the SLC5A5 gene, causing deficient iodide accumulation in thyroid follicular cells (Martín and Nicola 2021). NIS mediates active iodide accumulation in the thyroid follicular cell. Autosomal recessive iodide transport defect (ITD)-causing loss-of-function NIS variants lead to dyshormonogenic congenital hypothyroidism (DCH) due to deficient iodide accumulation for thyroid hormonogenesis (Bernal Barquero et al. 2022). An intramolecular interaction between R130 and D369 is required for NIS maturation and plasma membrane expression (Bernal Barquero et al. 2022). An Inverse agonist of estrogen-related receptor gamma, GSK5182, enhances Na⁺/I^- symporter function in radioiodine-refractory papillary thyroid cancer cells (Singh et al. 2023). The identification of sodium/iodide symporter metastable intermediates provides insights into conformational transition between principal thermodynamic states (Chakrabarti et al. 2023).  Advanced differentiated thyroid cancer that is resistant to radioactive iodine therapy may become responsive with a unique treatment combination of chloroquine and vorinostat. This treatment was demonstrated in cellular and animal models of thyroid cancer to inhibit endocytosis of the plasma membrane bound iodine transporter, NIS, and restore iodine uptake (Lechner and Brent 2024).  CMTM 6 promotes the development of thyroid cancer by inhibiting NIS activity by activating the MAPK signaling pathway (Chen et al. 2024).

Animals

SLC5A5 of Homo sapiens

Na⁺-dependent multivitamin (pantothenate, biotin, lipoate) transporter (de Carvalho and Quick 2011). Broad specificity. May be useful for drug delivery using biotin-conjugated drugs such as Biotin-Acyclovir (B-ACV) (Vadlapudi et al. 2012).  Present in the inclusion membrane that encases Chlamydia trachomatis where it transports vitamins such as biotin (Fisher et al. 2012).  May also take up iodide (de Carvalho and Quick 2011).

Animals

SMVT of Rattus norvegicus

Na⁺-dependent short chain fatty acid transporter SLC5A8 (tumor suppressor gene product, down-regulated in colon cancer) (substrates: lactate, pyruvate, acetate, propionate, butyrate (Km ≈1 mM)) [propionate:Na⁺ = 1:3] (Miyauchi et al., 2004). Pyroglutamate (5-oxoproline) is also transported in a Na⁺- coupled mechanism (Miyauchi et al., 2010). SMCT1 and SMCT2 may transport monocarboxylate drugs (e.g. nicotinate and its derivatives) across the intestinal brush boarder membrane (Gopal et al., 2007; Frank et al. 2008). Wilson et al., 2009 have proposed mechanistic details. SMCT1 can transport urate in a testosterone regulated process (Hosoyamada et al., 2010).  It's phsiological functions have been reviewed (Halestrap 2013). The system transports anti-tumor agents, 3-bromopyruvate anddichloroacetate (Su et al. 2016). The mouse ortholog has similar properties (Gopal et al. 2004).

Animals

SLC5A8 of Homo sapiens

Sodium-dependent multivitamin transporter (Na⁺-dependent multivitamin transporter) (Solute carrier family 5 member 6) of 521 aas and 11 TMSs.  It transports biotin (vitamin B7), pantothenate (vitamin B5), α-lipoic acid, and iodide (Holling et al. 2022). Compound heterozygous SLC5A6 variants have been reported in individuals with variable multisystemic disorder, including failure to thrive, developmental delay, seizures, cerebral palsy, brain atrophy, gastrointestinal problems, immunodeficiency, and/or osteopenia. Holling et al. 2022 expanded the phenotypic spectrum associated with biallelic SLC5A6 variants affecting function by reporting five individuals from three families with motor neuropathies. Missense variants p.(Tyr162Cys) and p.(Ser429Gly) did not affect plasma membrane localization of the ectopically expressed multivitamin transporter, suggesting reduced function, such as lower catalytic activity (Holling et al. 2022).

Animals

SLC5A6 of Homo sapiens

Sodium-coupled transporter, SLC5A11 or cupcake of 600 aas.  A mutant lacking this protein is insensitive to the nutritional value of sugars. It is most similar to mammalian sodium/monocarboxylate co-transporters.  It was prominently expressed in 10-13 pairs of R4 neurons of the ellipsoid body in the brain and functioned in these neurons for selecting appropriate foods (Dus et al. 2013).

Animals

Cupcake of Drosophila melanogaster

Urea active transporter (also transports polyamines; Uemura et al., 2007; Kashiwagi and Igarashi, 2011).

Animals

DUR3 of Saccharomyces cerevisiae

The major transporter for high-affinity urea transport across the plasma membrane of nitrogen-deficient Arabidopsis roots, Dur3 (Kojima et al., 2006; Mérigout et al., 2008). An orthologue of the same function has been characterized in corn (ZmDUR3) (Liu et al. 2014),

Plants

Dur3 of Arabidopsis thaliana (Q9FHJ8)

Rice Dur3 (like 2.A.21.6.2; Wang et al., 2012)

Plants

DUR3 of Oryza sativa (Q7XBS0)

Probable histatin 5 antimicrobial peptide uptake system. May also take up spermidine and be required for morphogenesis (Mayer et al., 2012).

Yeast

Dur31 of Candida albicans (Q59VF2)

Fungal SSS homologue

Fungi

TRP homologue of Neurospora crassa

Urea transporter, UreA of 693 aas and ~17 TMSs.  A three-dimensional model of UreA which, combined with mutagenesis studies, led to the identification of residues important for binding, recognition and translocation of urea, and in the sorting of UreA to the membrane. Residues W82, Y106, A110, T133, N275, D286, Y388, Y437 and S446, located in transmembrane helixes 2, 3, 7 and 11, were found to be involved in the binding, recognition and/or translocation of urea and the sorting of UreA to the membrane. Y106, A110, T133 and Y437 seem to play a role in substrate selectivity, while S446 is necessary for proper sorting of UreA to the membrane (Sanguinetti et al. 2014). A pair of non-optimal codons are necessary for the correct biosynthesis of UreA (Sanguinetti et al. 2019).

Fungi

UreA of Emericella nidulans (Aspergillus nidulans)

Acetate/glyoxylate/pyruvate permease, ActP or YjcG (Gimenez et al., 2003).  Also transports tellurite (TeO₃^2-) (Elías et al. 2015). It may depend on the 2 TMS auxiliary subunit, YjcH (TC#9.B.136.1.1), the gene for which is adjacent to the yjcG gene (Zhuge et al. 2019). Expression of these two genes is coordinately regulated and plays a role in the bacterial growth in macrophage. Intracellular acetate consumption during facultative intracellular bacterial replication within macrophages promotes immunomodulatory disorders, resulting in excessively pro-inflammatory responses of host macrophages (Zhuge et al. 2019).

Bacteria

ActP (YjcG) of E. coli (NP_418491)

Bacteria

MctC of Corynebacterium glutamicum (Q8NS49)

Acetate uptake permease, ActP1; also takes up tellurite (Borghese and Zannoni 2010; Borghese et al. 2011).

Proteobacteria

ActP1 of Rhodobacter capsulatus

Acetate permease ActP-2/ActP2/ActP3 (Borghese and Zannoni 2010; Borghese et al. 2011).  Also takes up tellurite (TeO₃^2-) (Borghese et al. 2016).

Proteobacteria

ActP2 of Rhodobacter capsulatus

High affinity neuronal choline:Na⁺ symporter, CHT1 (chloride-dependent).  Present in presynaptic terminals of cholinergic neurons.  Has 13 TMSs (Haga 2014).

Animals

CHT1 of Rattus norvegicus

High affinity choline transporter 1 (Hemicholinium-3-sensitive choline transporter) (CHT1) (Solute carrier family 5 member 7).  It is required for synthesis of acetyl choline in cholinergic nerve terminals.  It's 13 TMS topology has been verified with an extracellular N-terminus and an intracellular C-terminus.  It is likely to be a homooligomer (Okuda et al. 2012).  It is defective in hereditary motor neuropathy (Barwick et al. 2012).

Animals

SLC5A7 of Homo sapiens

Putative porter of 436 aas and 13 TMSs

Spirochaetes

Porter of Leptospira biflexa