2.A.21 The Solute:Sodium Symporter (SSS) Family

Members of the SSS family catalyze solute:Na+ symport. The solutes transported may be sugars, amino acids, organo cations such as choline, nucleosides, inositols, vitamins, urea or anions, depending on the system. Members of the SSS family have been identified in bacteria, archaea and animals, and all functionally well-characterized members normally catalyze solute uptake via Na+ symport. The human placental multivitamin symporter cotransports an anionic vitamin with two Na+. In the rabbit Na+:D-glucose cotransporter, SGLT1, the glucose translocation pathway probably involves TMSs 10-13, and the binding site for the inhibitor, phlorizin, involves loop 13 (residues 604-610). Cation binding in the N-terminal domain may induce transport-related conformational changes. A conserved tyrosine in the first transmembrane segment of solute:sodium symporters is involved in Na+-coupled substrate co-transport (Mazier et al., 2011).  Mechanistic aspects of Na+ binding sites in LeuT-like fold symporters has been discussed in detail (Perez and Ziegler 2013).

In the human homologue (hSGLT1), H+ can replace Na+, but the apparent affinity for glucose reduces 20x from 0.3 mM to 6 mM. The apparent affinity for H+ is 6 μM, 1000x higher than for Na+ (6 mM). The transport stoichiometry is 1 glucose:2 Na+ or H+. If Asp204 is replaced by glutamate (D204E), the apparent affinity for H+ increases >20x with no change in apparent Na+ affinity. The D204N or D204C mutation promotes phlorizin-sensitive H+ currents that are 10x greater than Na+ currents, and the glucose:H+ stoichiometry is then as great as 1:145. The mutant system thus behaves as a glucose-gated H+ channel.

Proteins of the SSS vary in size from about 400 residues to about 700 residues and probably possess thirteen to fifteen putative transmembrane helical spanners (TMSs). They generally share a core of 13 TMSs, but different members of the family may have different numbers of TMSs. A 13 TMS topology with a periplasmic N-terminus and a cytoplasmic C-terminus has been experimentally determined for the proline:Na+ symporter, PutP, of E. coli. Residues important for substrate and Na+ binding in PutP are found in TMSs 2, 7 and 9 as well as adjacent loops (Jung, 2002). A 14 TMS topology with periplasmic N- and C-termini has been established for the V. parahaemolyticus SglT carrier. SglT transports sugar:Na with a 1:1 stoichiometry. However, MctP of Rhizobium leguminosarum may take up monocarboxylates via an H+ symport mechanism as a dependency on Na+ could not be demonstrated and uptake was strongly inhibited by 10 μM CCCP.

Faham et al., 2008 reported the crystal structure of a member of the solute sodium symporters (SSS), the Vibrio parahaemolyticus sodium/galactose symporter (vSGLT). The approximately 3.0 angstrom structure contains 14 transmembrane (TM) helices in an inward-facing conformation with a core structure of inverted repeats of 5 TM helices (TM2 to TM6 and TM7 to TM11). Galactose is bound in the center of the core, occluded from the outside solutions by hydrophobic residues. The architecture of the core is similar to that of the leucine transporter (LeuT) (TC#2.A.22.4.2) from the NSS family. Modeling the outward-facing conformation based on the LeuT structure, in conjunction with biophysical data, provided insight into structural rearrangements for active transport (Faham et al., 2008).

Some bacterial sensor kinases (2.A.21.9.1 and 2.A.22.9.2) have N-terminal, 12 TMS, sensor domains that regulate the C-terminal kinase domains. The latter are homologous to the kinase domain of NtrB (Pao and Saier, 1995). The N-terminal sensor domains are homologous, but distantly related to members of the SSS. The closest homologues are PutP of E. coli (2.A.21.2.1) and PanF of E. coli (2.A.21.1.1). Homologous regulatory domains are found in Agrobacterium, Mesorhizobium, Sinorhizobium, Vibrio cholera and Bacillus species. While it is clear that these domains function as sensors, it is not known if they also transport the small molecules they sense.

The generalized transport reaction catalyzed by the members of this family is:

solute (out) + nNa+ (out) → solute (in) + nNa+ (in)

This family belongs to the APC Superfamily.



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TC#NameOrganismal TypeExample

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


PanF of E. coli


TC#NameOrganismal TypeExample

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).


PutP of E. coli

2.A.21.2.2Sodium/proline symporter (Proline permease)Bacteria

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).


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). 


PutP of Bacillus subtilis


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


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.


PutP of Helicobacter pylori


TC#NameOrganismal TypeExample

Glucose or galactose:Na+ symporter, SGLT1 (galactose > glucose > fucose). Cotransports water against an osmotic gradient (Naftalin, 2008). TMS IV of the high-affinity sodium-glucose cotransporter participates in sugar binding (Liu et al., 2008).  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).


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). 


STM1128 (NanP) of Salmonella enterica (Q8ZQ35)


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


ToaA in Vibrio splendida (A3UWQ1) 


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


ToaB in Vibrio splendida (A3UWQ9)


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


ToaC in Vibrio splendida (A3UR54)

2.A.21.3.14Sodium/myo-inositol cotransporter (Na(+)/myo-inositol cotransporter) (Sodium/myo-inositol transporter 1) (SMIT1) (Solute carrier family 5 member 3)AnimalsSLC5A3 of Homo sapiens

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


SLC5A10 of Homo sapiens


Sodium/glucose cotransporter 2 (Na+/glucose cotransporter 2) (Low affinity sodium-glucose cotransporter) (Solute carrier family 5 member 2) of 672 aas and 14 TMSs.  Shows increased expression in human diabetic nephrophathy. Inhibition causes decreased renal lipid accumulation, inflamation and disease symptoms (Wang et al. 2017).


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).


SLC5A9 of Homo sapiens


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


SLC5A4 of Homo sapiens


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


AraP (Q8AAV7) of Bacteroides thetaiotaomicron


Glucose or galactose:Na+ symporter, SglS or SglT. The 3.0Å 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 (Watanabe et al., 2010). The involvement of aromatic residue pi interactions, especially with Na+ binding, has been examined (Jiang et al. 2012).


SglS of Vibrio parahaemolyticus


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


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).

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

2.A.21.3.3Nucleoside or glucose(?):Na+ symporter Animals SNST of Oryctolagus cuniculus
2.A.21.3.4Glucose:Na+ symporter 3 (low affinity) Animals SAAT1 of Sus scrofa
2.A.21.3.5Myoinositol:Na+ symporter, SMIT1 (Aouameur et al., 2007).AnimalsSMIT of Canis familiaris

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).


SLC5A11 of Homo sapiens

2.A.21.3.7Putative sialic acid uptake permease, NanP (D.A. Rodionov, pers. commun.)BacteriaNanP of Vibrio fischeri (Q5E733)

The putative mannose porter, ManPll (Rodionov et al. 2010).


ManPll of Shewanella amazonensis (A1S2A8)


The putative galactose porter, GalPll (Rodionov et al., 2010).


GalPll of Shewanella pealeana (A8H019)


TC#NameOrganismal TypeExample

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


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).


YodF of Bacillus subtilis


TC#NameOrganismal TypeExample

Sodium iodide symporter (NIS; 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). 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 stoichiometry is Na+:I-= 2:1. 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).


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).


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). Transports anti-tumor agents, 3-bromopyruvate anddichloroacetate (Su et al. 2016).


SLC5A8 of Homo sapiens

2.A.21.5.4The low affinity (Km (lactate) = 2mM) electroneutral Na+:monocarboxylate (lactate, pyruvate, butyrate, nicotinate) transporter, SMCTn (Plata et al., 2007) AnimalsSMCTn of Danio rerio
2.A.21.5.5The high affinity (Km (lactate) = 0.2mM) electrogenic Na+ monocarboxylate (lactate, pyruvate, butyrate, nicotinate) transporter, SMCTe (Plata et al., 2007).AnimalsSMCTe of Danio rerio
2.A.21.5.6Sodium-coupled monocarboxylate transporter 2 (Electroneutral sodium monocarboxylate cotransporter) (Low-affinity sodium-lactate cotransporter) (Solute carrier family 5 member 12)AnimalsSLC5A12 of Homo sapiens

Sodium-dependent multivitamin transporter (Na+-dependent multivitamin transporter) (Solute carrier family 5 member 6)


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).


Cupcake of Drosophila melanogaster


TC#NameOrganismal TypeExample

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


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),


Dur3 of Arabidopsis thaliana (Q9FHJ8)


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


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).


Dur31 of Candida albicans (Q59VF2)


Fungal SSS homologue


TRP homologue of Neurospora crassa


Urea transporter, UreA of 693 aas.  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).


UreA of Emericella nidulans (Aspergillus nidulans)


TC#NameOrganismal TypeExample
2.A.21.7.1Phenylacetate permease, Ppa Bacteria Phenylacetate permease Ppa of Pseudomonas putida

Acetate/glyoxylate permease, ActP (Gimenez et al., 2003).  Also transports tellurite (TeO32-) (Elías et al. 2015).


ActP (YjcG) of E. coli (NP_418491)

2.A.21.7.3Pyruvate/acetate/propionate: H+ symporter, MctC (DhlC; cg0953).


MctC of Corynebacterium glutamicum (Q8NS49)


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


ActP1 of Rhodobacter capsulatus


Acetate permease ActP-2/ActP2/ActP3 (Borghese and Zannoni 2010; Borghese et al. 2011).  Also takes up tellurite (TeO32-) (Borghese et al. 2016).


ActP2 of Rhodobacter capsulatus


TC#NameOrganismal TypeExample

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


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).


SLC5A7 of Homo sapiens


Putative porter of 436 aas and 13 TMSs


Porter of Leptospira biflexa


TC#NameOrganismal TypeExample
2.A.21.9.1The nitrogen sensor-receptor domain of the CbrA sensor kinaseBacteriaCbrA sensor domain of Pseudomonas aeruginosa
2.A.21.9.2The proline sensor-receptor domain of the PrlS sensor kinaseBacteriaPrlS of Aeromonas hydrophila