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). The mechanisms of LacY (TC# 2.A.1.5.1) and vSGLT (TC# 2.A.21.3.1) have been compared and discussed (Abramson and Wright 2021).

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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Sasseville, L.J., J.P. Longpré, B. Wallendorff, and J.Y. Lapointe. (2014). The transport mechanism of the human sodium/myo-inositol transporter 2 (SMIT2/SGLT6), a member of the LeuT structural family. Am. J. Physiol. Cell Physiol. 307: C431-441.

Sasseville, L.J., M. Morin, M.J. Coady, R. Blunck, and J.Y. Lapointe. (2016). The Human Sodium-Glucose Cotransporter (hSGLT1) Is a Disulfide-Bridged Homodimer with a Re-Entrant C-Terminal Loop. PLoS One 11: e0154589.

Severi, E., A.H. Hosie, J.A. Hawkhead, and G.H. Thomas. (2010). Characterization of a novel sialic acid transporter of the sodium solute symporter (SSS) family and in vivo comparison with known bacterial sialic acid transporters. FEMS Microbiol. Lett. 304: 47-54.

Singh, A.K. and R. Singh. (2020). Cardiovascular outcomes with SGLT-2 inhibitors and GLP-1 receptor agonist in Asians with type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. Diabetes Metab Syndr 14: 715-722.

Spiegelhalter, F. and E. Bremer. (1998). Osmoregulation of the opuE proline transport gene from Bacillus subtilis: contributions of the sigma A- and sigma B-dependent stress-responsive promoters. Mol. Microbiol. 29: 285-296.

Stoupa, A., G. Al Hage Chehade, D. Kariyawasam, C. Tohier, C. Bole-Feysot, P. Nitschke, H. Thibault, M.L. Jullie, M. Polak, and A. Carré. (2020). First case of fetal goitrous hypothyroidism due to SLC5A5/NIS mutations. Eur J Endocrinol 183: K1-K5.

Su, X., R. Li, K.F. Kong, and J.S. Tsang. (2016). Transport of haloacids across biological membranes. Biochim. Biophys. Acta. 1858: 3061-3070.

Tatsumi KI., Fujiwara H., Tanaka S. and Amino N. (201). Characterization of Thr-354 in the human sodium/iodide symporter (NIS) by site-directed mutagenesis. Endocr J. 57(11):997-9.

Turk, E. and E.M. Wright. (1997). Membrane topology motifs in the SGLT cotransporter family. J. Membr. Biol. 159: 1-20.

Turk, E., O. Kim, J. le Coutre, J.P. Whitelegge, S. Eskandari, J.T. Lam, M. Kreman, G. Zampighi, K.F. Faull, and E.M. Wright. (2000). Molecular characterization of Vibrio parahaemolyticus vSGLT: a model for sodium-coupled sugar cotransporters. J. Biol. Chem. 275: 25711-25716.

Turk, E., O.K. Gasymov, S. Lanza, J. Horwitz, and E.M. Wright. (2006). A reinvestigation of the secondary structure of functionally active vSGLT, the vibrio sodium/galactose cotransporter. Biochemistry 45: 1470-1479.

Uemura, T., K. Kashiwagi, and K. Igarashi. (2007). Polyamine uptake by DUR3 and SAM3 in Saccharomyces cerevisiae. J. Biol. Chem. 282: 7733-7741.

Vadlapudi AD., Vadlapatla RK., Pal D. and Mitra AK. (2012). Functional and molecular aspects of biotin uptake via SMVT in human corneal epithelial (HCEC) and retinal pigment epithelial (D407) cells. AAPS J. 14(4):832-42.

Vadlapudi, A.D., R.K. Vadlapatla, and A.K. Mitra. (2012). Sodium dependent multivitamin transporter (SMVT): a potential target for drug delivery. Curr Drug Targets 13: 994-1003.

Vallari, D.S. and C.O. Rock. (1985). Isolation and characterization of Escherichia coli pantothenate permease (panF) mutants. J. Bacteriol. 164: 136-142.

Veenstra, M., S. Lanza, B.A. Hirayama, E. Turk, and E.M. Wright. (2004). Local conformational changes in the Vibrio Na+/galactose cotransporter. Biochemistry 43: 3620-3627.

Velic, A., J.R. Hirsch, J. Bartel, R. Thomas, R. Schröter, H. Stegemann, B. Edemir, C. August, E. Schlatter, and G. Gabriëls. (2004). Renal transplantation modulates expression and function of receptors and transporters of rat proximal tubules. J Am Soc Nephrol 15: 967-977.

von Blohn, C., B. Kempf, R.M. Kappes, and E. Bremer. (1997). Osmostress response in Bacillus subtilis: characterization of a proline uptake system (OpuE) regulated by high osmolarity and the alternative transcription factor sigma B. Mol. Microbiol. 25: 175-187.

Wang X., Xu X., Ma M., Zhou W., Wang Y. and Yang L. (2012). pH-dependent channel gating in connexin26 hemichannels involves conformational changes in N-terminus. Biochim Biophys Acta. 1818(5):1148-1157.

Wang, H., W. Huang, Y.-J. Fei, H. Xia, T.L. Yang-Feng, F.H. Leibach, L.D. Devoe, V. Ganapathy, and P.D. Prasad. (1999). Human placental Na+-dependent multivitamin transporter. J. Biol. Chem. 274: 14875-14883.

Wang, X.X., J. Levi, Y. Luo, K. Myakala, M. Herman-Edelstein, L. Qiu, D. Wang, Y. Peng, A. Grenz, S. Lucia, E. Dobrinskikh, V.D. D''Agati, H. Koepsell, J.B. Kopp, A. Rosenberg, and M. Levi. (2017). SGLT2 Expression is increased in Human Diabetic Nephropathy: SGLT2 Inhibition Decreases Renal Lipid Accumulation, Inflammation and the Development of Nephropathy in Diabetic Mice. J. Biol. Chem. [Epub: Ahead of Print]

Wargacki, A.J., E. Leonard, M.N. Win, D.D. Regitsky, C.N. Santos, P.B. Kim, S.R. Cooper, R.M. Raisner, A. Herman, A.B. Sivitz, A. Lakshmanaswamy, Y. Kashiyama, D. Baker, and Y. Yoshikuni. (2012). An engineered microbial platform for direct biofuel production from brown macroalgae. Science 335: 308-313.

Watanabe, A., S. Choe, V. Chaptal, J.M. Rosenberg, E.M. Wright, M. Grabe, and J. Abramson. (2010). The mechanism of sodium and substrate release from the binding pocket of vSGLT. Nature 468: 988-991.

Watanabe, Y., R.S. Ebrhim, M.A. Abdullah, and R.E. Weiss. (2018). A Novel Missense Mutation in the SLC5A5 Gene in a Sudanese Family with Congenital Hypothyroidism. Thyroid 28: 1068-1070.

Wilson MC., Meredith D., Bunnun C., Sessions RB. and Halestrap AP. (2009). Studies on the DIDS-binding site of monocarboxylate transporter 1 suggest a homology model of the open conformation and a plausible translocation cycle. J Biol Chem. 284(30):20011-21.

Xie, Z., E. Turk, and E.M. Wright. (2000). Characterization of the Vibrio parahaemolyticus Na+/glucose cotransporter: a bacterial member of the sodium/glucose transporter (SGLT) family. J. Biol Chem. 275: 25959-25964.

Xiong, Y., D. Delic, S. Zeng, X. Chen, C. Chu, A.A. Hasan, B.K. Krämer, T. Klein, L. Yin, and B. Hocher. (2022). Regulation of SARS CoV-2 host factors in the kidney and heart in rats with 5/6 nephrectomy-effects of salt, ARB, DPP4 inhibitor and SGLT2 blocker. BMC Nephrol 23: 117.

Yoshida, K., H. Yamaguchi, M. Kinehara, Y.H. Ohki, Y. Nakaura, and Y. Fujita. (2003). Identification of additional TnrA-regulated genes of Bacillus subtilis associated with a TnrA box. Mol. Microbiol. 49: 157-165.

Zhang, C.X., J.X. Zhang, L. Yang, C.R. Zhang, F. Cheng, R.J. Zhang, Y. Fang, Z. Wang, F.Y. Wu, P.Z. Li, J. Liang, R. Li, and H.D. Song. (2021). Novel Compound Heterozygous Pathogenic Mutations of in a Chinese Patient With Congenital Hypothyroidism. Front Endocrinol (Lausanne) 12: 620117.

Zhuge, X., Y. Sun, M. Jiang, J. Wang, F. Tang, F. Xue, J. Ren, W. Zhu, and J. Dai. (2019). Acetate metabolic requirement of avian pathogenic Escherichia coli promotes its intracellular proliferation within macrophage. Vet Res 50: 31.

Examples:

TC#NameOrganismal TypeExample
2.A.21.1.1

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

Bacteria

PanF of E. coli

 
Examples:

TC#NameOrganismal TypeExample
2.A.21.2.1

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

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

PutP of Staphylococcus aureus

 
2.A.21.2.3

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

 
2.A.21.2.4

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

 
2.A.21.2.5

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).

Firmicutes

OpuE of Bacillus subtilis

 
2.A.21.2.6

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

 
2.A.21.2.7

Sodium:proline symporter of 428 aas and 11 TMSs

Proline uptake porter of Methanosarcina mazei (Methanosarcina frisia)

 
Examples:

TC#NameOrganismal TypeExample
2.A.21.3.1

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).

Animals

SLC5A1 of Homo sapiens

 
2.A.21.3.10

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)

 
2.A.21.3.11

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

Bacteria

ToaA in Vibrio splendida (A3UWQ1) 

 
2.A.21.3.12

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

Bacteria

ToaB in Vibrio splendida (A3UWQ9)

 
2.A.21.3.13

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

Bacteria

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
 
2.A.21.3.15

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

Animals

SLC5A10 of Homo sapiens

 
2.A.21.3.16

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).

Animals

SLC5A2 of Homo sapiens

 
2.A.21.3.17

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

 
2.A.21.3.18

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

Animals

SLC5A4 of Homo sapiens

 
2.A.21.3.19

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

Bacteroidetes

AraP (Q8AAV7) of Bacteroides thetaiotaomicron

 
2.A.21.3.2

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).

Bacteria

SglS of Vibrio parahaemolyticus

 
2.A.21.3.20

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

Firmicutes

NanT of Lactobacillus sakei

 
2.A.21.3.21

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

YidK of E. coli

 
2.A.21.3.22

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)

 
2.A.21.3.23

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)

 
2.A.21.3.24

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

Sodium:Glucose symporter of Aeromonas virus 44RR2

 
2.A.21.3.25

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)

 
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
 
2.A.21.3.6

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).

Animals

SLC5A11 of Homo sapiens

 
2.A.21.3.7Putative sialic acid uptake permease, NanP (D.A. Rodionov, pers. commun.)BacteriaNanP of Vibrio fischeri (Q5E733)
 
2.A.21.3.8

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

Proteobacteria

ManPll of Shewanella amazonensis (A1S2A8)

 
2.A.21.3.9

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

Proteobacteria

GalPll of Shewanella pealeana (A8H019)

 
Examples:

TC#NameOrganismal TypeExample
2.A.21.4.1

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).

Bacteria

MctP of Rhizobium leguminosarum

 
2.A.21.4.2

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

 
Examples:

TC#NameOrganismal TypeExample
2.A.21.5.1

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).

Animals

SLC5A5 of Homo sapiens

 
2.A.21.5.2

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

 
2.A.21.5.3

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

 
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
(Q7T384)
 
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
(Q3ZMH1)
 
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
 
2.A.21.5.7

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

 
2.A.21.5.8

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

 
Examples:

TC#NameOrganismal TypeExample
2.A.21.6.1

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

Animals

DUR3 of Saccharomyces cerevisiae

 
2.A.21.6.2

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)

 
2.A.21.6.3

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

Plants

DUR3 of Oryza sativa (Q7XBS0)

 
2.A.21.6.4

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)

 
2.A.21.6.5

Fungal SSS homologue

Fungi

TRP homologue of Neurospora crassa

 
2.A.21.6.6

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)

 
Examples:

TC#NameOrganismal TypeExample
2.A.21.7.1Phenylacetate permease, Ppa Bacteria Phenylacetate permease Ppa of Pseudomonas putida
 
2.A.21.7.2

Acetate/glyoxylate/pyruvate permease, ActP or YjcG (Gimenez et al., 2003).  Also transports tellurite (TeO32-) (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)

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

Bacteria

MctC of Corynebacterium glutamicum (Q8NS49)

 
2.A.21.7.4

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

Proteobacteria

ActP1 of Rhodobacter capsulatus

 
2.A.21.7.5

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

Proteobacteria

ActP2 of Rhodobacter capsulatus

 
Examples:

TC#NameOrganismal TypeExample
2.A.21.8.1

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

 
2.A.21.8.2

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

 
2.A.21.8.3

Putative porter of 436 aas and 13 TMSs

Spirochaetes

Porter of Leptospira biflexa

 
Examples:

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