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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.

References associated with 2.A.21 family:

Anba-Mondoloni, J., S. Chaillou, M. Zagorec, and M.C. Champomier-Vergčs. (2013). Catabolism of N-acetylneuraminic acid, a fitness function of the food-borne lactic acid bacterium Lactobacillus sakei, involves two newly characterized proteins. Appl. Environ. Microbiol. 79: 2012-2018. 23335758
Aouameur, R., S. Da Cal, P. Bissonnette, M.J. Coady, and J.Y. Lapointe. (2007). SMIT2 mediates all myo-inositol uptake in apical membranes of rat small intestine. Am. J. Physiol. Gastrointest. Liver. Physiol. 293(6):G1300-G1307.
Barwick, K.E., J. Wright, S. Al-Turki, M.M. McEntagart, A. Nair, B. Chioza, A. Al-Memar, H. Modarres, M.M. Reilly, K.J. Dick, A.M. Ruggiero, R.D. Blakely, M.E. Hurles, and A.H. Crosby. (2012). Defective presynaptic choline transport underlies hereditary motor neuropathy. Am J Hum Genet 91: 1103-1107. 23141292
Borghese, R. and D. Zannoni. (2010). Acetate permease (ActP) Is responsible for tellurite (TeO32-) uptake and resistance in cells of the facultative phototroph Rhodobacter capsulatus. Appl. Environ. Microbiol. 76: 942-944. 19966028
Borghese, R., S. Cicerano, and D. Zannoni. (2011). Fructose increases the resistance of Rhodobacter capsulatus to the toxic oxyanion tellurite through repression of acetate permease (ActP). Antonie Van Leeuwenhoek 100: 655-658. 21735076
Chen, M.L., L. Yi, X. Jin, Q. Xie, T. Zhang, X. Zhou, H. Chang, Y.J. Fu, J.D. Zhu, Q.Y. Zhang, and M.T. Mi. (2013). Absorption of resveratrol by vascular endothelial cells through passive diffusion and an SGLT1-mediated pathway. J Nutr Biochem. [Epub: Ahead of Print] 23927891
Coady, M.J., B. Wallendorff, D.G. Gagnon, and J.-Y. Lapointe. (2002). Identification of a novel Na+/myo-inositol cotransporter. J. Biol. Chem. 277: 35219-35224. 12133831
Darrouzet, E., S. Lindenthal, D. Marcellin, J.L. Pellequer, and T. Pourcher. (2014). The sodium/iodide symporter: State of the art of its molecular characterization. Biochim. Biophys. Acta. 1838: 244-253. 23988430
Dohán, O., C. Portulano, C. Basquin, A. Reyna-Neyra, L.M. Amzel, and N. Carrasco. (2007). The Na+/I symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate. Proc. Natl. Acad. Sci. U.S.A. 104: 20250-20255. 18077370
Eskandari, S., D.D.F. Loo, G. Dai, O. Levy, E.M. Wright, and N. Carrasco. (1997). Thyroid Na+/I- symporter: mechanism, stoichiometry, and specificity. J. Biol. Chem. 272: 27230-27238. 9341168
Faham, S., A. Watanabe, G.M. Besserer, D. Cascio, A. Specht, B.A. Hirayama, E.M. Wright, and J. Abramson. (2008). The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport. Science 321: 810-814. 18599740
Fisher, D.J., R.E. Fernández, N.E. Adams, and A.T. Maurelli. (2012). Uptake of biotin by Chlamydia Spp. through the use of a bacterial transporter (BioY) and a host-cell transporter (SMVT). PLoS One 7: e46052. 23029384
Frank, H., N. Gröger, M. Diener, C. Becker, T. Braun, and T. Boettger. (2008). Lactaturia and loss of sodium-dependent lactate uptake in the colon of SLC5A8-deficient mice. J. Biol. Chem. 283: 24729-24737. 18562324
Gimenez, R., M.F. Nuńez, J. Badia, J. Aguilar, and L. Baldoma. (2003). The gene yjcG, cotranscribed with the gene acs, encodes an acetate permease in Escherichia coli. J. Bacteriol. 185: 6448-6455. 14563880
Gopal, E., S. Miyauchi, P.M. Martin, S. Ananth, P. Roon, S.B. Smith, and V. Ganapathy. (2007). Transport of nicotinate and structurally related compounds by human SMCT1 (SLC5A8) and its relevance to drug transport in the mammalian intestinal tract. Pharm Res 24: 575-584. 17245649
Hopkins, A.P., J.A. Hawkhead, and G.H. Thomas. (2013). Transport and catabolism of the sialic acids N-glycolylneuraminic acid and 3-keto-3-deoxy-d-glycero-d-galactonononic acid by Escherichia coli K-12. FEMS Microbiol. Lett. [Epub: Ahead of Print] 23848303
Hosie, A.H., D. Allaway, and P.S. Poole. (2002). A monocarboxylate permease of Rhizobium leguminosarum is the first member of a new subfamily of transporters. J. Bacteriol. 184: 5436-5448. 12218032
Huc-Brandt, S., D. Marcellin, F. Graslin, O. Averseng, L. Bellanger, P. Hivin, E. Quemeneur, C. Basquin, V. Navarro, T. Pourcher, and E. Darrouzet. (2011). Characterisation of the purified human sodium/iodide symporter reveals that the protein is mainly present in a dimeric form and permits the detailed study of a native C-terminal fragment. Biochim. Biophys. Acta. 1808: 65-77. 20797386
Jiang, X., D.D. Loo, B.A. Hirayama, and E.M. Wright. (2012). The importance of being aromatic: π interactions in sodium symporters. Biochemistry 51: 9480-9487. 23116249
Johnson, D.A., S.G. Tetu, K. Phillippy, J. Chen, Q. Ren, and I.T. Paulsen. (2008). High-throughput phenotypic characterization of Pseudomonas aeruginosa membrane transport genes. PLoS Genet 4: e1000211. 18833300
Jung, H. (2002). The sodium/substrate symporter family: structural and functional features. FEBS Lett. 529: 73-77. 12354616
Jung, H., D. Hilger, and M. Raba. (2012). The Na+/L-proline transporter PutP. Front Biosci 17: 745-759. 22201772
Jung, H., R. Rübenhagen, S. Tebbe, K. Leifker, N. Tholema, M. Quick, and R. Schmid. (1998). Topology of the Na+/proline transporter of Escherichia coli. J. Biol. Chem. 273: 26400-26407. 9756872
Kashiwagi, K. and K. Igarashi. (2011). Identification and assays of polyamine transport systems in Escherichia coli and Saccharomyces cerevisiae. Methods Mol Biol 720: 295-308. 21318881
Kojima, S., A. Bohner, and N. von Wirén. (2006). Molecular mechanisms of urea transport in plants. J. Membr. Biol. 212: 83-91. 17264988
Kojima, S., A. Bohner, B. Gassert, L. Yuan, and N. von Wirén. (2007). AtDUR3 represents the major transporter for high-affinity urea transport across the plasma membrane of nitrogen-deficient Arabidopsis roots. Plant J. 52: 30-40. 17672841
Li, W., J.P. Nicola, L.M. Amzel, and N. Carrasco. (2013). Asn441 plays a key role in folding and function of the Na+/I- symporter (NIS). FASEB J. 27: 3229-3238. 23650190
Liu, T., B. Lo, P. Speight, and M. Silverman. (2008). Transmembrane IV of the high-affinity sodium-glucose cotransporter participates in sugar binding. Am. J. Physiol. Cell Physiol. 295: C64-72. 18448629
Mayer, F.L., D. Wilson, I.D. Jacobsen, P. Miramón, K. Große, and B. Hube. (2012). The Novel Candida albicans Transporter Dur31 Is a Multi-Stage Pathogenicity Factor. PLoS Pathog 8: e1002592. 22438810
Mazier, S., M. Quick, and L. Shi. (2011). Conserved tyrosine in the first transmembrane segment of solute:sodium symporters is involved in Na+-coupled substrate co-transport. J. Biol. Chem. 286: 29347-29355. 21705334
Mérigout, P., M. Lelandais, F. Bitton, J.P. Renou, X. Briand, C. Meyer, and F. Daniel-Vedele. (2008). Physiological and transcriptomic aspects of urea uptake and assimilation in Arabidopsis plants. Plant Physiol. 147: 1225-1238. 18508958
Miyauchi S., Gopal E., Babu E., Srinivas SR., Kubo Y., Umapathy NS., Thakkar SV., Ganapathy V. and Prasad PD. (2010). Sodium-coupled electrogenic transport of pyroglutamate (5-oxoproline) via SLC5A8, a monocarboxylate transporter. Biochim Biophys Acta. 1798(6):1164-71. 20211600
Miyauchi, S., E. Gopal, Y.-J. Fei, and V. Ganapathy. (2004). Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na+-coupled transporter for short-chain fatty acids. J. Biol. Chem. 279: 13293-13296. 14966140
Moses, S., T. Sinner, A. Zaprasis, N. Stöveken, T. Hoffmann, B.R. Belitsky, A.L. Sonenshein, and E. Bremer. (2012). Proline utilization by Bacillus subtilis: uptake and catabolism. J. Bacteriol. 194: 745-758. 22139509
Naftalin, R.J. (2008). Osmotic water transport with glucose in GLUT2 and SGLT. Biophys. J. 94: 3912-3923. 18234816
Nishijyo, T., D. Haas, and Y. Itoh. (2001). The CbrA-CbrB two-component regulatory system controls the utilization of multiple carbon and nitrogen sources in Pseudomonas aeruginosa. Mol. Microbiol. 40: 917-931. 11401699
Okuda, T. and T. Haga. (2000). Functional characterization of the human high-affinity choline transporter. FEBS Lett. 484: 92-97. 11068039
Okuda, T., C. Osawa, H. Yamada, K. Hayashi, S. Nishikawa, T. Ushio, Y. Kubo, M. Satou, H. Ogawa, and T. Haga. (2012). Transmembrane topology and oligomeric structure of the high-affinity choline transporter. J. Biol. Chem. [Epub: Ahead of Print] 23132865
Okuda, T., T. Haga, Y. Kanai, H. Endou, T. Ishihara, and I. Katsura. (2000). Identification and characterization of the high-affinity choline transporter. Nature Neurosci. 3: 120-125. 10649566
Pao, G.M. and M.H. Saier, Jr. (1995). Response regulators of bacterial signal transduction systems: selective domain shuffling during evolution. J. Molec. Evol. 40: 136-154. 7699720
Paroder-Belenitsky, M., M.J. Maestas, O. Dohán, J.P. Nicola, A. Reyna-Neyra, A. Follenzi, E. Dadachova, S. Eskandari, L.M. Amzel, and N. Carrasco. (2011). Mechanism of anion selectivity and stoichiometry of the Na+/I- symporter (NIS). Proc. Natl. Acad. Sci. USA 108: 17933-17938. 22011571
Perez, C. and C. Ziegler. (2013). Mechanistic aspects of sodium-binding sites in LeuT-like fold symporters. Biol Chem. [Epub: Ahead of Print] 23362203
Plata C., C.R. Sussman, A. Sindic, J.O. Liang, D.B. Mount, Z.M. Josephs, M.H. Chang, M.F. Romero. (2007). Zebrafish Slc5a12 encodes an electroneutral sodium monocarboxylate transporter (SMCTn). A comparison with the electrogenic SMCT (SMCTe/Slc5a8). J. Biol. Chem. 282: 11996-12009. 17255103
Portulano, C., M. Paroder-Belenitsky, and N. Carrasco. (2014). The Na+/I(-) Symporter (NIS): Mechanism and Medical Impact. Endocr Rev 35: 106-149. 24311738
Prasad, P.D., H. Wang, R. Kekuda, T. Fujita, Y.-J. Fei, L.D. Devoe, F.H. Leibach, and V. Ganapathy. (1998). Cloning and functional expression of a cDNA encoding a mammalian sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin, and lipoate. J. Biol. Chem. 273: 7501-7506. 9516450
Quick, M., D.D.F. Loo, and E.M. Wright. (2001). Neutralization of a conserved amino acid residue in the human Na+/glucose transporter (hSGLT1) generates a glucose-gated H+ channel. J. Biol. Chem. 276: 1728-1734. 11024018
Reizer, J., A. Reizer, and M.H. Saier, Jr. (1994). A functional superfamily of sodium/solute symporters. Biochim. Biophys. Acta 1197: 133-166. 8031825
Rivera-Ordaz, A., S. Bracher, S. Sarrach, Z. Li, L. Shi, M. Quick, D. Hilger, R. Haas, and H. Jung. (2013). The Sodium/Proline Transporter PutP of Helicobacter pylori. PLoS One 8: e83576. 24358297
Rodionov, D.A., C. Yang, X. Li, I.A. Rodionova, Y. Wang, A.Y. Obraztsova, O.P. Zagnitko, R. Overbeek, M.F. Romine, S. Reed, J.K. Fredrickson, K.H. Nealson, and A.L. Osterman. (2010). Genomic encyclopedia of sugar utilization pathways in the Shewanella genus. BMC Genomics 11: 494. 20836887
Sarker, R.I., W. Ogawa, T. Shimamoto, T. Shimamoto, and T. Tsuchiya. (1997). Primary structure and properties of the Na+/glucose symporter (SglS) of Vibrio parahaemolyticus. J. Bacteriol. 179: 1805-1808. 9045844
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. 20100283
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. 9701821
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. 20834191
Turk, E. and E.M. Wright. (1997). Membrane topology motifs in the SGLT cotransporter family. J. Membr. Biol. 159: 1-20. 9309206
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. 10835424
Uemura, T., K. Kashiwagi, and K. Igarashi. (2007). Polyamine uptake by DUR3 and SAM3 in Saccharomyces cerevisiae. J. Biol. Chem. 282: 7733-7741. 17218313
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. [Epub: Ahead of Print] 22420308
Vadlapudi, A.D., R.K. Vadlapatla, D. Pal, and A.K. Mitra. (2012). Functional and Molecular Aspects of Biotin Uptake via SMVT in Human Corneal Epithelial (HCEC) and Retinal Pigment Epithelial (D407) Cells. AAPS J. [Epub: Ahead of Print] 22927035
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. 11902719
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. 22285739
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. 10329687
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. 22267807
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. 21131949
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. 19473976
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. 10852908