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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Pantothenate:Na+ symporter, PanF (Vallari and Rock 1985; Jackowski and Alix 1990; Reizer et al. 1991).
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).
PutP of E. coli
|2.A.21.2.2||Sodium/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
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).
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.21.3.14||Sodium/myo-inositol cotransporter (Na(+)/myo-inositol cotransporter) (Sodium/myo-inositol transporter 1) (SMIT1) (Solute carrier family 5 member 3)||Animals||SLC5A3 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; 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).
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 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).
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). 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)
|2.A.21.3.3||Nucleoside or glucose(?):Na+ symporter ||Animals ||SNST of Oryctolagus cuniculus|
|2.A.21.3.4||Glucose:Na+ symporter 3 (low affinity) ||Animals ||SAAT1 of Sus scrofa |
|2.A.21.3.5||Myoinositol:Na+ symporter, SMIT1 (Aouameur et al., 2007).||Animals||SMIT 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). The potential for modulation of plasma myoinositol by variation in SLC5A11 has been assessed (Weston et al. 2022).
SLC5A11 of Homo sapiens
|2.A.21.3.7||Putative sialic acid uptake permease, NanP (D.A. Rodionov, pers. commun.)||Bacteria||NanP 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)
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
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).
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). The system transports anti-tumor agents, 3-bromopyruvate anddichloroacetate (Su et al. 2016). The mouse ortholog has similar properties (Gopal et al. 2004).
SLC5A8 of Homo sapiens
|2.A.21.5.4||The low affinity (Km (lactate) = 2mM) electroneutral Na+:monocarboxylate (lactate, pyruvate, butyrate, nicotinate) transporter, SMCTn (Plata et al., 2007) ||Animals||SMCTn of Danio rerio|
|2.A.21.5.5||The high affinity (Km (lactate) = 0.2mM) electrogenic Na+ monocarboxylate (lactate, pyruvate, butyrate, nicotinate) transporter, SMCTe (Plata et al., 2007).||Animals||SMCTe of Danio rerio|
|2.A.21.5.6||Sodium-coupled monocarboxylate transporter 2 (Electroneutral sodium monocarboxylate cotransporter) (Low-affinity sodium-lactate cotransporter) (Solute carrier family 5 member 12)||Animals||SLC5A12 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).
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
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 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).
UreA of Emericella nidulans (Aspergillus nidulans)
|2.A.21.7.1||Phenylacetate permease, Ppa ||Bacteria ||Phenylacetate permease Ppa of Pseudomonas putida |
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).
ActP (YjcG) of E. coli (NP_418491)
|2.A.21.7.3||Pyruvate/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
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
|2.A.21.9.1||The nitrogen sensor-receptor domain of the CbrA sensor kinase||Bacteria||CbrA sensor domain of Pseudomonas aeruginosa |
|2.A.21.9.2||The proline sensor-receptor domain of the PrlS sensor kinase||Bacteria||PrlS of Aeromonas hydrophila |