| 2.A.47 The Divalent Anion:Na+ Symporter (DASS) Family
Functionally characterized proteins of the DASS family (also called the SLC13 family) transport (1) organic di- and tricarboxylates of the Krebs Cycle as well as dicarboxylate amino acid, (2) inorganic sulfate and (3) phosphate. These proteins are found in Gram-negative bacteria, cyanobacteria, archaea, plant chloroplasts, yeast and animals. They vary in size from 432 amino acyl residues (M. jannaschii) to 923 residues (Saccharomyces cerevisiae). The three S. cerevisiae proteins are large (881-923 residues); the animal proteins are substantially smaller (539-616 residues), and the bacterial proteins are still smaller (461-612 residues). They exhibit 11-14 putative transmembrane α-helical spanners (TMSs). An 11 TMS model for the animal NaDC-1 and hNaSi-1 carriers has been proposed (Li and Pajor, 2003; Pajor, 1999). Two serine residues in the human sulfate transporter, hNaSi-1 (Q9BZW2), one in TMS 5 and one in TMS 6, are required for sulfate transport (Li and Pajor, 2003). The former carrier and the other NaDC isoforms cotransport 3 Na+ with each dicarboxylate. Protonated tricarboxylates are also cotransported with 3 Na+. Several organisms possess multiple paralogues of the DASS family (e.g., 4 for E. coli; 2 for H. influenzae, 3 for S. cerevisiae, and at least 4 for C. elegans). Members of this family have been reported to have this IT fold (Ferrada and Superti-Furga 2022).
Proteins of the DASS family are divided into two groups of transporters with distinct anion specificities: the Na+-sulfate (NaS) cotransporters and the Na+-carboxylate (NaC) cotransporters. Mammalian members of this family are: SLC13A1 (NaS1), SLC13A2 (NaC1), SLC13A3 (NaC3), SLC13A4 (NaS2) and SLC13A5 (NaC2) (Markovich 2012). DASS family proteins encode plasma membrane polypeptides with 8-13 putative transmembrane domains, and are expressed in a variety of tissues. They are all Na+-coupled symporters. The Na+:anion coupling ratio is 3:1, indicative of electrogenic properties. They have a substrate preference for divalent anions, which include tetra-oxyanions for the NaS cotransporters or Krebs cycle intermediates (including mono-, di- and tricarboxylates) for the NaC cotransporters. The molecular and cellular mechanisms underlying the biochemical, physiological and structural properties of DASS family members have been reviewed (Markovich, 2012).
The phylogenetic tree for the DASS family reveals six clusters as follows: (1) all animal homologues; (2) all yeast proteins; (3) a functionally uncharacterized protein from Ralstonia eutrophus; (4) three E. coli proteins plus one from H. influenzae and one from spinach chloroplasts (the SodiT1 oxoglutarate:malate translocator); (5) an E. coli Orf that clusters loosely with a sulfur deprivation regulated protein of Synechocystis, and (6) an M. jannaschii protein that clusters loosely with an H. influenzae Orf.
Distant homologues of DASS family proteins may include members of the Ars (arsenite exporter) (TC #3.A.4) family as well as the NhaB (TC #2.A.34) and NhaC (TC #2.A.35) Na+/H+ antiporter families. The DASS family is therefore a member of the ion transporter (IT) superfamily (Rabus et al., 1999).
The generalized transport reaction catalyzed by the DASS family proteins is probably:
Anion2- (out) + nM+ [Na+ or H+] (out) → Anion2- (in) + nM+ (in)
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This family belongs to the ArsB Membrane Protein (ArsB) Superfamily.
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| References: |
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Liu, L., M. Zacchia, X. Tian, L. Wan, A. Sakamoto, M. Yanagisawa, R.J. Alpern, and P.A. Preisig. (2010). Acid regulation of NaDC-1 requires a functional endothelin B receptor. Kidney Int 78: 895-904.
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Pajor, A.M. and N.N. Sun. (2010). Role of isoleucine-554 in lithium binding by the Na+/dicarboxylate cotransporter NaDC1. Biochemistry 49: 8937-8943.
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Pajor, A.M., N. Sun, L. Bai, D. Markovich, and P. Sule. (1997). The substrate recognition domain in the Na+/dicarboxylate and Na+/sulfate cotransporters is located in the carboxy-terminal portion of the protein. Biochim. Biophys. Acta 1370: 98-106.
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Pajor, A.M., N.N. Sun, A.D. Joshi, and K.M. Randolph. (2011). Transmembrane helix 7 in the Na+/dicarboxylate cotransporter 1 is an outer helix that contains residues critical for function. Biochim. Biophys. Acta. 1808: 1454-1461.
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Pos, K.M., P. Dimroth, and M. Bott. (1998). The Escherichia coli citrate carrier CitT: a member of a novel eubacterial transporter family related to the 2-oxoglutarate/malate translocator from spinach chloroplasts. J. Bacteriol. 180: 4160-4165.
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Quentmeier, A., A. Holzenburg, F. Mayer, and G. Antranikian. (1987). Reevaluation of citrate lyase from Escherichia coli. Biochim. Biophys. Acta. 913: 60-65.
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Youn, J.W., E. Jolkver, R. Krämer, K. Marin, and V.F. Wendisch. (2008). Identification and characterization of the dicarboxylate uptake system DccT in Corynebacterium glutamicum. J. Bacteriol. 190: 6458-6466.
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 2.A.47.1.1 | Anion transporter of unknown specificity | Archaea | Anion transporter of Methanospirillum hungatei (Q2FMC1) |
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| 2.A.47.1.10 | Cation-independent, electroneutral tri- and di-carboxylate transporter with a preference for tricarboxylates, Indy (I'm not dead yet) [When Indy is mutated flies live about twice as long as wild type] (Inoue et al., 2002) | Animals | Indy of Drosophila melanogaster (Q9VVT2) |
| |
| 2.A.47.1.11 | The Na+ (or Li+):dicarboxylate (2:1) symporter, SdcS (catalyzes succinate:succinate antiport as well as electroneutral symport in reconstituted proteoliposomes (Hall and Pajor, 2007; Joshi and Pajor, 2009). Transports succinate, malate and fumarate with similar affiinities (7 μM, 8 μM and 15 μM, respectively), but aspartate and α-ketoglutarate with very low affinities (Hall and Pajor 2005; Hall and Pajor 2007). | Bacteria | SdcS of Staphylococcus aureus (Q2FFH9) |
| |
| 2.A.47.1.12 | The aerobic dicarboxylate (succinate (Km, 30 μM), fumarate (Km, 79 μM), malate (Km, 360 μM)) transporter, DcsT or DccT. Also transports oxaloacetate with low affinity (Ebbighausen et al. 1991; Teramoto et al., 2008; Youn et al. 2008). | Bacteria | DcsT (DccT) of Corynebacterium glutamicum (A4QAL6) |
| |
| 2.A.47.1.13 |
The Na+-coupled dicarboxylate (succinate; malate; fumarate) transporter, SdcL (transports aspartate, α-ketoglutarate and oxaloacetate with low affinity). Km for succinate, ~6 μM; Km for Na+, 0.9 mM; Na :substrate = 2:1 (Strickler et al., 2009). | Bacteria | SdcL of Bacillus licheniformis (Q65NC0) |
| |
| 2.A.47.1.14 | solute carrier family 13 (sodium/sulfate symporters), member 4, NaS2. Transports anions such as sulfate, thiosulfate and selenate (Bergeron et al. 2013). | Animals | SLC13A4 of Homo sapiens |
| |
| 2.A.47.1.15 | Solute carrier family 13 member 3, SLC13A3 (Na+/dicarboxylate cotransporter 3; NaDC-3; hNaDC3; SDCT2) (Sodium-dependent high-affinity dicarboxylate transporter 2) of 602 aas with about 16 TMSs in a possible 4 - 7 + 9 or 10 TMS arrangement. (Bergeron et al. 2013; Schlosser et al. 2023). The SLC13A3 gene encodes a plasma membrane-localized Na+/dicarboxylate cotransporter 3 (NaDC3) primarily expressed in the kidney, astrocytes and choroid plexus. In addition to three Na+ ions, it brings four to six carbon dicarboxylates into the cytosol (Hussain et al. 2023). Patients with acute reversible leukoencephalopathy and α-ketoglutarate accumulation (ARLIAK) carry pathogenic mutations in the SLC13A3 gene (Hussain et al. 2023). | Animals | SLC13A3 of Homo sapiens |
| |
| 2.A.47.1.16 | Solute carrier family 13 member 1 (Renal and intestinal sodium/sulfate cotransporter) (Na+/sulfate cotransporter) (hNaSi-1). Also transports thiosulfate and selenium. It is inhibited by many di- and tri-valent organic and inorganic anions (Markovich 2013). | Animals | SLC13A1 of Homo sapiens |
| |
| 2.A.47.1.17 |
Solute carrier family 13 member 2 (Na /di- and tricarboxylate cotransporter 1) (NaDC-1) (Renal sodium/dicarboxylate cotransporter). Transports citrate and other Krebs cycle intermediates across the
apical membrane of kidney proximal tubules and small intestinal cells (Pajor and Sun 2010; Bergeron et al. 2013). Transmembrane helices 7 and 11 in NaDC1 contains residues critical for function (Pajor and Sun 2010; Pajor et al. 2011). The mouse ortholog can transport succinate and adipate, but the rabbit transporter transports only succinate. Multiple amino acids in TMSs 8, 9 and 10 contribute to the transport of adipate, and A504 plays an important role while TMSs 3 and 4 function in substrate recognitioin (Oshiro and Pajor 2006; Oshiro et al. 2006). Pajor and Randolph 2005 have provided evidence for large-scale changes in the structure of NaDC-1 during the transport cycle.
| Animals | SLC13A2 or NaDC1 of Homo sapiens |
| |
| 2.A.47.1.18 | Organic acid transporter, SdcF. Transports succinate, malate, fumarate, tartrate and oxaloacetate (A. Pajor, personal communication) | Firmicutes | SdcF of Bacillus licheniformis |
| |
| 2.A.47.1.19 | Solute carrier family 13, Slc13a1; Sodium/sulfate symporter, member 1, NaS1 of 583 aas and 14 TMSs. Na+-sulfate cotransport is inhibited by thiosulfate, selenate, molybdate and
tungstate (Markovich et al. 2008). | | NaS1 of Danio ririo |
| |
| 2.A.47.1.2 |
Renal sodium:sulfate cotransporter (Ssc, NaSi-1 or Nas1) (also transports tungstate, molybdate, thiosulfate and selenate) (Beck and Markovich 2000; Lee et al 2006; Li and Pajor, 2003; Bergeron et al. 2013). | Animals | Ssc of Rattus norvegicus |
| |
| 2.A.47.1.3 |
The brush boarder intestinal and renal electrogenic, Na -dependent, low affinity (0.1-4.0mM), dicarboxylate (succinate, fumarate, malate, α-ketoglutarate, oxaloacetate, L- and D-glutamate, and citrate):H cotransporter, NaDC-1 or SDCT1. Functions in acid regulation. An acidic pH stimullates citrate uptake; acid stimulation is mediated by endothelin-1 (ET-1) and its receptor (Liu et al. 2010). | Animals | NaDC-1 or SDCT1 of Rattus norvegicus (O35055) |
| |
| 2.A.47.1.4 | The basolateral intestinal and renal electrogenic, Na+-dependent high affinity (2-50µM) dicarboxylate:(Na+)3 cotransporter (NaDC-3) (substrate range similar to that of NDC-1 except that tricarboxylates are transported with very low affinity). Na+:succinate = 3:1. Also transports N-acetyl-L-aspartate, an abundant amino acid in the nervous system (Yodoya et al., 2006). | Animals | NaDC-3 of Rattus norvegicus |
| |
| 2.A.47.1.5 | Basolateral Na+: di- and tricarboxylate (succinate cis-aconitate, citrate, etc.) cotransporter, fNaDC-3 | Animals | fNaDC-3 of Pseudopleuronectes americanus (the winter flounder) |
| |
| 2.A.47.1.6 | The tonoplast dicarboxylate (malate) transporter, AtDCT (Kovermann et al., 2007). The ortholog (70% identity) in tomatos increases the malate while decreasing the citrate concentrations, influencing flavor (Liu et al. 2017). | Plants | AttDT of malate:Na+ symporter (and possibly malate:citrate antiporter) of Arabidopsis thaliana |
| |
| 2.A.47.1.7 |
Low affinity dicarboxylate:Na+ symporter, NaDC1 (INDY1) (relative affinities: succinate > fumarate > α-ketoglutarate > malate > lactate > maleate) (Fei et al., 2003). | Animals | NaDC1 of Caenorhabditis elegans |
| |
| 2.A.47.1.8 | High affinity dicarboxylate:Na+ symporter, NaDC2 (INDY2) (relative affinities: fumarate > malate > α-ketoglutarate > maleate > succinate > lactate) (Fei et al., 2003) | Animals | NaDC2 of Caenorhabditis elegans |
| |
| 2.A.47.1.9 |
Na+-coupled citrate transporter (NaCT) (Km=20 μM) (also may transport dicarboxylates and other tricarboxylates with lower affinity) (Inoue et al., 2002b; Bergeron et al. 2013). Na+:citrate = 3-4:1 (Wada et al., 2006).Targeting longevity gene SLC13A5 provides a novel approach to preventing age-related bone fragility and osteoporosis (Zahn et al. 2023). Homozygous variants of SLC13A5 expand the functional heterogeneity of a homogeneous syndrome of early infantile epileptic encephalopathy (Alsemari et al. 2024). | Animals | SLC13A5 of Homo sapiens |
| |
| Examples: |
| TC# | Name | Organismal Type | Example |
| 2.A.47.2.1 | Inorganic phosphate transporter, Pho87 of 923 aas and 12 TMSs. Also transports selenite (Lazard et al., 2010). | Yeast | Pho87 of Saccharomyces cerevisiae |
| |
| 2.A.47.2.2 |
Vacuolar low affinity phosphate transporter, Pho91 (Estrella et al., 2008) with 12 C-terminal TMSs and an N-terminal 360 hydrophilic region. Also transports selenite (Lazard et al., 2010). Pyrophosphate stimulates the phosphate-sodium symporter of Trypanosoma brucei (TC# 2.A.47.2.4) acidocalcisomes and Saccharomyces cerevisiae vacuoles (this protein) (Potapenko et al. 2019). | Yeast | Pho91 of Saccharomyces cerevisiae (P27514) |
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| 2.A.47.2.3 |
Low affinity phosphate transporters (881aas). Also transports selenite (Lazard et al., 2010).
| Yeast | Pho90 of Saccharomyces cerevisiae (P39535) |
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| 2.A.47.2.4 | Contractile vacuole phosphate:Na+ symporter of 727 aas and 12 TMSs, Pho91 (Pho90; Pho87). Has an N-terminal SPX domain and a C-terminal anion permease domain. Plays an indirect role in pyrophosphate and oligophosphate synthesis (Jimenez and Docampo 2015). Pyrophosphate stimulates the phosphate-sodium symporter of Trypanosoma brucei acidocalcisomes and Saccharomyces cerevisiae vacuoles (Potapenko et al. 2019). | Euglenozoa | Pho91 of Trypanosoma cruzi |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 2.A.47.3.1 | 2-oxoglutarate:malate antiporter (SodiTl) | Plant chloroplasts | SodiTl of Spinacia oleracea |
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| 2.A.47.3.2 | Citrate:succinate antiporter (Pos et al. 1998). Binds and presumably regulates the heterodimeric citrate lyase, CitE/CitF which converts citrate to succinate and acetate (Quentmeier et al. 1987). These proteins form a metabolon which together catalyze citrate fermentation under anaerobic conditions. | Bacteria | CitT of E. coli (P0AE74) |
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| 2.A.47.3.3 | L-tartrate:succinate antiporter, TtdT (YgjE). (also takes up meso and L-tartrate and succinate; does not transport D-tartrate) (Kim and Unden, 2007). It is induced in the presence of L- or meso tartrate under anaerobic conditions in the presence of TtdR (Kim et al. 2009). | Bacteria | TtdT (YgjE) of E. coli (P39414) |
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| 2.A.47.3.4 | The pmf-dependent citrate uptake system, Cit1 (Urbany and Neuhaus, 2008) | Bacteria | Cit1 of Erwinia carotovora subsp. atroseptica (Q6D017) |
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| 2.A.47.3.5 | Putative anion (tri- or di-carboxylic acid) transporter of 477 aas, YbhI. | | YbhI of E. coli |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 2.A.47.4.1 | Sulfur-deprivation response protein | Cyanobacteria | SdrP of Synechocystis |
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| 2.A.47.4.2 | Antimonite resistance protein (inducible by both arsenite and antimonite). | Archaea | ArsB of Halobacterium spNRC-1 (AAG20642) |
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| 2.A.47.4.3 | The Na+/sulfate symporter, Slt1 (Pootakham et al., 2010).
| Algae | Slt1 of Chlamydomonas reinhardtii (A8IJF8) |
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| 2.A.47.4.4 | The Na+/sulfate symporter, Slt2 (Pootakham et al., 2010).
| Algae | Slt2 of Chlamydomonas reinhardtii (A8IHV5)
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| 2.A.47.4.5 | Na+:SO4= symporter | Bacteria | Na+:So4 symporter of Bacillus halodurans (Q9K7H7) |
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| 2.A.47.4.6 | The oxyanion (molybdate, sulfate, tungstate and vanidate) permease PerO (Gisin et al., 2010). | Bacteria | PerO of Rhodobacter capsulatus (D5AQ60) |
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| 2.A.47.4.7 | Uncharacterized protein of 426 aas. | Proteobacteria | UP of E. coli |
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| 2.A.47.4.8 | Putative uncharacterized permease of 610 aas, YfbS | | YfbS of E. coli |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 2.A.47.5.1 | Hypothetical Na+ cotransporter, Orfl | Archaea | Orfl of Methanococcus jannaschii |
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| 2.A.47.5.2 | Dicarboxylate (succinate, fumarate, malate) transporter, vcINDY. The 3-d structure is known to 3.2 Å resolution with citrate and Na+ bound (Mancusso et al. 2012). INDY may also transport citrate, glutamate and sulfate with low affinity. It can use Na+ or Li+ as the cotransported cation. MtrF (TC# 2.A.68.1.2) and YdaH (TC# 2.A.68.1.4) have been shown to have similar 3-d folds as vcINDY (Vergara-Jaque et al. 2015), confirming the assignment of these two families to the same superfamily (Prakash et al. 2003). Solvent accessibility studies suggested differential substrate effects in a multistep mechanism where Na+ binding drives a conformational change, involving rearrangement of the substrate binding site-associated re-entrant hairpin loops (Sampson et al. 2020). | Bacteria | INDY of Vibrio cholerae |
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| 2.A.47.5.3 | The Na+-dependent C4-dicarboxylate (fumarate, succinate) uptake transporter, SdcA of 425 aas and 15 TMSs (Rhie et al. 2014). | | SdcA of Actinobacillus succinogene |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 2.A.47.6.1 | Putative cation transporter of 370 aas and 11 TMSs. | Archaea | The putative cation transporter of Methanosarcina mazei (gi 21227352) |
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| 2.A.47.6.2 | DUF1646 protein of 351 aas and 10 TMSs | Crenarchaea | DUF1646 protein of Pyrobaculum neutrophilum (Thermoproteus neutrophilus) |
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| 2.A.47.6.3 | DUF1646 protein of 359 aas and 10 TMSs | Firmicutes | DUF1646 protein of Caldicellulosiruptor obsidiansis |
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