1.A.11 The Ammonium Channel Transporter (Amt) Family

The proteins of the Amt family vary in size from 391 to 622 amino acyl residues and possess 11 (N-terminus out; most members) or 12 (N-terminus in) transmembrane α-helical spanners (TMSs). The E. coli AmtB is a trimer (Blakey et al., 2002). It appears to have dual functions, transporting NH4+ and regulating nitrogen metabolism by directly interacting with regulatory proteins such as the PII protein and its homologue, GlnK (Blauwkamp and Ninfa, 2003). amtB and glnK form an operon, and GlnK regulates the activity of AmtB. Homologues are probably ubiquitous. In Azospirillum brasilense, AmtB forms a ternary complex between AmtB, GlnZ and the nitrogenase regulatory enzyme DraG (Huergo et al., 2007). Eukaryotic AmtB homologues, in general, are larger than the prokaryotic proteins. Most functionally characterized members of the family are ammonium uptake transporters (Soupene et al., 2002d). Some, but not other Amt proteins also transport methylammonium (Andrade and Einsle, 2007; Musa-Aziz et al., 2009).  Detailed phylogenetic analyses of plant homologues have been published (von Wittgenstein et al. 2014). Rhesus (Rh) proteins allow the rapid transport of CO2 across membranes (Michenkova et al. 2021).

The structures of the E. coli AmtB (1.35 Å) (Khademi et al., 2004) and the Archaeoglobus fulgidus Amt-1 (Andrade et al., 2005) have been determined. They were considered to be gas channels with two structurally similar halves that span the membrane with opposite polarity. There is a vestibule that recruits NH4+, a binding site for NH4+ or CH3-NH3+ and a 20 Å long hydrophobic channel that lowers the NH4+ pKa to below 6 using weak interactions with C-H hydrogen bond donors such as those provided by conserved histidines. Reconstitution of AmtB into vesicles led to the conclusion that it conducts uncharged NH3, releasing H+ on the outside (Soupene et al., 2002a,b,c). However, a more recent study (Fong et al., 2007) concludes that NH4+ in the transported species. Hall and Kustu (2011) showed that NH4+ transport does not require the two histidyl residues, H168 and H318, which can be replaced by acidic residues with retention of activity. Ortiz-Ramirez et al. (2011) have concluded that the bean Amt1 protein is an H+/NH4+ symporter.

The E. coli ammonium channel, AmtB, and the PII signal transduction protein, GlnK, constitute an ammonium sensory system that effectively couples the intracellular nitrogen regulation system to external changes in ammonium availability. Direct binding of GlnK to AmtB inactivates the channel, thereby controlling ammonium influx in response to the intracellular nitrogen status. The stoichiometry of the complex is 1:1 for AmtB:GlnK (Durand and Merrick, 2006). Only the fully deuridylylated form of GlnK co-purifies with AmtB. Interaction of GlnK with AmtB is dependent on ATP and is sensitive to 2-oxoglutarate. Thus in vivo association and dissociation of the complex might not only be dependent on the uridylylation status of GlnK but also on the intracellular pools of ATP and 2-oxoglutarate (Durand and Merrick, 2006).

The 11 TMSs (M1-M11) of AmtB form a right handed helical bundle around each channel. Residues from helices M1, M6, M7, M8 and M9 of one monomer interact with residues from helices M1, M2 and M3 of the neighboring subunit to form an interacting surface area of 2716 Å2. Polar aromatic residues (Y and W) comprise part of the membrane-aqueous phase interface. AMTs may use a conserved allosteric control mechanism to regulate ammonium flux, potentially using a gating mechanism that limits flux to protect against ammonium toxicity (Loque et al., 2009).

Amt proteins are homotrimers, in which each subunit contains a narrow pore through which substrate transport occurs. Two conserved histidyl residues in the pore of the E. coli AmtB are absolutely necessary for ammonia conductance. Crystal structures of variants confirmed that substitution of the histidine residues does not affect AmtB structure. In a subgroup of Amt proteins found only in fungi, one of the histidines is replaced by glutamate. The equivalent substitution in E. coli AmtB is partially active, and the structure of this variant suggests that the glutamate side chain can make similar interactions to those made by histidine (Javelle et al., 2006).  As expected for a channel, NH3 uniport appears to occur by energy-independent, non-concentrative, bidirectional diffusion (Soupene et al., 2002a; Loque et al., 2007), but NH4+ may be the true substrate (Fong et al., 2007).

Amt proteins facilitate ammonium ion transport across the membranes of plants, fungi, and bacteria.  On the basis of the structural data for E. coli AmtB, Wang et al. (2012) deduced the mechanism by which electrogenic transport occurs. Free energy calculations show that NH4+ is stable in the AmtB pore, reaching a binding site from which it can spontaneously transfer a proton to a pore-lining histidine residue (His168). The substrate may diffuse down the pore in the form of NH3, while the proton is cotransported through a highly conserved hydrogen-bonded His168-His318 pair. This constitutes a novel permeation mechanism that confers to the histidine dyad an essential mechanistic role that is equivalent to symport (Wang et al. 2012).  Thus these systems blur the boundary between channels and secondary carriers.

Plant AMTs have been reported to mediate electrogenic transport as noted above. Functional analysis of AMT2 from Arabidopsis (TC #1.A.11.2.2) expressed in yeast and oocytes suggests that NH4+ is the recruited substrate, but the uncharged form (NH3) is conducted (Neuhäuser et al., 2009). AMT2 partially co-localizes with electrogenic AMTs and conducts methylamine with low affinity. This transport mechanism may apply to other plant ammonium transporters and explains the different capacities of AMTs to accumulate ammonium in the plant cell.

A P(II) signal transduction protein, GlnK, is a regulator of transmembrane ammonia conductance by  AmtB in Escherichia coli. The complex formed between AmtB and inhibitory GlnK at 1.96-A resolution shows that the trimeric channel is blocked directly by GlnK. In response to intracellular nitrogen status, the ability of GlnK to block the channel is regulated by uridylylation/deuridylylation at Y51. ATP and Mg2+ augment the interaction of GlnK. The hydrolyzed product, adenosine 5'-diphosphate, orients the surface of GlnK for AmtB blockade. 2-Oxoglutarate diminishes AmtB/GlnK association (Gruswitz et al., 2007). MepB, in contrast to MepA and MepC, similarly appears to be the primary NH4+ transporter and serves as a regulator for nitrogen sensing in Fusarium fujikuroi (Teichert et al., 2007).

Many organisms from all major kingdoms of living organisms possess multiple homologues. Rhodobacter capsulatus has two Amt family homologues, AmtB and AmtY. The former, but not the latter, has been reported to be an NH4+ sensor as well as a NH3 transporter (Yakunin and Hallenbeck, 2002). Mep2 of Saccharomyces cerevisiae has been shown to function both as a transporter and as a sensor, generating a signal that regulates filamentous growth (pseudohyphal differentiation) in response to ammonium starvation (Lorenz and Heitman, 1998). This protein has an N-terminal, asparaginyl-linked glycosylated domain where only Asn-4 is glycosylated. Mep2, but not Mep1 or Mep3, has an extracytoplasmic N-terminus (Marini and André, 2000). This N-terminal domain is not required for either transport or sensing. Of the three S. cerevisiae Amt family paralogues, Mep2 exhibits higher affinity for NH4+ (1 μM) than Mep1 (10 μM), and Mep1 exhibits higher affinity than Mep3 (1 mM).

The Amt family includes the Rhesus (Rh) family of proteins, both erythroid (RhAG, RhD and RhCE) and non-erythroid (RhCG, RhBG and RhGK). In the mammalian kidney collecting duct, RhBG is in the basolateral membrane while RhCG is in the apical membrane. Basolateral anchoring of RhBG requires ankyrin-G (Lopez et al., 2005). It has been proposed that some of these proteins are CO2 channels, but this suggestion has not been substantiated (Soupene et al., 2002d).

Loque et al. (2007) have shown that the soluble, cytosolic C-terminus of Amt1.1 of Arabidopsis thaliana is an allosteric regulator. This domain is conserved between bacteria, fungi and plants. Mutations in this domain lead to loss of transport activity. The crystal structure of an Amt family member from Archaeoglobus fulgidus suggests that the C-terminal domain interacts physically with the cytosolic loops of the neighboring subunit. Phosphorylation of conserved sites in the C-terminal domain with conformational coupling between monomers may allow tight regulation of transport and sensing (Loque et al., 2007).

In Cryptococcus neoformans, Amt1 and Amt2 are low and high affinity ammonium permeases, respectively. AMT2 is transcriptionally induced in response to nitrogen limitation whereas AMT1 is constitutively expressed. Amt2 is required for the initiation of invasive growth of haploid cells under low nitrogen conditions and for the mating of wild type cells under the same conditions. It was proposed that Amt2 may be a new fungal ammonium sensor and an element of the signaling cascades that govern the mating of C. neoformans in response to environmental nutritional cues (Rutherford et al., 2007).

The C-terminal cytoplasmic domains allosterically activate adjacent channels in the trimeric structures of Amt channels. Mutations in helix 1 yield up to 100-fold lower affinity with 10-fold increased flux (Loqué et al., 2007; Loqué et al., 2009) in A. fulgidus (TC# 1.A.11.2.7). The A. thaliana protein, Amt1;1 (TC# 1.A.11.2.1), is phosphorylated on Thr460 giving rise to inhibition in response to high [NH3] (Lalonde et al., 2008; Lanquar et al., 2009; Yuan et al., 2007).

There is presently no direct evidence to support the idea that Rh proteins transport CO2/H2CO3. However, physiological studies in the green alga Chlamydomonas reinhardtii do suggest its Rh1 protein is involved in CO2 metabolism (Soupene et al., 2004). In addition, structural work on the Rh protein of Nitrosomonas europaea identified a CO2 binding site on the substrate conduction pathway (Andrade et al., 2005a). By analogy to the Amt proteins (transport of hydrated ammonia), some Rh proteins may transport H2CO3, but this is hypothetical.

Amt proteins appear to function as channel/carrier hybrids. Consistent with these proteins functioning as channels, structural studies indicate that there are no large overall conformational differences between substrate-free and substrate-complexed proteins. Andrade et al., 2005b did find evidence that TMS5 of Archaeoglobus fulgidus Amt-1 could move in a way that could be functionally significant. Genetic work (Inwood et al., 2009) suggests that such movement - an oscillation of TMS5 - may control the opening of both the entrance and exit to the AmtB conduction pore.  Furthermore, work conducted by (Fong et al., 2007) indicated that AmtB concentrates methylammonium. The movement of TMS5 during substrate transport and the ability to concentrate substrate are characteristics of a carrier-type transporter. Whether NH4+ dissociates as it goes through the channel with NH3 going through the pore and H+ taking another route is a separate question. Because the conduction pore is hydrophobic, a mechanism based on NH4+ dissociation to NH3 and H+ appears possible.

The transport of NH4+ is an active process as has been shown experimentally by several groups. By working with an AmtB mutant in a ΔglnA background, methylammonium was concentrated roughly 100-fold (Fong et al., 2007). Accumulation was prevented by CCCP and, thus, was dependent upon the proton motive force.

The X-ray structures have revealed that the pore of the Amt and Rh proteins is characterized by a hydrophobic portion about 12A long in which electronic density was observed in the crystallographic study of AmtB from Escherichia coli. This electronic density was initially only observed when crystals were grown in the presence of ammonium and was thus attributed to ammonia molecules. The Amt/Rh protein mechanism might involve the single-file diffusion of NH3 molecules. However, the pore could also be filled with water molecules. The possible presence of water molecules in the pore lumen calls for a reassessment of the notion that Amt/Rh proteins work as plain NH3 channels. Indeed, functional experiments on plant ammonium transporters and rhesus proteins suggest a variety of permeation mechanisms including the passive diffusion of NH3, the antiport of NH4+/H+, the transport of NH4+, or the cotransport of NH3/H+Lamoureux et al. (2010) discuss these mechanisms in light of functional and simulation studies on the AmtB transporter.

Note: The AMT family was previously given the TC# 2.A.49.

The generalized transport reactions catalyzed by members of the Amt family are suggested to be:

(1) NH4+ (out) ⇌ NH4+ (in)

[In E. coli, NH4+, rather than NH3, may be the substrate of AmtB, but controversy still exists (Fong et al., 2007; Ishikita and Knapp, 2007; Javelle et al., 2006). If NH4+ is transported, K+ possibly serves as a counter ion in an antiport process with K+ (Fong et al., 2007).]


 

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Siewe, R.M., B. Weil, A. Burkovski, B.J. Eikmanns, M. Eikmanns, and R. Krämer. (1995). Functional and genetic characterization of the (Methyl)ammonium uptake carrier of Corynebacterium glutamicum. J. Biol. Chem. 271: 5398-5403.

Sohlenkamp, C., M. Shelden, S. Howitt, and M. Udvardi. (2000). Characterization of Arabidopsis AtAMT2, a novel ammonium transporter in plants. FEBS Lett. 467: 273-278.

Soupene, E., H. Lee, and S. Kustu. (2002b). Ammonium/methylammonium transport (Amt) proteins facilitate diffusion of NH3 bidirectionally. Proc. Natl. Acad. Sci. U.S.A. 99(6):3926-3931.

Soupene, E., L. He, D. Yan, and S. Kustu. (1998). Ammonia acquisition in enteric bacteria: physiological role of the ammonium/methylammonium transport B (AmtB) protein. Proc. Natl. Acad. Sci. USA 95: 7030-7034.

Soupene, E., N. King, E. Feild, P. Liu, K.K. Niyogi, C.-H. Huang, and S. Kustu. (2002d). Rhesus expression in a green alga is regulated by CO2. Proc. Natl. Acad. Sci. USA 99: 7769-7773.

Soupene, E., R.M. Ramirez, and S. Kustu. (2002c). Evidence that fungal MEP proteins mediate diffusion of the uncharged species NH3 across the cytoplasmic membrane. Mol. Cell Biol. 21(17):5733-5741.

Soupene, E., T. Chu, R.W. Corbin, D.F. Hunt, and S. Kustu. (2002a). Gas channels for NH3: proteins from hyperthermophiles complement an Escherichia coli mutant. J. Bacteriol. 184(12):3396-3400.

Soupene, E., W. Inwood, and S. Kustu. (2004). Lack of the Rhesus protein Rh1 impairs growth of the green alga Chlamydomonas reinhardtii at high CO2. Proc. Natl. Acad. Sci. USA 101: 7787-7792.

Szekely, D., B.E. Chapman, W.A. Bubb, and P.W. Kuchel. (2006). Rapid exchange of fluoroethylamine via the Rhesus complex in human erythrocytes: 19F NMR magnetization transfer analysis showing competition by ammonia and ammonia analogues. Biochemistry 45: 9354-9361.

Teichert, S., J.C. Rutherford, M. Wottawa, J. Heitman, and B. Tudzynski. (2008). Impact of ammonium permeases mepA, mepB, and mepC on nitrogen-regulated secondary metabolism in Fusarium fujikuroi. Eukaryot. Cell. 7(2): 187-201.

Thies, A.B., A.R. Quijada-Rodriguez, H. Zhouyao, D. Weihrauch, and M. Tresguerres. (2022). A Rhesus channel in the coral symbiosome membrane suggests a novel mechanism to regulate NH and CO delivery to algal symbionts. Sci Adv 8: eabm0303.

Thomas, G.H., J.G.L. Mullins, and M. Merrick. (2000). Membrane topology of the Mep/Amt family of ammonium transporters. Mol. Microbiol. 37: 331-344.

Thornton, J., D. Blakey, E. Scanlon, and M. Merrick. (2006). The ammonia channel protein AmtB from Escherichia coli is a polytopic membrane protein with a cleavable signal peptide. FEMS Microbiol. Lett. 258: 114-120.

Vázquez-Bermúdez, M.F., J. Paz-Yepes, A. Herrero, and E. Flores. (2002). The NtcA-activated amt1gene encodes a permease required for uptake of low concentrations of ammonium in the cyanobacterium Synechococcus sp. PCC7942. Microbiology 148: 861-869.

von Wittgenstein, N.J., C.H. Le, B.J. Hawkins, and J. Ehlting. (2014). Evolutionary classification of ammonium, nitrate, and peptide transporters in land plants. BMC Evol Biol 14: 11.

Walter, B., M. Küspert, D. Ansorge, R. Krämer, and A. Burkovski. (2008). Dissection of ammonium uptake systems in Corynebacterium glutamicum : mechanism of action and energetics of AmtA and AmtB. J. Bacteriol. 190: 2611-2614.

Wang, S., E.A. Orabi, S. Baday, S. Bernèche, and G. Lamoureux. (2012). Ammonium transporters achieve charge transfer by fragmenting their substrate. J. Am. Chem. Soc. 134: 10419-10427.

Weidinger, K., B. Neuhäuser, S. Gilch, U. Ludewig, O. Meyer, and I. Schmidt. (2007). Functional and physiological evidence for a rhesus-type ammonia transporter in Nitrosomonas europaea. FEMS Microbiol. Lett. 273: 260-267.

Westhoff, C.M., D.L. Siegel, C.G. Burd, and J.K. Foskett. (2004). Mechanism of genetic complementation of ammonium transport in yeast by human erythrocyte Rh-associated glycoprotein. J. Biol. Chem. 279: 17443-17448.

Westhoff, C.M., M. Ferreri-Jacobia, D.O. Mak, and J.K. Foskett. (2002). Identification of the erythrocyte Rh blood group glycoprotein as a mammalian ammonium transporter. J. Biol. Chem. 277: 12499-12502.

Worrell, R.T., L. Merk, and J.B. Matthews. (2008). Ammonium transport in the colonic crypt cell line, T84: role for Rhesus glycoproteins and NKCC1. Am. J. Physiol. Gastrointest Liver Physiol 294: G429-440.

Yakunin, A.F. and P.C. Hallenbeck. (2002). AmtB is necessary for NH4+-induced nitrogenase switch-off and ADP-ribosylation in Rhodobacter capsulatus. J. Bacteriol. 184: 4081-4088.

Yoshino, R., T. Morio, Y. Yamada, H. Kuwayama, M. Sameshima, Y. Tanaka, H. Sesaki, and M. Iijima. (2007). Regulation of Ammonia Homeostasis by the Ammonium Transporter AmtA in Dictyostelium discoideum. Eukaryot. Cell. 6: 2419-2428.

Yuan, L., D. Loqué, F. Ye, W.B. Frommer, and N. von Wirén. (2007). Nitrogen-dependent posttranscriptional regulation of the ammonium transporter AtAMT1;1. Plant Physiol. 143: 732-744.

Yuan, L., L. Graff, D. Loqué, S. Kojima, Y.N. Tsuchiya, H. Takahashi, and N. von Wirén. (2009). AtAMT1;4, a pollen-specific high-affinity ammonium transporter of the plasma membrane in Arabidopsis. Plant Cell Physiol. 50: 13-25.

Zidi-Yahiaoui N., Callebaut I., Genetet S., Le Van Kim C., Cartron JP., Colin Y., Ripoche P. and Mouro-Chanteloup I. (2009). Functional analysis of human RhCG: comparison with E. coli ammonium transporter reveals similarities in the pore and differences in the vestibule. Am J Physiol Cell Physiol. 297(3):C537-47.

Examples:

TC#NameOrganismal TypeExample
1.A.11.1.1

Ammonia transporter and regulatory sensor, AmtB (Blauwkamp and Ninfa, 2003; Khademi et al., 2004).  It has a cleavable N-terminal signal peptide, and while Amt proteins in Gram-negative bacteria appear to utilize a signal peptide, the homologous proteins in Gram-positive organisms do not (Thornton et al. 2006).

Bacteria

AmtB of E. coli (P69681)

 
1.A.11.1.2High affinity ammonia/methylammonia uptake carrier, Amt1 or AmtA (Walter et al., 2008)BacteriaAmt1 of Corynebacterium glutamicum (P54146)
 
1.A.11.1.3Low affinity (KM > 3mM) ammonia uptake carrier, AmtB (Walter et al., 2008)BacteriaAmtB of Corynebacterium glutamicum (Q79VF1)
 
1.A.11.1.4Ammonia channel protein, AmtB (forms a ternary complex with the trimeric PII protein, GlnZ (AAG10012) and the nitrogenous regulatory glycohydrolase enzyme, DraG, causing DraG sequestration and N2ase regulation (Huergo et al., 2007)BacteriaAmtB of Azospirillum brasilense (P70731)
 
1.A.11.1.5Ammonia channel (Ammonia transporter)BacteriaAmt of Aquifex aeolicus
 
1.A.11.1.6Trimeric ammonia channel protein, Amt-1 (391 aas)ArchaeaAmt-1 of Archaeoglobus fulgidus (O29285)
 
1.A.11.1.7The ammonium transporter channel, AmtA (regulates NH3 homeostasis during growth and development (Yoshino et al., 2007). Slime moldsAmtA of Dictyostelium discoideum (Q9BLG4)
 
1.A.11.1.8

AMT of 514 aas and 11 TMSs. Trypanosoma cruzi, the etiologic agent of Chagas disease, undergoes drastic metabolic changes when it transits between a vector and mammalian hosts. Amino acid catabolism leads to the production of NH4+, which must be detoxified. Cruz-Bustos et al. 2018 identified an intracellular ammonium transporter of T. cruzi (TcAMT) that localizes to acidic compartments (reservosomes, lysosomes). TcAMT possesses all conserved and functionally important residues that form the pore in other ammonium transporters. Functional expression in Xenopus oocytes followed by a two-electrode voltage clamp showed an inward current that is NH4+ dependent at a resting membrane potential lower than -120 mV and is not pH dependent, suggesting that TcAMT is an NH4+or NH3/H+ transporter. Ablation of TcAMT resulted in defects in epimastigote and amastigote replication, differentiation, and resistance to starvation and osmotic stress (Cruz-Bustos et al. 2018). 

Amt of Trypanosoma cruzi

 
1.A.11.1.9

Ammonium transporter, NrgA, of 411 aas and 11 TMSs. The nrgA gene is co-transcribed with the glnB gene, and may play a role in molecular export and biofilm formation (Ardin et al. 2014).

NrgA of Streptococcus mutans

 
Examples:

TC#NameOrganismal TypeExample
1.A.11.2.1

High-affinity electrogenic ammonia/methylammonia transporter (allosterically activated by the C-terminus (Loqué et al., 2009).  NH4+ is stable in the AmtB pore, reaching a binding site from which it can spontaneously transfer a proton to a pore-lining histidine residue (His168). The substrate diffuses down the pore in the form of NH3, while the proton is cotransported through a highly conserved hydrogen-bonded His168-His318 pair (Wang et al. 2012).

Plants

Amt1 of Arabidopsis thaliana (P54144)

 
1.A.11.2.10Putative ammonium transporter 2Wormamt-2 of Caenorhabditis elegans
 
1.A.11.2.11

Ammonium transporter, AmtB or Amt1 of 463 aas and 9 TMSs.  Regulated by direct interaction with GlnK (Pedro-Roig et al. 2013).

AmtB of Haloferax mediterranei (Halobacterium mediterranei)

 
1.A.11.2.12

Ammonium uptake transporter, Amt1 of 458 aas and 11 TMSs.  62% identical to Amt1 of Pyropia yezoensis (Rhodophyta) which is 483 aas long with 11 TMSs and is induced by nitrogen deficiency (Kakinuma et al. 2016).

Amt1 of Chondrus crispus (Carrageen Irish moss) (Polymorpha crispa)

 
1.A.11.2.13

High affinity (~50 mμM) ammonium transporter, Amt1.3 of 498 aas and 10 TMSs (Loqué et al. 2006). The tobacco orthologue, of 464 aas and 10 TMSs, NtAMT1.3, is present in roots and leaves and faciltates NH4+ entry. It is up regulated upon nitrogen starvation (Fan et al. 2017).

Ant1.3 of Arabidopsis thaliana (Mouse-ear cress)

 
1.A.11.2.14

Putative ammonia/ammonium transporter of 439 aas and 11 TMSs.

NH3 transporter of Ostreococcus tauri virus RT-2011

 
1.A.11.2.2

Ammonia-specific uptake carrier, Amt2. For AMT2 from Arabidopsis thaliana NH4+ is the recruited substrate, but the uncharged form NH3 is conducted.  AtAMT2 partially co-localizes with electrogenic AMTs and conducts methylamine with low affinity (Neuhäuser et al., 2009). This may explain the different capacities of AMTs to accumulate ammonium in the plant cell.

Plants

Amt2 of Arabidopsis thaliana

 
1.A.11.2.3High-affinity ammonia/methylammonia transporter, Amt1(Paz-Yepes et al., 2007)CyanobacteriaAmt1 of Synechococcus elongatus sp. PCC7942 (Q93IP6)
 
1.A.11.2.4

High-affinity ammonia/methylammonia transporter, LeAMT1;1. The ammonium transporter 1 (AMT1) gene family in tomato (Solanum lycopersicum L.) and individual members of the family exhibit different physiological and expression patterns under drought and salt stress conditions (Filiz and Akbudak 2020).

Plants

LeAMT1;1 of Lycopersicon esculentum (P58905)

 
1.A.11.2.5

Ammonium/methyl ammonium uptake permease, AmtB (may need AmtB to concentrate [14C]methyl ammonium (Paz-Yepes et al., 2007))

Cyanobacteria

AmtB of Synechococcus sp CC9311 (Q0IDE4)

 
1.A.11.2.6Pollen-specific, plasma membrane, high affinity (17μM) ammonium uptake transporter, Amt1;4 (Yuan et al., 2009) (most similar to 1.A.11.2.1).

Plants

Amt1;4 of Arabidopsis thaliana (Q9SVT8)

 
1.A.11.2.7

Amt2 NH4+/CH3-NH3+ transporter, subject to allosteric activation by a C-terminal region (Loqué et al., 2009).

Archaea

Amt2 of Archaeoglobus fulgidus (O28528)

 
1.A.11.2.8

Amt1;1, a proposed NH4+:H+ sumporter (Ortiz-Ramirez et al., 2011)

Plants

Amt1;1 of Phaseolus vulgaris (E2CWJ2)

 
1.A.11.2.9

Ammonium transporter 2, AmtB

Amoeba

AmtB of Dictyostelium discoideum

 
Examples:

TC#NameOrganismal TypeExample
1.A.11.3.1Low-affinity ammonia transporter, Mep1 (Has a pair of conserved his/glu residues; Boeckstaens et al., 2008)YeastMep1 of Saccharomyces cerevisiae (P40260)
 
1.A.11.3.2High-affinity ammonia transporter and sensor, Mep2 (also an NH4+ sensor) (Javelle et al., 2003a; Rutherford et al., 2008) (has a pair of conserved his/his residues; mutation to his/glu as in Mep1 leads to uncoupling of transport and sensor functions (Boeckstaens et al., 2008))YeastMep2 of Saccharomyces cerevisiae (P41948)
 
1.A.11.3.3High affinity ammonia/methylamine transporter, Amt1 (may also serve as a sensor) (Javelle et al., 2003b)FungiAmt1 of Hebeloma cylindrosporum (Q8NKD5)
 
1.A.11.3.4Low affinity ammonia transporter, Amt2 (Javelle et al., 2001, 2003b)FungiAmt2 of Hebeloma cylindrosporum (Q96UY0)
 
1.A.11.3.5The Mep2 ammonium transporter 60% identical to the S. cerevisiae Mep2 (1.A.11.3.2). (Distinct residues mediate transport and signaling; Dabas et al., 2009).

Yeast

Mep2 of Candida albicans (Q59UP8)

 
Examples:

TC#NameOrganismal TypeExample
1.A.11.4.1

Rhesus (Rh) type C glycoprotein NH3/NH4+ transporter, RhCG (also called tumor-related protein DRC2) (Bakouh et al., 2004; Worrell et al., 2007). Zidi-Yahiaoui et al. (2009) have described characteristics of the pore/vestibule. The structure is known to 2.1 Å resolution (Gruswitz et al., 2010). Each monomer contains 12 transmembrane helices, one more than in the bacterial homologs. Reconstituted into proteoliposomes, RhCG conducts NH3 to raise the internal pH. Models of the erythrocyte Rh complex based on the RhCG structure suggest that the erythrocytic Rh complex is composed of stochastically assembled heterotrimers of RhAG, RhD, and RhCE (Gruswitz et al., 2010). Rh proteins also transport CO2 (Michenkova et al. 2021).

Animals

RhCG of Homo sapiens (Q9UBD6)

 
1.A.11.4.10

RH (Rhesus) antigen-related protein, Rhr-1 or Rh1, of 463 aas and 12 TMSs.  CeRh1 is abundantly expressed in all developmental stages of C. elegans, with highest levels in adults, whereas CeRh2 shows a differential and much lower expression pattern. It is required for passage throung the late stages of C. elegans embryonic development and hypodermal function (Ji et al. 2006). Transports NH3, NH4+ and CO2 (Michenkova et al. 2021).

Rhr-1 of Caenorhabditis elegans

 
1.A.11.4.11

Rh protein of 478 aas and 11 TMSs. It is a primary contributor to ammonia/ammonium ions and CO2 excretion (Michenkova et al. 2021), and poor expression changes the expression levels of many enzymes (Si et al. 2018).

Rh protein of Portunus trituberculatus (the swimming crab)

 
1.A.11.4.12

The rhesus protein, Rhp1, of 479 aas and 11 TMSs.  Reef-building corals maintain an intracellular photosymbiotic association with dinoflagellate algae. As the algae are hosted inside the symbiosome, all metabolic exchanges must take place across the symbiosome membrane. Thies et al. 2022 established that Acropora yongei Rh (ayRhp1) facilitates transmembrane NH3 and CO2 diffusion, and that it is present in the symbiosome membrane. Furthermore, ayRhp1 abundance in the symbiosome membrane was highest around midday and lowest around midnight. Probably ayRhp1 mediates a symbiosomal NH4+-trapping mechanism that promotes nitrogen delivery to algae during the day - necessary to sustain photosynthesis-and restrict nitrogen delivery at night-to keep the algae under nitrogen limitation (Thies et al. 2022).

Rhp1 of Acropora yongei

 
1.A.11.4.2

Rhesus (Rh) type B glycoprotein NH3/NH4+ transporter, RhBG (~50% identical to type C) (Lopez et al., 2005; Worrell et al., 2008). Electrogenic NH4+ transport is stimulated by alkaline pH(out) but inhibited by acidic pH(out) (Nakhoul et al., 2010). Regulated by Wnt/β-catenin signalling, a pathway frequently deregulated in many cancers and associated with tumorigenesis (Merhi et al. 2015). Rh proteins also transport CO2 (Michenkova et al. 2021).

Animals

RhBG of Homo sapiens (Q9H310)

 
1.A.11.4.3

Rhesus (Rh) complex (tetramer: RhAG2, RhCE1, RhD1) of 409 aas and 12 TMSs. Exports ammonia from human red blood cells (Conroy et al., 2005). RhAG is also called RH50.  RhAG variants (I61R, F65S), associated with overhydrated hereditary stomatocytosis (OHSt), a disease affecting erythrocytes, are alterred for bidirectional ammonium transport (Deschuyteneer et al. 2013).  The system transports ammonia, methylammonia, ethylammonia, fluoroethylamine and CO2 Michenkova et al. 202119F-fluoroethylamine has been used to study rapid transport as its NMR spectra are different inside and outside of human red blook cells (Szekely et al. 2006).

Animals

The RhAG/RhCE/RhD, complex of Homo sapiens
RhAG (Q02094)
RhCE (P18577)
RhD (Q02161)

 
1.A.11.4.4

The RH50 NH3 channel (most like human Rh proteins TC# 1.A.11.4.1 and 2; 36-38% identity) (Cherif-Zahar et al., 2007). The Rh CO2 channel protein (3-D structure ± CO2 available) (3B9Z_A; 3B9Y_A) (Li et al., 2007; Lupo et al., 2007) (also transports methyl ammonia) (Weidinger et al., 2007).

Gram-negative bacteria

RH50 of Nitrosomonas europaea (Q82X47)

 

 
1.A.11.4.5

Kidney rhesus glycoprotein p2 (Rhp 2). Transports NH3, methylammonium and CO2 (Nakada et al., 2010; Michenkova et al. 2021).

Animals

Rhp2 of Triakis scyllium (D0VX38)

 
1.A.11.4.6

Rhesus-like glycoprotein A (Rh50-like protein RhgA).  Transports NH3 and CO2 (Michenkova et al. 2021).

Amoeba

RhgA of Dictyostelium discoideum

 
1.A.11.4.7

Ammonium/ammonia/CO2 transporter of 391 aas and 12 TMSs (Michenkova et al. 2021).  Shows limited seqences similarity with 9.B.124.1.7 (e-5) (residues 1-5 align with residues 4 - 8 in 9.B.124.1.7).

Ammonium transporter of [Clostridium] papyrosolvens

 
1.A.11.4.8

NH3 (NH4+) and CO2 transporting Rhesus glycoprotein, Rhag, of 437 aas and 11 TMSs.  Induced by ammonia exposure in the apical membrane of gill epithelia (Chen et al. 2017).

Rhag of Anabas testudineus (climbing perch)

 
1.A.11.4.9

NH3 (NH4+)/CO2 transporting Rhesus glycoprotein, Rhcg2, of 482 aas and 11 TMSs.  Induced by ammonia exposure in the basolateral membrane of gill epithelia (Chen et al. 2017; Michenkova et al. 2021).

Rhcg2 of Anabas testudineus (climbing perch)

 
Examples:

TC#NameOrganismal TypeExample