2.A.35 The NhaC Na⁺:H⁺ Antiporter (NhaC) Family Two members of the NhaC family have been functionally characterized. One is believed to be a Na⁺:H⁺ antiporter (Ito et al., 1997); the other is a malate · H⁺:lactate · Na⁺ antiporter (Wei et al., 2000). Several paralogues are found in Vibrio cholerae, and two paralogues each are found encoded in the completely sequenced genomes of Haemophilus influenzae and Bacillus subtilis. E. coli lacks such a homologue. Pyrococcus species also have at least one homologue each. Thus, members of the NhaC family are found in both Gram-negative bacteria and Gram-positive bacteria as well as archaea. NhaC of B. firmus is 462 amino acyl residues long and possesses 12 putative transmembrane α-helical segments. MleN of B. subtilis (468 aas) also exhibits 12 putative TMSs. The transport reaction catalyzed by NhaC is probably: Na+ (in) + nH+ (out) ⇌ Na+ (out) + nH+ (in). (n > 1) That catalyzed by MleN is probably: Malate (out) + H⁺ (out) + Lactate (in) + Na⁺ (in) ⇌ Malate (in) + H⁺ (in) + Lactate (out) + Na⁺ (out)
This family belongs to the IT Superfamily.
References:
Ito, M., A.A. Guffanti, J. Zemsky, D.M. Ivey, and T.A. Krulwich. (1997). Role of the nhaC-encoded Na⁺/H⁺ antiporter of alkaliphilic Bacillus firmus OF4. J. Bacteriol. 179: 3851-3857.
Ivey, D.M., A.A. Guffanti, J.S. Bossewitch, E. Padan, and T.A. Krulwich. (1991). Molecular cloning and sequencing of a gene from alkaliphilic Bacillus firmus OF4 that functionally complements an Escherichia coli strain carrying a deletion in the nhaA Na⁺/H⁺ antiporter gene. J. Biol. Chem. 266: 23484-23489.
Liew, C.W., R.M. Illias, N.M. Mahadi, and N. Najimudin. (2007). Expression of the Na⁺/H⁺ antiporter gene (g1-nhaC) of alkaliphilic Bacillus sp. G1 in Escherichia coli. FEMS Microbiol Lett. 276(1):114-122.
Panina, E.M., A.G. Vitreschak, A.A. Mironov, and M.S. Gelfand. (2003). Regulation of biosynthesis and transport of aromatic amino acids in low-GC Gram-positive bacteria. FEMS Microbiol. Lett. 222: 211-220.
Ravcheev, D.A., A.A. Best, N. Tintle, M. Dejongh, A.L. Osterman, P.S. Novichkov, and D.A. Rodionov. (2011). Inference of the transcriptional regulatory network in Staphylococcus aureus by integration of experimental and genomics-based evidence. J. Bacteriol. 193: 3228-3240.
Rodionov, D.A., A.G. Vitreschak, A.A. Mironov, and M.S. Gelfand. (2003). Regulation of lysine biosynthesis and transport genes in bacteria: yet another RNA riboswitch? Nucleic Acids Res 31: 6748-6757.
Rodionov, D.A., A.G. Vitreschak, A.A. Mironov, and M.S. Gelfand. (2004). Comparative genomics of the methionine metabolism in Gram-positive bacteria: a variety of regulatory systems. Nucleic Acids Res 32: 3340-3353.
Rodionov, D.A., P. Hebbeln, A. Eudes, J. ter Beek, I.A. Rodionova, G.B. Erkens, D.J. Slotboom, M.S. Gelfand, A.L. Osterman, A.D. Hanson, and T. Eitinger. (2009). A novel class of modular transporters for vitamins in prokaryotes. J. Bacteriol. 191: 42-51.
Rodionov, D.A., P.S. Novichkov, E.D. Stavrovskaya, I.A. Rodionova, X. Li, M.D. Kazanov, D.A. Ravcheev, A.V. Gerasimova, A.E. Kazakov, G.Y. Kovaleva, E.A. Permina, O.N. Laikova, R. Overbeek, M.F. Romine, J.K. Fredrickson, A.P. Arkin, I. Dubchak, A.L. Osterman, and M.S. Gelfand. (2011). Comparative genomic reconstruction of transcriptional networks controlling central metabolism in the Shewanella genus. BMC Genomics 12Suppl1: S3.
Wei, Y., A.A. Guffanti, M. Ito, and T.A. Krulwich. (2000). Bacillus subtilis YqkI is a novel malic/Na⁺-lactate antiporter that enhances growth on malate at low protonmotive force. J. Biol. Chem. 275: 30287-30292.
Wimmer, F., T. Oberwinkler, B. Bisle, J. Tittor, and D. Oesterhelt. (2008). Identification of the arginine/ornithine antiporter ArcD from Halobacterium salinarum. FEBS Lett. 582: 3771-3775.
Examples:
TC#	Name	Organismal Type	Example
2.A.35.1.1	*Na⁺:H⁺ antiporter (Ito et al.* 1997).**	Bacteria	NhaC of Bacillus firmus

2.A.35.1.2	*Malate + H⁺: lactate + Na⁺ antiporter, MleN or YqkI of 468 aas and 12 TMSs in a 6 + 6 TMS arrangement (Wei et al.* 2000).**	Bacteria	MleN (YqkI) of Bacillus subtilis

2.A.35.1.3	*The putative tyrosine permease, TyrT, of 472 aas and 12 TMSs. Also called NhaC2 (Panina et al., 2003; Rodionov et al.* 2004).**	Bacteria	*TyrT of Enterococcus faecalis* (Q838N7)**

2.A.35.1.4	*The arginine/ornithine antiporter ArcD (Wimmer et al.* 2008)**	Archaea	*ArcD of Halobacterium salinarum* (BOR9X2)**

2.A.35.1.5	*The putative methionine porter, MetT. Regulated by S-adenosylmethionine-dependent repressor MetJ (Rodionov et al.* 2011).**	Proteobacteria, Firmicutes	*MetT of Shewanella oneidensis* (Q8EHX2)**

2.A.35.1.6	*YheL; TyrT, putative tyrosine uptake cation symporter; NhaC, putative Na⁺/H⁺ antiporter (Sodium/hydrogen antiporter) (Rodionov et al.* 2004).**	Bacilli	NhaC of Bacillus subtilis

2.A.35.1.7	*Predicted to be a tyrosine uptake cation symporter, TyrT or NhaC, of 459 aas and 12 TMSs (Rodionov et al.* 2004).**		TyrT of Neisseria meningitidis

2.A.35.1.8	*Predicted methionine uptaie cation symporter, MetT, of 433 aas and 12 TMSs (Rodionov et al.* 2004).**		MetT of Bacteroides thetaiotaomicron

2.A.35.1.9	*Predicted methioine:cation symporter of 459 aas and 12 TMSs, MetT (Rodionov et al.* 2004). Also called NhaC.**		MetT of Staphylococcus aureus

Examples:
TC#	Name	Organismal Type	Example
2.A.35.2.1	Na⁺/H⁺ antiporter of the NhaC family	Archaea	*NhaC homologue of Methanococcus maripaludis* (Q6LZF0)**

2.A.35.2.2	*Putative lysine transporter, LysW. Regulated by Lysine riboswitch (Rodionov et al.* 2003)**	Bacteria	*LysW of Shewanella oneidensis* (Q8EI43)**

2.A.35.2.3	*The NhaC Na⁺:H⁺ antiporter, G1-NhaC (functions in Na⁺ extrusion at lower pH values and in pH homeostasis at pH 10 under Na⁺-limiting conditions) (Liew et al., 2007).*	Bacteria	*G1-NhaC of Bacillus sp. G1* (Q0PHV8)**

2.A.35.2.5	Putative transporter	Bacteria	*Putative transporter of Enterococcus faecalis* (gi 29342485)**

Examples:
TC#	Name	Organismal Type	Example