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1.A.16 The Formate-Nitrite Transporter (FNT) Family

FNT family members have been sequenced from Gram-negative and Gram-positive bacteria, archaea and yeast. The prokaryotic proteins of the FNT family probably function in the transport of the structurally related compounds, formate and nitrite.

With the exception of the yeast protein (627 amino acyl residues), all members of the family are of 256-285 residues in length and exhibit 6-8 putative transmembrane α-helical spanners (TMSs). In one case, that of the E. coli FocA protein, a 6 TMS topology has been established. The yeast protein has a similar apparent topology but has a large C-terminal hydrophilic extension of about 400 residues.

The phylogenetic tree shows clustering according to function and organismal phylogeny. The putative formate efflux transporters (FocA) of bacteria associated with pyruvate-formate lyase (pfl) comprise cluster I; the putative formate uptake permeases (FdhC) of bacteria and archaea associated with formate dehydrogenase comprise cluster II; the nitrite uptake permeases (NirC) of bacteria comprise cluster III, and a yeast protein comprises cluster IV.

The energy coupling mechanisms for proteins of the FNT family have not been extensively characterized. HCO2- and NO2- uptakes are probably coupled to H symport. HCO2- efflux may be driven by the membrane potential by a uniport mechanism or by H antiport. FocA of E. coli catalyzes bidirectional formate transport, has a pentameric quaternary structure and may function by a channel-type mechanism (Falke et al., 2010).

FocA, a representative member of the formate-nitrite transporter family, transports short-chain acids in bacteria, archaea, fungi, algae and certain eukaryotic parasites. Wang et al. (2009) reported the crystal structure of the E. coli FocA at 2.25 A resolution. FocA forms a symmetric pentamer, with each protomer consisting of six TMSs. Despite a lack of sequence homology, the overall structure of the FocA protomer closely resembles that of aquaporin, indicating that FocA is a channel rather than a carrier. Structural analysis identified potentially important channel residues, defined the channel path and revealed two constriction sites. Unlike aquaporin, FocA is impermeable to water but allows the passage of formate.

FocA (2.A.44.1.1) may be able to switch its mode of operation from a passive export channel at high external pH to a secondary active formate/H importer at low pH. The crystal structure of Salmonella typhimurium FocA at pH 4.0 shows that this switch involves a major rearrangement of the amino termini of individual protomers in the pentameric channel (et al., 2011). The amino-terminal helices open or block transport in a concerted, cooperative action that indicates how FocA is gated in a pH-dependent way. Electrophysiological studies show that the protein acts as a specific formate channel at pH 7.0 and that it closes upon a shift of pH to 5.1.

The probable transport reactions catalyzed by different members of the FNT family are:

(1) RCO2- or NO2- (out) ⇌ RCO2- or NO2- (in),

(2) HCO2- (in) ⇌ HCO2- (out),

(3) HS- (out) ⇌ HS- (in).

This family belongs to the: Major Intrinsic Protein (MIP) Superfamily.

References associated with 1.A.16 family:

Andrews, S.C., B.C. Berks, J. McClay, A. Ambler, M.A. Quail, P. Golby, and J.R. Guest. (1997). A 12-cistron Escherichia coli operon (hyf) encoding a putative proton-translocating formate hydrogenlyase system. Microbiology 143(Pt11): 3633-3647. 9387241
Czyzewski, B.K. and D.N. Wang. (2012). Identification and characterization of a bacterial hydrosulphide ion channel. Nature 483: 494-497. 22407320
Falke, D., K. Schulz, C. Doberenz, L. Beyer, H. Lilie, B. Thiemer, and R.G. Sawers. (2010). Unexpected oligomeric structure of the FocA formate channel of Escherichia coli : a paradigm for the formate-nitrite transporter family of integral membrane proteins. FEMS Microbiol. Lett. 303: 69-75. 20041954
Jia, W., N. Tovell, S. Clegg, M. Trimmer, and J. Cole. (2009). A single channel for nitrate uptake, nitrite export and nitrite uptake by Escherichia coli NarU and a role for NirC in nitrite export and uptake. Biochem. J. 417: 297-304. 18691156
Kuzminov, A. and F.W. Stahl. (1997). Stability of linear DNA in recA mutant Escherichia coli cells reflects ongoing chromosomal DNA degradation. J. Bacteriol. 179: 880-888. 9006046
Lü, W., J. Du, T. Wacker, E. Gerbig-Smentek, S.L. Andrade, and O. Einsle. (2011). pH-dependent gating in a FocA formate channel. Science 332: 352-354. 21493860
Moraes, T.F. and R.A. Reithmeier. (2012). Membrane transport metabolons. Biochim. Biophys. Acta. 1818: 2687-2706. 22705263
Nakata, K., M.M. Koh, T. Tsuchido, and Y. Matsumura. (2010). All genomic mutations in the antimicrobial surfactant-resistant mutant, Escherichia coli OW66, are involved in cell resistance to surfactant. Appl. Microbiol. Biotechnol. 87: 1895-1905. 20480162
Nölling, J. and J.N. Reeve. (1997). Growth- and substrate-dependent transcription of the formate dehydrogenase (fdhCAB) operon in Methanobacterium thermoformicicum Z-245. J. Bacteriol. 179: 899-908. 9006048
Park, J.S., S.J. Lee, H.G. Rhie, and H.S. Lee. (2008). Characterization of a chromosomal nickel resistance determinant from Klebsiella oxytoca CCUG 15788. J Microbiol Biotechnol 18: 1040-1043. 18600044
Pui, C.H., W.M. Crist, and A.T. Look. (1990). Biology and clinical significance of cytogenetic abnormalities in childhood acute lymphoblastic leukemia. Blood 76: 1449-1463. 2207320
Rycovska-Blume, A., W. Lü, S. Andrade, K. Fendler, and O. Einsle. (2015). Structural and Functional Studies of NirC from Salmonella typhimurium. Methods Enzymol 556: 475-497. 25857796
Unkles, S.E., K.L. Hawker, C. Grieve, E.I. Campbell, P. Montague, and J.R. Kinghorn. (1991). crnA encodes a nitrate transporter in Aspergillus nidulans. Proc. Natl. Acad. Sci. USA 88: 204-208. 1986367
Unkles, S.E., V.F. Symington, Z. Kotur, Y. Wang, M.Y. Siddiqi, J.R. Kinghorn, and A.D. Glass. (2011). Physiological and biochemical characterization of AnNitA, the Aspergillus nidulans high-affinity nitrite transporter. Eukaryot. Cell. 10: 1724-1732. 22021238
Waight, A.B., J. Love, and D.N. Wang. (2010). Structure and mechanism of a pentameric formate channel. Nat Struct Mol Biol 17: 31-37. 20010838
Wang, Y., Y. Huang, J. Wang, C. Cheng, W. Huang, P. Lu, Y.N. Xu, P. Wang, N. Yan, and Y. Shi. (2009). Structure of the formate transporter FocA reveals a pentameric aquaporin-like channel. Nature 462: 467-472. 19940917
Wood, G.E., A.K. Haydock, and J.A. Leigh. (2003). Function and regulation of the formate dehydrogenase genes of the methanogenic archaeon Methanococcus maripaludis. J. Bacteriol. 185: 2548-2554. 12670979