Origin and Evolution of the Sodium -Pumping NADH: Ubiquinone Oxidoreductase

Abstract

The sodium -pumping NADH: ubiquinone oxidoreductase (Na+-NQR) is the main ion pump and the primary entry site for electrons into the respiratory chain of many different types of pathogenic bacteria. This enzymatic complex creates a transmembrane gradient of sodium that is used by the cell to sustain ionic homeostasis, nutrient transport, ATP synthesis, flagellum rotation and other essential processes. Comparative genomics data demonstrate that the nqr operon, which encodes all Na+-NQR subunits, is found in a large variety of bacterial lineages with different habitats and metabolic strategies. Here we studied the distribution, origin and evolution of this enzymatic complex. The molecular phylogenetic analyses and the organizations of the nqr operon indicate that Na+-NQR evolved within the Chlorobi/Bacteroidetes group, after the duplication and subsequent neofunctionalization of the operon that encodes the homolog RNF complex. Subsequently, the nqr operon dispersed through multiple horizontal transfer events to other bacterial lineages such as Chlamydiae, Planctomyces and α, β, γ and δ -proteobacteria. Considering the biochemical properties of the Na+-NQR complex and its physiological role in different bacteria, we propose a detailed scenario to explain the molecular mechanisms that gave rise to its novel redox- dependent sodium -pumping activity. Our model postulates that the evolution of the Na+-NQR complex involved a functional divergence from its RNF homolog, following the duplication of the rnf operon, the loss of the rnfB gene and the recruitment of the reductase subunit of an aromatic monooxygenase.

Development of a novel rationally designed antibiotic to inhibit a nontraditional bacterial target

“…M, mol/L. zymes is implicated in the binding of korormicin (Hayashi et al 2002) and is absent in a homologous subunit of RNF (Reyes-Prieto et al 2014). Because Clostridium difficile was not sensitive to PEG-2S (data not shown), one can conclude that PEG-2S may require Gly140 to bind to Na + -NQR.…”

“…Na + -NQR is present in a variety of pathogenic bacteria including Chlamydia pneumoniae, Treponema denticola, Porphyromonas gingivalis, Tannerella forsythia, Aggregatibacter actinomycetemcomitans, Legionella pneumophila, Neisseria meningitidis, Neisseria gonorrhoeae, and many others (Dibrov et al 2004;Häse et al 2001;Reyes-Prieto et al 2014;Steuber et al 2014). Each may rely on Na + -NQR for its energetics to different degrees and, therefore, will have differing sensitivities to anti-NQR drugs.…”

“…All chlamydial genomes encode a complete Na + cycle including the Na + -translocating NADH:ubiquinone oxidoreductase (Na + -NQR) as a major primary Na + pump (Dibrov et al 2004;Dzioba et al 2003;Häse et al 2001;Reyes-Prieto et al 2014). The Na + -NQR is the major respiratory Na + pump in aerobic pathogens (Häse et al 2001;Reyes-Prieto et al 2014).…”

“…All chlamydial genomes encode a complete Na + cycle including the Na + -translocating NADH:ubiquinone oxidoreductase (Na + -NQR) as a major primary Na + pump (Dibrov et al 2004;Dzioba et al 2003;Häse et al 2001;Reyes-Prieto et al 2014). The Na + -NQR is the major respiratory Na + pump in aerobic pathogens (Häse et al 2001;Reyes-Prieto et al 2014). Although not homologous to the respiratory Complex I (Dibrov et al 2004;Dzioba et al 2003;Reyes-Prieto et al 2014;Steuber et al 2014), it occupies the same position in the electron transport chain, using the oxidation of NADH by ubiquinone to drive translocation of Na + across the membrane.…”

“…The Na + -NQR is the major respiratory Na + pump in aerobic pathogens (Häse et al 2001;Reyes-Prieto et al 2014). Although not homologous to the respiratory Complex I (Dibrov et al 2004;Dzioba et al 2003;Reyes-Prieto et al 2014;Steuber et al 2014), it occupies the same position in the electron transport chain, using the oxidation of NADH by ubiquinone to drive translocation of Na + across the membrane. Reduction of quinone by the NQR complex is tightly coupled with Na + translocation (Juárez et al 2009;Steuber et al 2014) and is inhibited by the quinone analogs HQNO and korormicin (Hayashi et al 2002;Nakayama et al 1999;Yoshikawa et al 1997).…”