The recent breakthrough in structural studies on Na+-translocating NADH:ubiquinone oxidoreductase (Na+-NQR) from the human pathogen Vibrio cholerae creates a perspective for the systematic design of inhibitors for this unique enzyme, which is the major Na+ pump in aerobic pathogens. Widespread distribution of Na+-NQR among pathogenic species, its key role in energy metabolism, its relation to virulence in different species as well as its absence in eukaryotic cells makes this enzyme especially attractive as a target for prospective antibiotics. In this review, the major biochemical, physiological and, especially, the pharmacological aspects of Na+-NQR are discussed to assess its 'target potential' for drug development. A comparison to other primary bacterial Na+ pumps supports the contention that NQR is a first rate prospective target for a new generation of antimicrobials. A new, narrowly targeted furanone inhibitor of NQR designed in our group is presented as a molecular platform for the development of anti-NQR remedies.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1093/femsre/fux032 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Transcriptomic responses of the fast-growing bacterium Vibrio natriegens during cold-induced loss of culturability.
Appl Microbiol Biotechnol
May 2023
College of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, 314001, Zhejiang, People's Republic of China.
Vibrio natriegens has massive biotechnological potential owing to its fast growth rate. However, this bacterium rapidly loses its culturability during low-temperature preservation (LTP), the reason for which is still unknown. To reveal the metabolic responses of V.
View Article and Find Full Text PDFCryo-EM structures of Na-pumping NADH-ubiquinone oxidoreductase from Vibrio cholerae.
Nat Commun
July 2022
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan.
The Na-pumping NADH-ubiquinone oxidoreductase (Na-NQR) couples electron transfer from NADH to ubiquinone with Na-pumping, generating an electrochemical Na gradient that is essential for energy-consuming reactions in bacteria. Since Na-NQR is exclusively found in prokaryotes, it is a promising target for highly selective antibiotics. However, the molecular mechanism of inhibition is not well-understood for lack of the atomic structural information about an inhibitor-bound state.
View Article and Find Full Text PDFThe side chain of ubiquinone plays a critical role in Na translocation by the NADH-ubiquinone oxidoreductase (Na-NQR) from Vibrio cholerae.
Biochim Biophys Acta Bioenerg
June 2022
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. Electronic address:
The Na-pumping NADH-ubiquinone (UQ) oxidoreductase (Na-NQR) is an essential bacterial respiratory enzyme that generates a Na gradient across the cell membrane. However, the mechanism that couples the redox reactions to Na translocation remains unknown. To address this, we examined the relation between reduction of UQ and Na translocation using a series of synthetic UQs with Vibrio cholerae Na-NQR reconstituted into liposomes.
View Article and Find Full Text PDFSpecific chemical modification explores dynamic structure of the NqrB subunit in Na-pumping NADH-ubiquinone oxidoreductase from Vibrio cholerae.
Biochim Biophys Acta Bioenerg
August 2021
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. Electronic address:
The Na-pumping NADH-ubiquinone oxidoreductase (Na-NQR) is a main ion transporter in many pathogenic bacteria. We previously proposed that N-terminal stretch of the NqrB subunit plays an important role in regulating the ubiquinone reaction at the adjacent NqrA subunit in Vibrio cholerae Na-NQR. However, since approximately three quarters of the stretch (NqrB-Met-Pro) was not modeled in an earlier crystallographic study, its structure and function remain unknown.
View Article and Find Full Text PDFIdentification of the binding sites for ubiquinone and inhibitors in the Na-pumping NADH-ubiquinone oxidoreductase from by photoaffinity labeling.
J Biol Chem
May 2017
From the Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan and
Article Synopsis
- The Na-pumping NADH-quinone oxidoreductase (Na-NQR) is a critical enzyme in bacteria that transports ions and has controversial binding sites for ubiquinone and inhibitors.
- Recent experiments with photoreactive ubiquinone and aurachin-type inhibitors have identified specific binding regions for these molecules on different subunits of Na-NQR.
- Findings show that while the inhibitory effects of the aurachin-type inhibitors can be disrupted by mutations in the enzyme, their binding remains unaffected, suggesting complex interactions that require further exploration through proposed models.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!