Dataset Information

Synthesis and Biological Screening of New Lawson Derivatives as Selective Substrate-Based Inhibitors of Cytochrome bo3 Ubiquinol Oxidase from Escherichia coli.

ABSTRACT: The respiratory chain of Escherichia coli contains two different types of terminal oxidase that are differentially regulated as a response to changing environmental conditions. These oxidoreductases catalyze the reduction of molecular oxygen to water and contribute to the proton motive force. The cytochrome bo3 oxidase (cyt bo3 ) acts as the primary terminal oxidase under atmospheric oxygen levels, whereas the bd-type oxidase is most abundant under microaerobic conditions. In E. coli, both types of respiratory terminal oxidase (HCO and bd-type) use ubiquinol-8 as electron donor. Here, we assess the inhibitory potential of newly designed and synthesized 3-alkylated Lawson derivatives through L-proline-catalyzed three-component reductive alkylation (TCRA). The inhibitory effects of these Lawson derivatives on the terminal oxidases of E. coli (cyt bo3 and cyt bd-I) were tested potentiometrically. Four compounds were able to reduce the oxidoreductase activity of cyt bo3 by more than 50?% without affecting the cyt bd-I activity. Moreover, two inhibitors for both cyt bo3 and cyt bd-I oxidase could be identified. Based on molecular-docking simulations, we propose binding modes of the new Lawson inhibitors. The molecular fragment benzyl enhances the inhibitory potential and selectivity for cyt bo3 , whereas heterocycles reduce this effect. This work extends the library of 3-alkylated Lawson derivatives as selective inhibitors for respiratory oxidases and provides molecular probes for detailed investigations of the mechanisms of respiratory-chain enzymes of E. coli.

SUBMITTER: Elamri I

PROVIDER: S-EPMC7497249 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthesis and Biological Screening of New Lawson Derivatives as Selective Substrate-Based Inhibitors of Cytochrome bo3 Ubiquinol Oxidase from Escherichia coli.

Elamri Isam I Radloff Melanie M Hohmann Katharina F KF Nimbarte Vijaykumar D VD Nasiri Hamid R HR Bolte Michael M Safarian Schara S Michel Hartmut H Schwalbe Harald H

ChemMedChem 20200414 14

The respiratory chain of Escherichia coli contains two different types of terminal oxidase that are differentially regulated as a response to changing environmental conditions. These oxidoreductases catalyze the reduction of molecular oxygen to water and contribute to the proton motive force. The cytochrome bo3 oxidase (cyt bo3 ) acts as the primary terminal oxidase under atmospheric oxygen levels, whereas the bd-type oxidase is most abundant under microaerobic conditions. ...[more]

PMID: 32159929

Similar Datasets

Project description:The R481 residue of cytochrome bo(3) ubiquinol oxidase from E. coli is highly conserved in the heme-copper oxidase superfamily. It has been postulated to serve as part of a proton loading site that regulates proton translocation across the protein matrix of the enzyme. Along these lines, proton pumping efficiency has been demonstrated to be abolished in many R481 mutants. However, R481Q in bo(3) from E. coli has been shown to be fully functional, implying that the positive charge of the arginine is not required for proton translocation [ Puustinen , A. and Wikstrom , M. ( 1999 ) Proc. Natl. Acad. Sci. U.S.A. 96 , 35 - 37 ]. In an effort to delineate the structural role of R481 in the bo(3) oxidase, we used resonance Raman spectroscopy to compare the nonfunctional R481L mutant and the functional R481Q mutant, to the wild type protein. Resonance Raman data of the oxidized and reduced forms of the R481L mutant indicate that the mutation introduces changes to the heme o(3) coordination state, reflecting a change in position and/or coordination of the Cu(B) located on the distal side of heme o(3), although it is approximately 10 A away from R481. In the reduced-CO adduct of R481L, the frequencies of the Fe-CO and C-O stretching modes indicate that, unlike the wild type protein, the Cu(B) is no longer close to the heme-bound CO. In contrast, resonance Raman data obtained from the various oxidation and ligation states of the R481Q mutant are similar to those of the wild type protein, except that the mutation causes an enhancement of the relative intensity of the beta conformer of the CO-adduct, indicating a shift in the equilibrium between the alpha and beta conformers. The current findings, together with crystallographic structural data of heme-copper oxidases, indicate that R481 plays a keystone role in stabilizing the functional structure of the Cu(B) site through a hydrogen bonding network involving ordered water molecules. The implications of these data on the proton translocation mechanism are considered.

Dataset Information

Synthesis and Biological Screening of New Lawson Derivatives as Selective Substrate-Based Inhibitors of Cytochrome bo3 Ubiquinol Oxidase from Escherichia coli.

Publications

Synthesis and Biological Screening of New Lawson Derivatives as Selective Substrate-Based Inhibitors of Cytochrome bo<sub>3</sub> Ubiquinol Oxidase from Escherichia coli.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets