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Free keywords:
Inhibitor design; membrane proteins; respiratory chain; cytochrome bo3; bd
Abstract:
The respiratory chain of Escherichia coli contains two different types of terminal oxidases that are differentially regulated to respond to changing environmental conditions. The oxidoreductases catalyze the reduction of 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, while the bd ‐type oxidase is most abundant under microaerobic conditions. In E. coli , both types of respiratory terminal oxidases (HCO and bd ‐type) utilize ubiquinol‐8 as electron donor. Here, we assess the inhibitory potential of 3 alkylated Lawson derivatives via the L‐proline‐catalyzed three‐ component reductive alkylation (TCRA). The inhibitory effects on the terminal oxidases (cyt. bo3 and cyt. bd ‐I) were tested potentiometrically. 4 compounds were able to reduce oxidoreductase activity of cyt. bo3 by more than 50% without affecting the cyt bd‐ I activity. Two inhibitors for both cyt. bo3 and cyt. bd ‐I oxidase could be identified. Based on MD simulations, we propose the binding mode of the new inhibitors. The mol. fragment benzyl enhances the inhibitory potential and selectivity for cyt. bo3 while heterocycles reduce this effect. This work extends the library of 3‐alkylated Lawson derivatives as selective inhibitors for respiratory oxidases and provides probes for investigations of the mechanisms of respiratory chain enzymes of E. coli.
