Pseudomonas aeruginosa acyl-CoA dehydrogenases and structure-guided inversion of their substrate specificity

• DOI: 10.1038/s41467-025-57532-z
• Publication Date: 2025-03-08T15:42:51Z
• Authors: Meng Wang; Prasanthi Medaram...; Thales Kronenberger; Tomas Deingruber; Paul Brear; Wendy Figueroa; Pok-Man Ho; Thomas Krueger; James C. Pearce; Antti Poso; James G. Wakefield; David R. Spring; Martin Welch
• Keywords: Acyl-CoA

Abstract Fatty acids are a primary source of carbon for Pseudomonas aeruginosa (PA) in the airways people with cystic fibrosis (CF). Here, we use tandem mass-tag proteomics to analyse protein expression profile CF clinical isolate grown on different fatty acids. Two acyl-CoA dehydrogenases (designated FadE1 and FadE2) strongly induced during growth displays strong preference long-chain acyl-CoAs, whereas FadE2 exclusively utilizes medium-chain acyl-CoAs. Structural analysis enzymes enables us identify residues comprising substrate selectivity filter each. Engineering these invert specificity each enzyme. Mutants fadE1 displayed impaired virulence an infection model, decreased long chain The unique features binding pocket enable inhibitor that is differentially active against FadE2.