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

Author

Listed:
  • Meng Wang

    (Tennis Court Road)

  • Prasanthi Medarametla

    (Tennis Court Road
    University of Eastern Finland)

  • Thales Kronenberger

    (University of Eastern Finland
    University of Tübingen
    German Center for Infection Research (DZIF))

  • Tomas Deingruber

    (Lensfield Road)

  • Paul Brear

    (Tennis Court Road)

  • Wendy Figueroa

    (Tennis Court Road)

  • Pok-Man Ho

    (Tennis Court Road)

  • Thomas Krueger

    (Tennis Court Road)

  • James C. Pearce

    (University of Exeter)

  • Antti Poso

    (University of Eastern Finland)

  • James G. Wakefield

    (University of Exeter)

  • David R. Spring

    (Lensfield Road)

  • Martin Welch

    (Tennis Court Road)

Abstract

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

Suggested Citation

  • Meng Wang & Prasanthi Medarametla & Thales Kronenberger & Tomas Deingruber & Paul Brear & Wendy Figueroa & Pok-Man Ho & Thomas Krueger & James C. Pearce & Antti Poso & James G. Wakefield & David R. Sp, 2025. "Pseudomonas aeruginosa acyl-CoA dehydrogenases and structure-guided inversion of their substrate specificity," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57532-z
    DOI: 10.1038/s41467-025-57532-z
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