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Peer-reviewedCC BY-NC-ND 4.0JACS Au

Total Biosynthesis of Pseudomonas aeruginosa -Derived Azabicyclocarbamates Identifies Distinct Dehydrating Condensation Family Proteins

  • Xiaohan Liu1
  • Soumaya Najah1
  • Andrea Calderari2
  • Zhilai Hong1
  • Sébastien Halary1
  • Carine Lombard1
  • Arnaud Bolard3
  • Katy Jeannot3
  • Arnaud Gruez2
  • Kira J. Weissman2
  • Yanyan Li1
  1. 1Unit Molecules of Communication and Adaptation of Microorganisms (MCAM), UMR 7245, CNRS-Muséum National d’Histoire Naturelle (MNHN) , ,
  2. 2Université de Lorraine, CNRS, IMoPA , ,
  3. 3Laboratoire de Bactériologie, Centre National de Référence (CNR) de la Résistance aux Antibiotiques, Centre Hospitalier Régional Universitaire (CHRU) de Besançon, UMR6249 ‘Chrono-Environnement’ , Boulevard Fleming , ,
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Abstract

Bacterial azabicyclocarbamates and related pyrrolizidine alkaloids play important roles in microbial interactions and are scaffolds of therapeutic potential. Their biosynthesis involves a bimodular nonribosomal peptide synthetase (NRPS) as well as a Baeyer–Villiger monooxygenase and tailoring enzymes, the latter contributing to the structural diversification of these compounds. Azetidomonamide A, a rare 4,7-bicyclocarbamate, is a core metabolite produced by the major human opportunistic pathogen Pseudomonas aeruginosa that is involved in virulence modulation. In this study, we elucidate the full set of tailoring reactions leading to azetidomonamide A and reconstitute its biosynthesis in vitro. Notably, this approach allows for detailed characterization of a condensation (C) domain-catalyzed online dehydration via chemical capture of NRPS-tethered intermediates. Furthermore, we identify the dehydratase AzeD as the founding member of a distinct group of standalone proteins of the C domain family. Combined structural, docking and biochemical analyses suggest that the AzeD catalytic mechanism is distinct from that of dehydrating C domains, expanding the known chemistry of these key biosynthetic enzymes. Overall, this work paves the way for accessing these complex molecules and their derivatives by pathway engineering or chemo-enzymatic synthesis.

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Cite

BibTeXRIS
BibTeX
@article{liu2026total,
  title = {{Total Biosynthesis of Pseudomonas aeruginosa -Derived Azabicyclocarbamates Identifies Distinct Dehydrating Condensation Family Proteins}},
  author = {Xiaohan Liu and Soumaya Najah and Andrea Calderari and Zhilai Hong and Sébastien Halary and Carine Lombard and Arnaud Bolard and Katy Jeannot and Arnaud Gruez and Kira J. Weissman and Yanyan Li},
  journal = {JACS Au},
  year = {2026},
  month = nov,
  doi = {10.1021/jacsau.6c01148},
  url = {https://pubs.acs.org/jaaucr/article/doi/10.1021/jacsau.6c01148/5464906/Total-Biosynthesis-of-Pseudomonas-aeruginosa},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Total Biosynthesis of Pseudomonas aeruginosa -Derived Azabicyclocarbamates Identifies Distinct Dehydrating Condensation Family Proteins
AU  - Xiaohan Liu
AU  - Soumaya Najah
AU  - Andrea Calderari
AU  - Zhilai Hong
AU  - Sébastien Halary
AU  - Carine Lombard
AU  - Arnaud Bolard
AU  - Katy Jeannot
AU  - Arnaud Gruez
AU  - Kira J. Weissman
AU  - Yanyan Li
PY  - 2026
DA  - 2026/11/05
JO  - JACS Au
DO  - 10.1021/jacsau.6c01148
UR  - https://pubs.acs.org/jaaucr/article/doi/10.1021/jacsau.6c01148/5464906/Total-Biosynthesis-of-Pseudomonas-aeruginosa
AB  - Bacterial azabicyclocarbamates and related pyrrolizidine alkaloids play important roles in microbial interactions and are scaffolds of therapeutic potential. Their biosynthesis involves a bimodular nonribosomal peptide synthetase (NRPS) as well as a Baeyer–Villiger monooxygenase and tailoring enzymes, the latter contributing to the structural diversification of these compounds. Azetidomonamide A, a rare 4,7-bicyclocarbamate, is a core metabolite produced by the major human opportunistic pathogen Pseudomonas aeruginosa that is involved in virulence modulation. In this study, we elucidate the full set of tailoring reactions leading to azetidomonamide A and reconstitute its biosynthesis in vitro. Notably, this approach allows for detailed characterization of a condensation (C) domain-catalyzed online dehydration via chemical capture of NRPS-tethered intermediates. Furthermore, we identify the dehydratase AzeD as the founding member of a distinct group of standalone proteins of the C domain family. Combined structural, docking and biochemical analyses suggest that the AzeD catalytic mechanism is distinct from that of dehydrating C domains, expanding the known chemistry of these key biosynthetic enzymes. Overall, this work paves the way for accessing these complex molecules and their derivatives by pathway engineering or chemo-enzymatic synthesis.
SN  - 2691-3704
ER  -