A single diiron enzyme catalyses the oxidative rearrangement of tryptophan to indole nitrile
Nitriles are uncommon in nature and are typically constructed from oximes through the oxidative decarboxylation of amino acid substrates or from the derivatization of carboxylic acids. Here we report a third nitrile biosynthesis strategy featuring the cyanobacterial nitrile synthase AetD. During the biosynthesis of the eagle-killing neurotoxin, aetokthonotoxin, AetD transforms the 2-aminopropionate portion of 5,7-dibromo-L-tryptophan to a nitrile. Employing a combination of structural, biochemical and biophysical techniques, we characterized AetD as a non-haem diiron enzyme that belongs to the emerging haem-oxygenase-like dimetal oxidase superfamily. High-resolution crystal structures of AetD together with the identification of catalytically relevant products provide mechanistic insights into how AetD affords this unique transformation, which we propose proceeds via an aziridine intermediate. Our work presents a unique template for nitrile biogenesis and portrays a substrate binding and metallocofactor assembly mechanism that may be shared among other haem-oxygenase-like dimetal oxidase enzymes.
Authors
- Sanjoy Adak (ORCID: https://orcid.org/0000-0003-2889-4272)
- Naike Ye
- Bradley S. Moore (ORCID: https://orcid.org/0000-0002-4652-1253)
- Kendall N. Houk (ORCID: https://orcid.org/0000-0002-8387-5261)
- April L. Lukowski (ORCID: https://orcid.org/0000-0003-4865-0910)
- Maria‐Eirini Pandelia (ORCID: https://orcid.org/0000-0002-6750-1948)
- Catherine L. Drennan (ORCID: https://orcid.org/0000-0001-5486-2755)
- Rebecca J. B. Schäfer
- Logan A Calderone (ORCID: https://orcid.org/0000-0002-0960-3831)
- Meng Duan (ORCID: https://orcid.org/0000-0002-4689-9811)
- Wilson Lubeck
Institutions
- Howard Hughes Medical Institute (US)
- Scripps Institution of Oceanography (US)
- University of California, Los Angeles (US)
- University of California San Diego (US)
- IIT@MIT (US)
- Massachusetts Institute of Technology (US)
- University of Montana (US)
- Brandeis University (US)
Publication Details
- Journal
- Nature Chemistry
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1038/s41557-024-01603-z
- Citations
- 21
- Primary Topic
- Metal-Catalyzed Oxygenation Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.33
Funders
- National Science Foundation
- Howard Hughes Medical Institute
- U.S. Department of Energy
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- Office of Science
- National Institute of General Medical Sciences
- National Institute of Environmental Health Sciences
- Division of Chemistry
- Basic Energy Sciences
- Biological and Environmental Research
- Argonne National Laboratory
- SLAC National Accelerator Laboratory