Stereodivergent photobiocatalytic radical cyclization through the repurposing and directed evolution of fatty acid photodecarboxylases.

Autor: Ju S; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA., Li D; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA., Mai BK; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA., Liu X; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA., Vallota-Eastman A; Interdepartmental Graduate Program for Marine Science, University of California Santa Barbara, Santa Barbara, CA, USA., Wu J; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA., Valentine DL; Marine Science Institute, University of California Santa Barbara, Santa Barbara, CA, USA.; Department of Earth Science, University of California Santa Barbara, Santa Barbara, CA, USA., Liu P; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA. pengliu@pitt.edu., Yang Y; Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA. yang@chem.ucsb.edu.; Biomolecular Science and Engineering (BMSE) Program, University of California Santa Barbara, Santa Barbara, CA, USA. yang@chem.ucsb.edu.
Jazyk: angličtina
Zdroj: Nature chemistry [Nat Chem] 2024 Aug; Vol. 16 (8), pp. 1339-1347. Date of Electronic Publication: 2024 Apr 17.
DOI: 10.1038/s41557-024-01494-0
Abstrakt: Despite their intriguing photophysical and photochemical activities, naturally occurring photoenzymes have not yet been repurposed for new-to-nature activities. Here we engineered fatty acid photodecarboxylases to catalyse unnatural photoredox radical C-C bond formation by leveraging the strongly oxidizing excited-state flavoquinone cofactor. Through genome mining, rational engineering and directed evolution, we developed a panel of radical photocyclases to facilitate decarboxylative radical cyclization with excellent chemo-, enantio- and diastereoselectivities. Our high-throughput experimental workflow allowed for the directed evolution of fatty acid photodecarboxylases. An orthogonal set of radical photocyclases was engineered to access all four possible stereoisomers of the stereochemical dyad, affording fully diastereo- and enantiodivergent biotransformations in asymmetric radical biocatalysis. Molecular dynamics simulations show that our evolved radical photocyclases allow near-attack conformations to be easily accessed, enabling chemoselective radical cyclization. The development of stereoselective radical photocyclases provides unnatural C-C-bond-forming activities in natural photoenzyme families, which can be used to tame the stereochemistry of free-radical-mediated reactions.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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