ACS Omega· 2026Q1
A Single Active-Site Water Molecule Encodes Two Distinct Proton-Coupled Electron Transfer Pathways in Fatty Acid Photodecarboxylase
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- Q1SCImago
- 2026year
Short summary
A single water molecule (Wat3) in fatty acid photodecarboxylase (FAP) mediates radical quenching via two distinct proton-coupled electron transfer (PCET) pathways, with the flavin semiquinone providing the electron in both.
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Key points
- A single water molecule (Wat3) in FAP mediates radical quenching via two distinct PCET pathways.
- The dominant pathway involves Wat3 stabilizing direct proton transfer from Cys432 to the alkyl radical.
- An alternative pathway uses Wat3 as a proton shuttle in a quasi-concerted two-proton transfer.
- The flavin semiquinone provides the electron in both PCET pathways.
- CO2 reaction with the thiolate forms a thiocarbonate adduct, explaining observed crystallographic electron density.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract Water molecules are key actors in enzymatic proton-coupled electron transfer (PCET), yet their mechanistic versatility remains underexplored. Using a multiscale computational approach, we show that a previously unidentified water molecule (Wat3) in fatty acid photodecarboxylase (FAP), a natural photoenzyme converting fatty acids into alkanes, mediates radical quenching via two PCET pathways: in the dominant one, which qualitatively agrees with the 100 ns experimental time scale, Wat3 stabilizes the transition state for direct proton transfer from Cys432 to the alkyl radical; in the alternative, the same molecule acts as a proton shuttle in a quasi-concerted two-proton transfer, with the flavin semiquinone providing the electron in both cases. The minor pathway, though less accessible in wild-type FAP, may become operative in engineered variants or related enzymes. Additionally, CO2 reacts with the thiolate to yield a thiocarbonate adduct, explaining unassigned crystallographic electron density. These results show how a single water molecule encodes mechanistic diversity in enzymatic PCET.
The authors' abstract, as published at the source. ACS Omega, 2026 · DOI ↗
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Field: Physical and Theoretical Chemistry
Physical and Theoretical ChemistryChemistry