Structural insights into S-lignin O-demethylation via a rare class of heme peroxygenase enzymes
Date
2025
Authors
Harlington, A.C.
Das, T.
Shearwin, K.E.
Bell, S.G.
Whelan, F.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Nature Communications, 2025; 16(1):1815-1-1815-12
Statement of Responsibility
Alix C. Harlington, Tuhin Das, Keith E. Shearwin, Stephen G. Bell, Fiona Whelan
Conference Name
Abstract
The O-demethylation of lignin aromatics is a rate-limiting step in their bioconversion to higher-value compounds. A recently discovered cytochrome P450, SyoA, demethylates the S-lignin aromatic syringol. In this work, we solve high-resolution X-ray crystal structures of substrate-free and substrate-bound SyoA and evaluate demethylation of para-substituted S-lignin aromatics via monooxygenase and peroxide shunt pathways. We find that SyoA demethylates S-lignin aromatics exclusively using the peroxide shunt pathway. The atomic-resolution structures reveal the position of non-canonical residues in the I-helix (Gln252, Glu253). Mutagenesis of this amide-acid pair in SyoA shows they are critical for catalytic activity. This work expands the enzymatic toolkit for improving the capacity to funnel lignin derived aromatics towards higher value compounds and defines the chemistry within the active site of the enzyme that enables peroxygenase activity. These insights provide a framework for engineering peroxygenase activity in other heme enzymes to generate easier to use biocatalysts.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/.