Ancestral Sequence Reconstruction Reveals Determinants of Regioselectivity in C(sp3)-H Oxyfunctionalization Reactions by CYP505Es

IF 11.3 1区 化学 Q1 CHEMISTRY, PHYSICAL ACS Catalysis Pub Date : 2024-12-23 DOI:10.1021/acscatal.4c06260
Ana C. Ebrecht, Jasmin C. Aschenbrenner, Yosephine Gumulya, Martha S. Smit, Diederik J. Opperman
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Abstract

Regioselective C–H functionalization of fatty acids and alcohols is a challenging reaction, especially in-chain/midchain hydroxylation. These hydroxy fatty acids or diols offer a synthetic route to valuable δ- and γ-lactones. Although terminal and subterminal hydroxylation of fatty acids and alcohols by cytochrome P450 monooxygenases have been extensively explored, the molecular determinants of in-chain hydroxylation are unknown. Here we performed ancestral sequence reconstruction (ASR) of the subfamily of CYP505Es, able to perform in-chain hydroxylation, together with their closest related subterminal hydroxylases. Three ancestors were resurrected, which represented the in-chain and subterminal hydroxylases, as well as their common ancestor, which displayed little regioselectivity. Mutations were introduced to investigate the divergence in regioselectivity observed in the natural evolution. Whereas subterminal hydroxylation appears to be through multiple additive mutations in the active site, in-chain hydroxylation was greatly affected by the BC-loop. ASR provides not only insight for directed evolution studies but also more promiscuous ancestors as templates for the starting point for laboratory evolution.

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ACS Catalysis
ACS Catalysis CHEMISTRY, PHYSICAL-
CiteScore
20.80
自引率
6.20%
发文量
1253
审稿时长
1.5 months
期刊介绍: ACS Catalysis is an esteemed journal that publishes original research in the fields of heterogeneous catalysis, molecular catalysis, and biocatalysis. It offers broad coverage across diverse areas such as life sciences, organometallics and synthesis, photochemistry and electrochemistry, drug discovery and synthesis, materials science, environmental protection, polymer discovery and synthesis, and energy and fuels. The scope of the journal is to showcase innovative work in various aspects of catalysis. This includes new reactions and novel synthetic approaches utilizing known catalysts, the discovery or modification of new catalysts, elucidation of catalytic mechanisms through cutting-edge investigations, practical enhancements of existing processes, as well as conceptual advances in the field. Contributions to ACS Catalysis can encompass both experimental and theoretical research focused on catalytic molecules, macromolecules, and materials that exhibit catalytic turnover.
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