image: a cost-effective, efficient, and enantioselective one-step biocatalytic pathway mediated by CYP152 peroxygenase for the conversion of phenylacetic acid derivatives into (R)-mandelic acid derivatives.
Credit: ©Science China Press
Cytochrome P450 enzymes are known as the “versatile catalysts of nature” for their remarkable ability to oxidize C–H bonds under mild conditions, outperforming many chemical catalysts. However, the dependence on expensive cofactors (NAD(P)H) and low electron transfer efficiency mediated by redox partners have limited the practical application of P450 monooxygenases. In contrast, P450 peroxygenases, represented by the CYP152 family, can directly utilize cheap hydrogen peroxide (H2O2) as an oxidant, making them attractive alternatives for green biocatalysis.
The group led by Prof. Shengying Li at the State Key Laboratory of Microbial Technology at Shandong University has long been engaged in research on microbial CYP152 peroxygenases, focusing on catalytic mechanisms, enzyme discovery, protein engineering, expansion of substrate scope, and functional applications (Angew. Chem. Int. Ed. 2025, 2021; Sci. Bull. 2024; Biotechnol. Biofuels 2020, 2019, 2017, 2015, 2014；ChemCatChem 2019; Sci. Rep. 2017).
In a recent study from this group (published in Sci. Bull.), the researchers developed a green, one-step biocatalytic platform that enables efficient and highly enantioselective α-hydroxylation of aromatic carboxylic acids. The engineered mutants (P450BSβ-F46A and P450BSβ-F292A) catalyzed the conversion of inexpensive phenylacetic acid and its derivatives into (R)-mandelic acid derivatives with excellent performance. The reactions achieved total turnover numbers (TTNs) up to 11,722 and enantiomeric excess (ee) values exceeding 99% in 10 examples. The researchers also demonstrated semi-preparative enzymatic synthesis of (R)-mandelic acid and (R)-p-fluoromandelic acid with isolated yields above 92%.
(R)-mandelic acid and its derivatives are widely used as chiral resolving agents and drug precursors in organic, medicinal, and pharmaceutical chemistry. However, the current prevailing methods for asymmetric synthesis of (R)-mandelic acid encounter several drawbacks, including low yields and enantioselectivity, harsh reaction conditions, high cost, and serious environmental concerns. This CYP152 peroxygenase-based system developed by Li et al. offers a green, atom-economical, and sustainable alternative for the cost-effective production of enantiopure hydroxy acids.
“This work expands the substrate scope of CYP152 peroxygenases and demonstrates their great potential in the green biomanufacturing of chiral high-value compounds,” said Prof. Li, the study’s corresponding author. “It also provides a new strategy for producing valuable intermediates for synthetic and medicinal chemistry.”
This study was supported by the National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province.