Accelerating discovery of substrate promiscuity in biocatalyzed oxidations

When: 21 February 2025, 15:00 GMT
Where: online

Enzymes collectively display a great breadth of catalytic properties yet are individually confined to one or a few specific catalytic tasks. Despite key advances in enzyme engineering, our capacity to predict the effects of mutations on function remains nebulous. Here we present advances in engineering non-native substrate recognition for biocatalyzed transformation into useful products. We examine cytochrome P450 oxidase from Bacillus megaterium (P450 BM3) in its capacity to functionalize C-H bonds. Cost-effective, high-throughput colorimetric screening at the whole-cell level had previously suggested a correlation between the production of indigo and increased substrate promiscuity, in a small number of P450 BM3 variants. We greatly expand the diversity of indigo-producing P450 BM3 variants and demonstrate a correlation with promiscuous aromatic hydroxylation reactions. We look ahead to the potential for large experimental datasets to train smarter design algorithms for enzyme engineering.

Figure 1 – Introduction of sequence diversity in cytochrome P450 oxidase from Bacillus megaterium (P450 BM3). image credit: Joelle Pelletier

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Biography:

image credit: Joelle Pelletier

Following a Ph.D. from McGill U. and postdoctoral fellowships at U. de Montréal and at the U. of Zürich, Joelle Pelletier became a Professor of Chemistry and Adjunct Professor of Biochemistry and Molecular and Cellular Biology at U. de Montréal in 1999. Professor Pelletier has established advanced methods for automated and high-throughput protein engineering, biocatalysis and computational models, as reported in over 120 publications and 15 patents. Evolution of antibiotic resistance, generation of ‘smart’ protein libraries and protein dynamics are prominent among her research topics. Her transdisciplinary research has provided remarkable insights into the fundamentals of protein biology. Since 2021, she holds the Canada Research Chair in Engineering of Applied Proteins.

She has also served for 12 years as co-director of PROTEO, the Québec Network for Protein Function, Engineering and Applications and is Associate Editor at ACS Catalysis since 2021. In 2015 she launched the start-up company Affinité Instruments where she serves as VP-Research. She has been awarded the 2021 Clara Benson award of the Canadian Society for Chemistry, recognizing her distinguished contribution to chemistry. Pelletier is passionate about mentoring and promoting the young scientists who now lead the new generation of researchers.