A biocatalytic platform for asymmetric alkylation of α-keto acids by mining and engineering of methyltransferases

Shuyun Ju, Kaylee P. Kuzelka, Rui Guo, Benjamin Krohn-Hansen, Jianping Wu, Satish K. Nair () and Yang Yang ()
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Shuyun Ju: University of California
Kaylee P. Kuzelka: University of Illinois at Urbana−Champaign
Rui Guo: University of California
Benjamin Krohn-Hansen: University of California
Jianping Wu: University of California
Satish K. Nair: University of Illinois at Urbana−Champaign
Yang Yang: University of California

Nature Communications, 2023, vol. 14, issue 1, 1-9

Abstract: Abstract Catalytic asymmetric α-alkylation of carbonyl compounds represents a long-standing challenge in synthetic organic chemistry. Herein, we advance a dual biocatalytic platform for the efficient asymmetric alkylation of α-keto acids. First, guided by our recently obtained crystal structures, we develop SgvMVAV as a general biocatalyst for the enantioselective methylation, ethylation, allylation and propargylation of a range of α-keto acids with total turnover numbers (TTNs) up to 4,600. Second, we mine a family of bacterial HMTs from Pseudomonas species sharing less than 50% sequence identities with known HMTs and evaluated their activities in SAM regeneration. Our best performing HMT from P. aeruginosa, PaHMT, displays the highest SAM regeneration efficiencies (TTN up to 7,700) among HMTs characterized to date. Together, the synergistic use of SgvMVAV and PaHMT affords a fully biocatalytic protocol for asymmetric methylation featuring a record turnover efficiency, providing a solution to the notorious problem of asymmetric alkylation.

Date: 2023
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DOI: 10.1038/s41467-023-40980-w

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