A biocatalytic platform for asymmetric alkylation of α-keto acids by mining and engineering of methyltransferases
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40980-w |
| _version_ | 1797558125591527424 |
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| author | Shuyun Ju Kaylee P. Kuzelka Rui Guo Benjamin Krohn-Hansen Jianping Wu Satish K. Nair Yang Yang |
| author_facet | Shuyun Ju Kaylee P. Kuzelka Rui Guo Benjamin Krohn-Hansen Jianping Wu Satish K. Nair Yang Yang |
| author_sort | Shuyun Ju |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:27:12Z |
| format | Article |
| id | doaj.art-2555906230c143d1b9985d3340ed3646 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:27:12Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-2555906230c143d1b9985d3340ed36462023-11-20T10:08:17ZengNature PortfolioNature Communications2041-17232023-09-011411910.1038/s41467-023-40980-wA biocatalytic platform for asymmetric alkylation of α-keto acids by mining and engineering of methyltransferasesShuyun Ju0Kaylee P. Kuzelka1Rui Guo2Benjamin Krohn-Hansen3Jianping Wu4Satish K. Nair5Yang Yang6Department of Chemistry and Biochemistry, University of CaliforniaDepartment of Biochemistry, Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−ChampaignDepartment of Chemistry and Biochemistry, University of CaliforniaDepartment of Chemistry and Biochemistry, University of CaliforniaDepartment of Chemistry and Biochemistry, University of CaliforniaDepartment of Biochemistry, Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana−ChampaignDepartment of Chemistry and Biochemistry, University of CaliforniaAbstract 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.https://doi.org/10.1038/s41467-023-40980-w |
| spellingShingle | Shuyun Ju Kaylee P. Kuzelka Rui Guo Benjamin Krohn-Hansen Jianping Wu Satish K. Nair Yang Yang A biocatalytic platform for asymmetric alkylation of α-keto acids by mining and engineering of methyltransferases Nature Communications |
| title | A biocatalytic platform for asymmetric alkylation of α-keto acids by mining and engineering of methyltransferases |
| title_full | A biocatalytic platform for asymmetric alkylation of α-keto acids by mining and engineering of methyltransferases |
| title_fullStr | A biocatalytic platform for asymmetric alkylation of α-keto acids by mining and engineering of methyltransferases |
| title_full_unstemmed | A biocatalytic platform for asymmetric alkylation of α-keto acids by mining and engineering of methyltransferases |
| title_short | A biocatalytic platform for asymmetric alkylation of α-keto acids by mining and engineering of methyltransferases |
| title_sort | biocatalytic platform for asymmetric alkylation of α keto acids by mining and engineering of methyltransferases |
| url | https://doi.org/10.1038/s41467-023-40980-w |
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