有機合成の新手法が化学の常識を覆す（Organic syntheses: new chemistry challenges dogma）

2025-04-09 ミュンヘン大学（LMU）

＜関連情報＞

• https://www.lmu.de/en/newsroom/news-overview/news/organic-syntheses-new-chemistry-challenges-dogma.html
• https://www.cell.com/chem/fulltext/S2451-9294(25)00128-7

キメラ補酵素がメチル基転移酵素触媒によるプレニル化を可能にする Chimeric cofactors enable methyltransferase-catalyzed prenylation

Nicolas V. Cornelissen∙ Arne Hoffmann∙ Pulak Ghosh∙ Yanis L. Pignot∙ Mehmet Erguven∙ Andrea Rentmeister
Chem  Published:April 9, 2025
DOI:https://doi.org/10.1016/j.chempr.2025.102538

Graphical abstract

The bigger picture

Enzymes can perform alkylation reactions of their target substrate with high selectivity under mild conditions. Suitable transferases can be found in different enzyme classes and rely on different cofactor scaffolds depending on whether they transfer one-carbon or non-methyl groups. S-Adenosyl-l-methionine (AdoMet or SAM) is characteristic of methyltransferases (C₁), whereas prenyltransferases (C₅) rely on dimethylallyl diphosphate (DMAPP). We engineered a chimeric AdoMet/DMAPP cofactor and found that it is efficiently converted by various methyltransferases acting on different targets at C, N, and O atoms. The chimeric cofactor is highly reactive, and prenylation is preferred over the methylation in direct competition with the natural AdoMet.

Our work unlocks hundreds of methyltransferases as biocatalysts for regioselective prenylation and will prove useful in making pseudo-natural products and new-to-nature bioconjugates. We also show that the concept can be extended to C₁₀ and C₁₅ units as well as clickable groups. The finding that the AdoMet scaffold can be used for efficient prenyl transfer by wild-type methyltransferases shows that there is no inherent chemical or enzymatic reason that C₁ and C₅ transfer is catalyzed by different enzyme classes. This relaxes the paradigm of one-carbon- versus non-methyl-group-transferring enzyme classes for biotransformations and therefore opens new doors in biocatalytic alkylation.

Highlights

• Chimeric cofactors make methyltransferases act as prenyltransferases
• The tested methyltransferases favor prenylation over natural methylation
• This strategy can transfer prenyl, geranyl, farnesyl, and clickable groups

Summary

Enzymatic alkylation is known for its selectivity and specificity. Transferases are found in enzymes that transfer one-carbon groups and in those that transfer non-methyl groups. Both classes catalyze the attack of a nucleophilic substrate but use different cofactors. S-Adenosyl-l-methionine (AdoMet or SAM) is characteristic of methyltransferases (MTases), whereas prenyltransferases (PTases) rely on dimethylallyl diphosphate (DMAPP). It is unclear whether this preference originates from inherent chemical or enzymatic requirements. We find that DNA, RNA, and small-molecule MTases acting on C, N, and O atoms function as PTases when offered a chimeric AdoMet-DMAPP cofactor (AdoPrenyl). This cofactor is highly reactive, necessitating its enzymatic in situ formation and leading to preferential MTase-catalyzed prenylation. The DNA-MTase M.TaqI efficiently transfers geranyl (C₁₀) and farnesyl (C₁₅) moieties as well. Our work shows that the AdoMet scaffold can function as an efficient prenyl donor. Because there are hundreds of MTases, this route to regio- and sequence-selective prenylation is versatile for forming pseudo-natural products and new-to-nature bioconjugates.