Organic syntheses: new chemistry challenges dogma

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Enzymes are highly specific tools of nature which allow chemical reactions to take place under mild conditions and with impressive precision. Transferases are a class of enzymes that transfer carbon chains, so-called alkyl groups, to target molecules. Before now, two major transferase types – methyltransferases and prenyltransferases – have been considered separate enzyme classes, as they transfer alkyl groups of different lengths (with one and five carbon atoms respectively, C₁ and C₅₎ and utilize different cofactors.

A team led by Professor Andrea Rentmeister from the Department of Chemistry at LMU has developed a hybrid cofactor that combines features of both systems (S-Adenosyl-L-methionine (SAM) and dimethylallyl diphosphate (DMAPP)). As the researchers report in the journal Chem, the new hybrid cofactor thus permits a broader range of applications. The chimeric compound is accepted surprisingly well by a wide variety of methyltransferases and predominantly leads to so-called prenylation – that is to say, the transfer of larger alkyl groups.

Chemical methods of alkylation are not selective enough

Regarding the background, Rentmeister explains: “Alkylation is an important strategy for influencing chemical and biological properties of small molecules, lipids, nucleic acids, and proteins. Strategies for selective alkylation are therefore extremely important for research and applications.”

Although it is possible to chemically alkylate biomolecules – using compounds such as alkyl halogenides – such reactions are not very selective, which is problematic in the case of complex molecules. By contrast, alkylating enzymes – the biological route, as it were – have proven to be highly selective.

When researchers have wanted to transfer prenyl groups to biomolecules using biotechnological means, the only option available to them has been prenyltransferases. The current research by Rentmeister’s team creates new possibilities. First, the scientists built a chimeric cofactor. “We managed to demonstrate that a cofactor chimera of DMAPP and AdoMet makes methyltransferases act as prenyl-transferring enzymes,” says Rentmeister. The researchers exploited the circumstance that the basic chemical reaction is the same independently of the length of the alkyl residue to be transferred and differs only by dint of the cofactor of the enzymes.

Methyltransferases, which ordinarily transfer methyl groups to molecules, did likewise with prenyl groups with the same specificity in the presence of the chimeric cofactor AdoPrenyl. Rentmeister’s team showed that with modified cofactors it is possible to connect, for example, chains containing 10 or 15 carbon atoms to various biomolecules.

New avenues for basic research and applications

Most notably: “The demonstration that naturally occurring methyltransferases can transfer prenyl groups contradicts the prevailing textbook opinion of a strict separation between C₁- and C₅-transferring enzyme classes,” says the scientist. This has delivered a blow to a fundamental dogma of enzyme chemistry – and opened up new questions about the underlying reaction mechanisms.

Rentmeister thinks the new principle could have promising applications in the field of protein chemistry. The targeted modification of proteins with longer-chained alkyl groups can change their biological activity and their localization in the cell or influence their recognition by other molecules. This makes alkylation an important tool in biotechnology, medicine, and pharmacy.

Nicolas V. Cornelissen, Arne Hoffmann, Pulak Ghosh, Yanis L. Pignot, Mehmet Erguven, Andrea Rentmeister: Chimeric cofactors enable methyltransferase-catalyzed prenylation. Chem, 2025