Biomimetic S-adenosylmethionine regeneration for nucleophilic and radical alkylation reactions and aminopropyltransfer

S-Adenosylmethionine (SAM) is an essential and versatile cofactor in nature. SAM-dependent enzymes, such as conventional methyltransferases (MTs), amino(carboxy)propyl transferases, and radical SAM enzymes, are of great interest as biocatalytic tools for chemical synthesis and the pharmaceutical industry. The use of SAM analogues adds to the diversity of reaction types and products. While SAM regeneration protocols for conventional MTs are available, in vitro SAM regeneration for polyamine-forming enzymes and radical SAM enzymes has not been solved yet. Here, we report a biomimetic cofactor regeneration cycle for three important types of SAM dependent enzymes featuring adenine as a central intermediate. SAM is regenerated from its main degradation products, S-adenosylhomocysteine, 5′ methylthioadenosine, and 5′-deoxyadenosine. We further show the chemical diversification of the system using SAM analogues such as S-adenosylethionine for MT reactions. Interestingly, the enzyme cascades also enable the transfer of an ethyl group with a cobalamin-dependent radical SAM MT. The possibility to regenerate SAM (analogues) for biocatalytic use with a broad range of enzymes will be a starting point for further application of the diverse chemistry accessible by SAM-based catalysis, as well as provide new options for mechanistic studies. ### Competing Interest Statement The authors have declared no competing interest.