S-Adenosylmethionine-dependent alkylation reactions: When are radical reactions used?

S-Adenosylmethionine (SAM) is a versatile small molecule used in many biological reactions. This review focuses on the mechanistic consideration of SAM-dependent methylation and 3-amino-3-carboxypropylation reactions. Special emphasis is given to methylation and 3-amino-3-carboxypropylation of carbon atoms, for which both nucleophilic mechanisms and radical mechanisms are used, depending on the specific enzymatic reactions. What is the logic behind Nature’s choice of different reaction mechanisms? Here I aim to rationalize the choice of different reaction mechanisms in SAM-dependent alkylation reaction by analyzing a few enzymatic reactions in depth. These reactions include SAM-dependent cyclopropane fatty acid synthesis, DNA cytosine methylation, RNA adenosine C2 and C8 methylation, and 3-amino-3-carboxypropylation involved in diphthamide biosynthesis and wybutosine biosynthesis.

Graphical abstractThe logic behind Nature’s choice of different chemistry in SAM-dependent alkylation reactions is analyzed.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Enzymatic reaction mechanisms for SAM-dependent alkylation reactions are discussed. ► Focus on alkylation of carbon atoms, for which both polar and radical mechanisms are used. ► The choice of polar or radical mechanism is rationalized. ► The rationalization could help to predict mechanisms of new SAM-dependent alkylation reactions.