Following the electrons: peculiarities in the catalytic cycles of radical SAM enzymes

Radical SAM enzymes use S -adenosyl- l -methionine as an oxidant to initiate radical-mediated transformations that would otherwise not be possible with Lewis acid/base chemistry alone. These reactions are either redox neutral or oxidative leading to certain expectations regarding the role of SAM as either a reusable cofactor or the ultimate electron acceptor during each turnover. However, these expectations are frequently not realized resulting in fundamental questions regarding the redox handling and movement of electrons associated with these biological catalysts. Herein we provide a focused perspective on several of these questions and associated hypotheses with an emphasis on recently discovered radical SAM enzymes. Electrons do not always go where you expect them to in the catalytic cycles of radical SAM enzymes. Herein, a number of examples are considered along with potential avenues for future investigation.