From Synthetic to Biological Fe4S4 Complexes: Redox Properties Correlated to Function of Radical S‐Adenosylmethionine Enzymes

By employing the computational protocol for calculation of reduction potentials of the Fe4S4‐containing species validated using a representative series of well‐defined synthetic complexes, we focused on redox properties of two prototypical radical SAM enzymes to reveal how they transform SAM into the reactive 5’‐deoxyadenosyl radical, and how they tune this radical for its proper biological function. We found the reduction potential of SAM is indeed elevated by 0.3–0.4 V upon coordination to Fe4S4, which was previously speculated in the literature. This makes a generation of 5’‐deoxyadenosyl radical from SAM less endergonic (by ca. 7–9 kcal mol−1) and hence more feasible in both enzymes as compared to the identical process in water. Furthermore, our calculations indicate that the enzyme‐bound 5’‐deoxyadenosyl radical has a significantly lower reduction potential than in referential aqueous solution, which may help the enzymes to suppress potential side redox reactions and simultaneously elevate its proton‐philic character, which may, in turn, promote the radical hydrogen‐atom ion ability. Radically different: Computational electrochemistry was used to elucidate the redox properties of the active sites of two prototypical radical SAM enzymes, including redox and related acidobasic properties of the reactive intermediate with the 5’‐deoxyadenosyl radical responsible for a substrate attack. Namely, the reduction potential of SAM is elevated upon coordination to Fe4S4, making the generation of 5’‐deoxyadenosyl radical from SAM less endergonic, while the radical has a significantly lower reduction potential than in referential aqueous solution, which may help the enzymes to suppress potential side redox reactions.