Spin‐Regulated Electron Transfer and Exchange‐Enhanced Reactivity in Fe4S4‐Mediated Redox Reaction of the Dph2 Enzyme During the Biosynthesis of Diphthamide.

The [4Fe‐4S]‐dependent radical S‐adenosylmethionine (SAM) proteins is one of large families of redox enzymes that are able to carry a panoply of challenging transformations. Despite the extensive studies of structure–function relationships of radical SAM (RS) enzymes, the electronic state‐dependent reactivity of the [4Fe‐4S] cluster in these enzymes remains elusive. Using combined MD simulations and QM/MM calculations, we deciphered the electronic state‐dependent reactivity of the [4Fe‐4S] cluster in Dph2, a key enzyme involved in the biosynthesis of diphthamide. Our calculations show that the reductive cleavage of the S−C(γ) bond is highly dependent on the electronic structure of [4Fe‐4S]. Interestingly, the six electronic states can be classified into a low‐energy and a high‐energy groups, which are correlated with the net spin of Fe4 atom ligated to SAM. Due to the driving force of Fe4−C(γ) bonding, the net spin on the Fe4 moiety dictate the shift of the opposite spin electron from the Fe1‐Fe2‐Fe3 block to SAM. Such spin‐regulated electron transfer results in the exchange‐enhanced reactivity in the lower‐energy group compared with those in the higher‐energy group. This reactivity principle provides fundamental mechanistic insights into reactivities of [4Fe‐4S] cluster in RS enzymes. [ABSTRACT FROM AUTHOR]