The cobalamin-binding domain of cobalamin-dependent radical S-adenosylmethionine enzymes: Familiarity in unfamiliar places.

Cobalamin (Cbl)-dependent Radical S-adenosylmethionine (RS) enzymes are well known for their use of two powerful cofactors to catalyze chemically challenging reactions, such as methylations on unactivated carbons and phosphorus centers, ring contractions, ring formations, and thioether bond formations. Our repertoire of Cbl-dependent RS enzyme structures has grown since the first solved structure of the oxetanocin A biosynthetic enzyme OxsB in 2017, which has provided insight into the structural basis of catalysis. In particular, the Cbl-binding domains of these RS enzymes have been found to have interesting structural variations that seem to correlate with enzymatic function, at least for the small number of enzymes that have been characterized. In this review, we highlight the recent research about the Cbl cofactor in Cbl-dependent RS enzymes. We compare modes of Cbl binding and demonstrate a previously undetected connection between a subgroup of Cbl-dependent RS enzymes and the corrinoid iron‑sulfur protein (CFeSP) from the Wood-Ljungdahl pathway of reductive acetogenesis. Additionally, we discuss recent mechanistic findings on Cbl-dependent RS enzymes OxsB and its close homolog AlsB, which have not been recently reviewed. As Cbl-dependent RS enzymes are involved in making antiviral and antibiotic compounds, herbicides, and other molecules of value, understanding and manipulating enzyme activity has implications in both medicine and agriculture.