Novel chemistry and structural perspectives in vitamin B₁₂-dependent radical SAM enzymes

Vitamin B₁₂ is one of the most complex vitamins and an essential cofactor for humans, but also for bacteria, which have evolved different strategies for its biosynthesis and acquisition. For decades, vitamin B₁₂ has been mainly assumed to be a source of nucleophilic methyl groups and radical initiators, in the forms of methyl-cobalamin and adenosyl-cobalamin. Recently, the importance and the chemical versatility of vitamin B₁₂ have been reconsidered in light of the emergence of the superfamily of radical SAM enzymes. In this review, we provide an overview of vitamin B₁₂, its role, and its diversity within the human microbiota, and in the emerging family of B₁₂-dependent radical SAM enzymes. We focus on the diversity of B₁₂-dependent radical SAM enzymes from a mechanistic and structural perspective, along with their potential evolutionary links to other B₁₂-dependent enzymes.