Radical SAM enzymes are arguably the largest and most functionally diverse enzyme superfamily with more than 500,000 enzymes predicted to be involved in more than 80 different types of biochemical transformations. These metalloenzymes catalyze chemically challenging reactions some of them having no counterpart in synthetic chemistry. Among them, the B12-dependent radical SAM enzymes are one of the major groups. They have been shown to catalyze diverse reactions including methyl transfer or ring formation in the biosynthesis of various natural products such as antibiotics and bacteriochlorophyll. The main objective of the Cob4SAM project is to obtain an integrated mechanistic and structural view of these emerging biocatalysts by investigating key representative B12-dependent radical SAM enzymes and combining advanced biochemical, spectroscopic and structural approaches.