B₁₂‐Cofactor Inactivation by Cobalt to Rhodium Mutation in Methylrhodibalamin: An Antivitamin B₁₂ and Antibiotic

Cobalt‐corrins, such as coenzyme B 12 (AdoCbl) and methylcobalamin (MeCbl), are indispensable enzyme‐cofactors found across all kingdoms of life. Their Rh‐homologues are promising coordination‐chemical and structural B 12 ‐mimics. Herein, the preparation of methylrhodibalamin (MeRhbl) in over 90% yield is reported, achieved through template‐assisted assembly from Rh β ‐methylrhodibyrate and the B 12 ‐nucleotide. NMR and X‐ray crystallography studies confirm that MeRhbl is iso‐structural with the B 12 ‐cofactor MeCbl. The human B 12 ‐tailoring enzyme CblC binds and activates MeRhbl, but Rh‐demethylation of MeRhbl is inhibited by its stable RhC bond, whose strength is also determined. Thus, MeRhbl meets the key criteria for a genuine antivitamin B 12 , making it a useful tool for biomedical applications. The B 12 ‐antimetabolite MeRhbl also acts as an effective growth inhibitor of the acne‐causing bacterium Cutibacterium acnes .