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

Cobalt-corrins, such as coenzyme B12 (AdoCbl) and methylcobalamin (MeCbl), are indispensable enzyme-cofactors found across all kingdoms of life. Their Rh-homologues are promising coordination-chemical and structural B12-mimics. Herein, the preparation of methylrhodibalamin (MeRhbl) in over 90% yield is reported, achieved through template-assisted assembly from Rhβ-methylrhodibyrate and the B12-nucleotide. NMR and X-ray crystallography studies confirm that MeRhbl is iso-structural with the B12-cofactor MeCbl. The human B12-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 B12, making it a useful tool for biomedical applications. The B12-antimetabolite MeRhbl also acts as an effective growth inhibitor of the acne-causing bacterium Cutibacterium acnes.