Journal Article

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

Ruetz, Markus, Kieninger, Christoph, Kreutz, Christoph, Warren, Martin J., Wurst, Klaus, Kräutler, Bernhard, Widner, Florian J., Deery, Evelyne, Paxhia, Michael D.

2025

Overview

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. Replacement of cobalt in the organometallic B12‐cofactor methylcobalamin (MeCbl) by rhodium furnishes a structural mimic with a significantly stronger metal–carbon bond. This synthetically challenging formal metal‐mutation converts the naturally optimized biological methyl‐transfer catalyst MeCbl into a designed antivitamin B12, an inactivated B12‐surrogate with promising applications as a fundamental growth‐inhibitor for B12‐dependent organisms.

• Publisher: Wiley-VCH
• Subject: crystal structures / enzyme inhibitors / growth inhibitors / organometallic catalysts / vitamin B12