The rhodium analogue of Coenzyme B 12 as an anti‐photoregulatory ligand inhibiting bacterial CarH photoreceptors

Coenzyme B12 (AdoCbl; 5′‐deoxy‐5′‐adenosylcobalamin), the quintessential biological organometallic radical catalyst, has a formerly unanticipated, yet extensive, role in photoregulation in bacteria. The light‐responsive cobalt‐corrin AdoCbl performs this nonenzymatic role by facilitating the assembly of CarH photoreceptors into DNA‐binding tetramers in the dark, suppressing gene expression. Conversely, exposure to light triggers the decomposition of this AdoCbl‐bound complex by a still elusive photochemical mechanism, activating gene expression. Here, we have examined AdoRhbl, the non‐natural rhodium analogue of AdoCbl, as a photostable isostructural surrogate for AdoCbl. We show that AdoRhbl closely emulates AdoCbl in its uptake by bacterial cells and structural functionality as a regulatory ligand for CarH tetramerization, DNA binding, and repressor activity. Remarkably, we find AdoRhbl is photostable even when bound “base‐off/His‐on” to CarH in vitro and in vivo. Thus, AdoRhbl, an antivitamin B12, also represents an unprecedented anti‐photoregulatory ligand, opening a pathway to precisely target biomimetic inhibition of AdoCbl‐based photoregulation, with new possibilities for selective antibacterial applications. Computational biomolecular analysis of AdoRhbl binding to CarH yields detailed structural insights into this complex, which suggest that the adenosyl group of photoexcited AdoCbl bound to CarH may specifically undergo a concerted non‐radical syn‐1,2‐elimination mechanism, an aspect not previously considered for this photoreceptor.