The isostructural rhodium analog of coenzyme B12 functions as an anti-photoregulatory ligand of CarH photoreceptors and yields structural insights into the puzzling nonradical photochemical mechanism of these photoreceptors.
Coenzyme B12 (5′-deoxy-5′-adenosylcobalamin or AdoCbl) is the quintessential biological organometallic cofactor in radical-based enzymatic reactions of exceptional efficiency and versatility. A once unanticipated nonenzymatic biological function of AdoCbl is its role as the chromophore of the CarH photoreceptor family, with members widespread across bacteria. CarH photoreceptors sense and respond to UV, blue or green light, and their unique properties have inspired exciting applications in optogenetics, synthetic biology, smart materials, and catalysis. AdoCbl modulates CarH oligomerization and its DNA binding to repress gene expression in the dark. Light disrupts CarH oligomers and their DNA binding to activate gene expression. Moreover, CarH alters the typical AdoCbl photochemistry to release a non-radical product in lieu of the highly reactive Ado radical that underpins AdoCbl role as an enzyme cofactor. Despite considerable efforts, the non-radical CarH photochemical mechanism has remained puzzling and the object of ongoing debate. In work directed by Prof. S. Padmanabhan/Padhu (Institute of Physical Chemistry Blas Cabrera; IQF-CSIC) and Prof. Montserrat Elías Arnanz (University of Murcia; IQF-CSIC Associated Unit) together with Prof. Bernhard Kräutler (University of Innsbruck, Austria), with valuable computational support from Prof. Modesto Orozco´s group (Institute for Research in Biomedicine, IRB Barcelona), the engineered non-natural rhodium analogue (AdoRhbl) of coenzyme B12 was studied as an isostructural AdoCbl surrogate in CarH function. AdoRhbl closely emulates AdoCbl in uptake by bacterial cells and in driving CarH tetramerization, DNA binding, and repressor activity, but inhibits photoregulation by CarH in vitro and in vivo. The study provides structural insights into the mysterious CarH-mediated non-radical AdoCbl photochemical mechanism, and reveals AdoRhbl as an “anti-photoregulatory” ligand that may open new possibilities for selective antibacterial applications. Published in Angewandte Chemie International Edition (Angew Chem Int Ed Engl. 2024 Apr 24; 63(18): e202401626. doi: 10.1002/anie.202401626)
