Heterobimetallic cofactors (i.e., a metal complex having two different metal atoms) have been discovered in a number of proteins responsible for life-sustaining chemical transformations. Since their discovery, heterobimetallic cofactors have piqued the interest of chemists and biologists alike because an understanding of the mechanisms behind metallocofactor assembly can aid in answering important questions regarding protein evolution and metal selectivity in native and engineered proteins. The most intriguing heterobimetallic cofactors are those that incorporate MnII and FeII, two metal ions of similar size and binding affinity, with apparent selectivity. So a great deal of scientific attention has been paid to the mechanism of heterobimetallic MnIIFeII cofactor assembly in vivo. Despite the valuable insights into the selective formation of MnIIFeII cofactors obtained via in vivo studies, comprehensive information about the protein structural features responsible for this cofactor assembly process has been difficult to come by.

The authors of this study report structural information of the first synthetic MnIIFeII complex. Synchrotron anomalous x-ray diffraction studies carried out with the advanced crystallography instrument of the NSF’s ChemMatCARS facility at Sector 15 of the Argonne Advanced Photon Source confirmed that the MnIIFeII model complex has the same site selectivity as R2lox and RNRIc, where MnII occupies the octahedral site and FeII occupies the distorted site. The structural similarities of the researcher’s model complex to R2lox and RNRIc, along with the same metal site selectivity, yield a proposed mechanism for heterobimetallic MnIIFeII formation that does not contradict the classical Irving−Williams series, which refers to the exchange of aqua (H2O) ligands for any other ligand within a metal complex. The authors note that their model study provides an alternative explanation as to why R2lox and RNRIc appear to be violating the fundamental thermodynamic rules governing coordination chemistry, and that this hypothesis is also consistent with the observation that the intracellular availability of metal ions plays a role in metal selection. Beyond correct cofactor formation, the authors believe that site differentiation likely has implications toward oxidative reactivity, as observed in R2lox.

Anna L. Poptic, Ying-Pin Chen, Tieyan Chang, Yu-Sheng Chen, Curtis E. Moore, and Shiyu Zhang, “Site-Differentiated MnIIFeII Complex Reproducing the Selective Assembly of Biological Heterobimetallic Mn/Fe Cofactors,” J. Am. Chem. Soc. 2023, 145, 3491−3498. https://doi.org/10.1021/jacs.2c11930

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