Title: Toward Functional Ni-SOD Biomimetics: Achieving a Structural/Electronic Correlation with Redox Dynamics
Authors: Eric M. Gale†, Andrew C. Simmonett†, Joshua Telser‡, Henry F. Schaefer, III†, and Todd C. Harrop*†
Journal: Inorganic Chemistry
Affiliation: Department of Chemistry and Center for Computational Chemistry, The University of Georgia
Department of Biological, Chemical and Physical Sciences, Roosevelt University
Superoxide is a radical species generated by the one-electron reduction of oxygen. These species form in aerobic organisms and are regulated by a class of enzymes called superoxide dismutases (SODs) which use metals to disproportionate superoxide into oxygen and hydrogen peroxide. Ni-SODs are an unusual type of SOD which uses nickel for its function. In this communication, the authors discuss the development of a new model for the active site of Ni-SOD. Their model strongly mimics the structure and electronic properties of the reduced state of Ni-SOD.
The coordination sphere of the nickel in the active site of Ni-SOD features a primary amine, a deprotonated amide, and two thiolates forming a square-planar configuration. In addition, an imidazole group from the histidine residue does not coordinate nickel when it is in the reduced state (NiII), but coordinates upon oxidation to NiIII. In the author’s model, the coordination sphere of the reduced state is strongly mimicked, with the same type of ligands about the nickel (two thiolates, deprotonated amide, and amine). Further, a dangling pyridine remains uncoordinated, similar to the imidazole in the biological system.
With a good mimic for the NiII state of the active site, the next step is to explore the electronic properties of the complex. Bulk oxidation with ferrocenium produced a dimeric compound from the formation of a disulfide bond between two thiolates previously bound trans to the carboxamido ligand. Although the product is not a pentacoordinate NiIII complex as in the enzyme, it shows that part of the function of the bulk protein environment around the active site prevents oxidation of the thiolates to form disulfide bridges.
To probe the mechanism of the oxidation, electron paramagnetic resonance (EPR) was used (in a brief summary, EPR detects unpaired electrons). Signals for a thiyl (S) radical and another likely to be from NiIII was observed. This supports their proposed mechanism where NiII is first oxidized to NiIII, forming a square-pyramidal structure. Afterwards, the thiolate is oxidized by NiIII and a bimolecular step combines two thiyl radical species to form the observed dimer. The disulfide bond was also shown to be broken with reduction with decamethylcobaltacene.
In summary, the authors synthesized the first mimic for Ni-SODred that matches the structural and electronic features of the enzyme. More details (including DFT calculations) are included in their communication.