title: Accessing Ni(III)-thiolate versus Ni(II)-thiyl bonding in a family of Ni-N2S2 synthetic models of NiSOD.
abstract: Superoxide dismutase (SOD) catalyzes the disproportionation of superoxide (O2(• -)) into H2O2 and O2(g) by toggling through different oxidation states of a first-row transition metal ion at its active site. Ni-containing SODs (NiSODs) are a distinct class of this family of metalloenzymes due to the unusual coordination sphere that is comprised of mixed N/S-ligands from peptide-N and cysteine-S donor atoms. A central goal of our research is to understand the factors that govern reactive oxygen species (ROS) stability of the Ni-S(Cys) bond in NiSOD utilizing a synthetic model approach. In light of the reactivity of metal-coordinated thiolates to ROS, several hypotheses have been proffered and include the coordination of His1-Nδ to the Ni(II) and Ni(III) forms of NiSOD, as well as hydrogen bonding or full protonation of a coordinated S(Cys). In this work, we present NiSOD analogues of the general formula [Ni(N2S)(SR')](-), providing a variable location (SR' = aryl thiolate) in the N2S2 basal plane coordination sphere where we have introduced o-amino and/or electron-withdrawing groups to intercept an oxidized Ni species. The synthesis, structure, and properties of the NiSOD model complexes (Et4N)[Ni(nmp)(SPh-o-NH2)] (2), (Et4N)[Ni(nmp)(SPh-o-NH2-p-CF3)] (3), (Et4N)[Ni(nmp)(SPh-p-NH2)] (4), and (Et4N)[Ni(nmp)(SPh-p-CF3)] (5) (nmp(2-) = dianion of N-(2-mercaptoethyl)picolinamide) are reported. NiSOD model complexes with amino groups positioned ortho to the aryl-S in SR' (2 and 3) afford oxidized species (2(ox) and 3(ox)) that are best described as a resonance hybrid between Ni(III)-SR and Ni(II)-(•)SR based on ultraviolet-visible (UV-vis), magnetic circular dichroism (MCD), and electron paramagnetic resonance (EPR) spectroscopies, as well as density functional theory (DFT) calculations. The results presented here, demonstrating the high percentage of S(3p) character in the highest occupied molecular orbital (HOMO) of the four-coordinate reduced form of NiSOD (NiSODred), suggest that the transition from NiSODred to the five-coordinate oxidized form of NiSOD (NiSODox) may go through a four-coordinate Ni-(•)S(Cys) (NiSODox-Hisoff) that is stabilized by coordination to Ni(II).
authors.affiliation: †Department of Chemistry and Center for Metalloenzyme Studies, The University of Georgia, 1001 Cedar Street, Athens, Georgia 30602, United States.
authors.forename: Ellen P
authors.initials: EP
authors.lastname: Broering
authors.affiliation: ‡Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dillon
authors.affiliation: †Department of Chemistry and Center for Metalloenzyme Studies, The University of Georgia, 1001 Cedar Street, Athens, Georgia 30602, United States.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Gale
authors.affiliation: †Department of Chemistry and Center for Metalloenzyme Studies, The University of Georgia, 1001 Cedar Street, Athens, Georgia 30602, United States.
authors.forename: Ramsey A
authors.initials: RA
authors.lastname: Steiner
authors.affiliation: §Department of Biological, Chemical and Physical Sciences, Roosevelt University, 430 South Michigan Avenue, Chicago, Illinois 60605, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Telser
authors.affiliation: ‡Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Brunold
authors.affiliation: †Department of Chemistry and Center for Metalloenzyme Studies, The University of Georgia, 1001 Cedar Street, Athens, Georgia 30602, United States.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Harrop
mesh_terms: D008958:Models, Molecular; D015394:Molecular Structure; D009532:Nickel / Q000737:chemistry / Q000378:metabolism*; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D009942:Organometallic Compounds; D013438:Sulfhydryl Compounds; D009532:Nickel; D013482:Superoxide Dismutase
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