Accessing Ni(III)-thiolate versus Ni(II)-thiyl bonding in a family of Ni-N2S2 synthetic models of NiSOD.

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).

Synthetic analogues of nickel superoxide dismutase: a new role for nickel in biology.

Nickel-containing superoxide dismutases (NiSODs) represent a novel approach to the detoxification of superoxide in biology and thus contribute to the biodiversity of mechanisms for the removal of reactive oxygen species (ROS). While Ni ions play critical roles in anaerobic microbial redox (hydrogenases and CO dehydrogenase/acetyl coenzyme A synthase), they have never been associated with oxygen metabolism. Several SODs have been characterized from numerous sources and are classified by their catalytic metal as Cu/ZnSOD, MnSOD, or FeSOD. Whereas aqueous solutions of Cu(II), Mn(II), and Fe(II) ions are capable of catalyzing the dismutation of superoxide, solutions of Ni(II) are not. Nonetheless, NiSOD catalyzes the reaction at the diffusion-controlled limit (~10(9) M(-1) s(-1)). To do this, nature has created a Ni coordination unit with the appropriate Ni(III/II) redox potential (~0.090 V vs Ag/AgCl). This potential is achieved by a unique ligand set comprised of residues from the N-terminus of the protein: Cys2 and Cys6 thiolates, the amino terminus and imidazole side chain of His1, and a peptide N-donor from Cys2. Over the past several years, synthetic modeling efforts by several groups have provided insight into understanding the intrinsic properties of this unusual Ni coordination site. Such analogues have revealed information regarding the (i) electrochemical properties that support Ni-based redox, (ii) oxidative protection and/or stability of the coordinated CysS ligands, (iii) probable H(+) sources for H(2)O(2) formation, and (iv) nature of the Ni coordination geometry throughout catalysis. This review includes the results and implications of such biomimetic work as it pertains to the structure and function of NiSOD.