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We present here the most active synthetic Ni superoxide dismutase (NiSOD) mimic reported to date. Reactive oxygen species are aggressive compounds, which concentrations are tightly regulated in vivo. Among them, the superoxide anion, O2⋅−, is controlled by superoxide dismutases. Capitalizing on the versatility of the Amino‐Terminal CuII‐ and NiII‐binding (ATCUN) peptide motif, we introduced positive charges around the NiII center to favor the interaction with the superoxide radical anion. At physiological pH, the pentapeptide H−Cys−His−Cys−Arg−Arg−NH2 coordinates NiII after the deprotonation of one thiol, two amides, and either the second thiol or the N‐terminal ammonium, leading to an equilibrium between the two N3S1 and N2S2 coordination modes. Under catalytic conditions, a kcat value of 8.6(4)×106 L.mol−1.s−1 was measured. Within the first second, the catalyst remained undegraded with quantitative consumption of O2⋅− (completed up to 37 catalytic cycles). An extra arginine (Arg) was introduced at the peptide C‐terminus to increase the global charge of the NiII complex from +1 to +2. This had no effect on the catalytic performance, highlighting the critical role of charge distribution in space as a determining factor influencing the reactivity. [ABSTRACT FROM AUTHOR]

Nickel superoxide dismutase (NiSOD) is an enzyme that protects cells against O 2 · - . While the structure of its active site is known, the mechanism of the catalytic cycle is still not elucidated. Its active site displays a square planar Ni II center with two thiolates, the terminal amine and an amidate. We report here a bioinspired Ni II complex built on an ATCUN-like binding motif modulated with one cysteine, which demonstrates catalytic SOD activity in water ( k cat = 8.4(2) × 10 5 M -1 s -1 at pH = 8.1). Its reactivity with O 2 · - was also studied in acetonitrile allowing trapping two different short-lived species that were characterized by electron paramagnetic resonance or spectroelectrochemistry and a combination of density functional theory (DFT) and time-dependent DFT calculations. Based on these observations, we propose that O 2 · - interacts first with the complex outer sphere through a H-bond with the peptide scaffold in a [Ni II O 2 · - ] species. This first species could then evolve into a Ni III hydroperoxo inner sphere species through a reaction driven by protonation that is thermodynamically highly favored according to DFT calculations.