Insight into the Structure and Mechanism of Nickel-Containing
Superoxide Dismutase Derived from Peptide-Based Mimics
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Abstract
ConspectusNickel superoxide dismutase (NiSOD) is a nickel-containing metalloenzyme
that catalyzes the disproportionation of superoxide through a ping-pong
mechanism that relies on accessing reduced Ni(II) and oxidized Ni(III)
oxidation states. NiSOD is the most recently discovered SOD. Unlike
the other known SODs (MnSOD, FeSOD, and (CuZn)SOD), which utilize
“typical” biological nitrogen and oxygen donors, NiSOD
utilizes a rather unexpected ligand set. In the reduced Ni(II) oxidation
state, NiSOD utilizes nitrogen ligands derived from the N-terminal
amine and an amidate along with two cysteinates sulfur donors. These
are unusual biological ligands, especially for an SOD: amine and amidate
donors are underrepresented as biological ligands, whereas cysteinates
are highly susceptible to oxidative damage. An axial histidine imidazole
binds to nickel upon oxidation to Ni(III). This bond is long (2.3–2.6
Å) owing to a tight hydrogen-bonding network.All of the
ligating residues to Ni(II) and Ni(III) are found within
the first 6 residues from the NiSOD N-terminus. Thus, small nickel-containing
metallopeptides derived from the first 6–12 residues of the
NiSOD sequence can reproduce many of the properties of NiSOD itself.
Using these nickel-containing metallopeptide-based NiSOD mimics, we
have shown that the minimal sequence needed for nickel binding and
reproduction of the structural, spectroscopic, and functional properties
of NiSOD is H<sub>2</sub>N-HCXXPC.Insight into how NiSOD avoids
oxidative damage has also been gained.
Using small NiN<sub>2</sub>S<sub>2</sub> complexes and metallopeptide-based
mimics, it was shown that the unusual nitrogen donor atoms protect
the cysteinates from oxidative damage (both one-electron oxidation
and oxygen atom insertion reactions) by fine-tuning the electronic
structure of the nickel center. Changing the nitrogen donor set to
a bis-amidate or bis-amine nitrogen donor led to catalytically nonviable
species owing to nickel–cysteinate bond oxidative damage. Only
the amine/amidate nitrogen donor atoms within the NiSOD ligand set
produce a catalytically viable species.These metallopeptide-based
mimics have also hinted at the detailed
mechanism of SOD catalysis by NiSOD. One such aspect is that the axial
imidazole likely remains ligated to the Ni center under rapid catalytic
conditions (i.e., high superoxide loads). This reduces the degree
of structural rearrangement about the nickel center, leading to higher
catalytic rates. Metallopeptide-based mimics have also shown that,
although an axial ligand to Ni(III) is required for catalysis, the
rates are highest when this is a weak interaction, suggesting a reason
for the long axial His–Ni(III) bond found in NiSOD. These mimics
have also suggested a surprising mechanistic insight: O<sub>2</sub><sup>–</sup> reduction via a “H<sup>•</sup>”
tunneling event from a R–S(H<sup>+</sup>)–Ni(II) moiety
to O<sub>2</sub><sup>–</sup> is possible. The importance of
this mechanism in NiSOD has not been verified