Molecular Playground/Nickel Superoxide Dismutase

Nickel superoxide dismutase (NiSOD) is one of the CBI Molecules being studied in the University of Massachusetts, Amherst Chemistry-Biology Interface Program at Umass Amherst and on display at the Molecular Playground.

Introduction

Nickel Superoxide Dismutase (NiSOD) is the newest member in a class of enzymes that protects organisms from oxidative stress caused by superoxide, a harmful free radical byproduct of aerobic metabolism. NiSOD reacts with two molecules of superoxide, to form O₂ and H₂O₂ with rates occurring at or near the diffusion limit. During catalysis, the redox-active nickel center cycles between an oxidized and reduced state. This reaction is termed the ping pong mechanism and is shown below.

M^{(n + 1)} + O₂^•- → Mⁿ⁺ + O₂

Mⁿ⁺ + O₂^•- + 2H⁺ → M^{(n + 1)} + H₂O₂
—————————————————

2O₂^•- + 2H⁺ → O₂ + H₂O₂

NiSOD is unique among SOD's for a variety of reasons.
NiSOD shares no sequence homology with the other known SOD's (Fig. 1).^[1]-[2] Copper, iron, and manganese SOD are redox active in aqueous media at biological pH. Nickel is not, and requires the coordination of the two cysteine ligands to tune its redox potential, which is estimated to lie above 2 eV, far outside the biologically relevant redox potential necessary to oxidize or reduce superoxide [-160 to +879 eV].^[3] The ligands employed in the redox-active metal center are distinct. Cu/Zn, Fe, and MnSOD employ only aspartic acids, waters, and histidines.^[4], ^[5], ^[6] In NiSOD, the nickel center is coordinated by the side chains of cysteine 2 and cysteine 6, as well as the N-terminal amine, the amide group of cysteine 2 and an axial histidine ligand (Fig. 1).
See also Superoxide Dismutase.

Fig. 1: Active site structures of the four known SOD's.

NiSOD Structure

NiSOD is a homohexamer (Fig. 2) composed of a dimer of trimers and binds one nickel ion per monomer. The residues coordinated to the nickel active site are located within the first six N-terminal amino acids, termed the nickel-hook. The nickel in the active site cycles between Ni(II) and Ni(III). In the Ni(II) state the nickel has a square planar geometry and is coordinated by the side chains of Cys2 and Cys5 as well as the N-terminal amine and the backbone amide group of Cys2. When oxidized to Ni(III), the imidazole group of His1 binds in the axial position forming a square pyramidal geometry.

Fig. 2: Hexameric NiSOD. Figure created with PyMol. PDB ID 1t6u.

Research Interests

The | Maroney Lab is currently investigating the details of the NiSOD catalytic mechanism, including how the enzyme maintains its nickel active sites at 50% Ni(II)/Ni(III) equilibrium despite strong oxidation. In addition, efforts are currently underway to characterize a previously observed intermediate.