Cu/Zn/histidine supramolecular assemblies with optimized Cu catalytic sites as an alternative of superoxide dismutase

Superoxide dismutase (SOD), featured with unique metal catalytic sites, is the first defense against reactive oxygen species (ROS) damage in vivo and well used in the treatment of oxidative stress-related diseases. However, the catalytic activity of natural SOD is limited by the metal ion coordination with rigid amino-acid residues. Inspired by the Cu2+/histidine residue coordination in Cu-Zn-SOD, in this work, the Gibbs free energy change of the break/reform of coordination bonds in the tetracoordinated structure formed by Cu2+ and different groups in histidine is calculated, which reveals that in comparison to the Cu catalytic site coordinated with four imidazolyls, the coordination with one amino, one carboxyl and two imidazolyls possesses the lowest overall energy as well as the lowest breaking energy of one of the coordination bonds. Thus, catalytic site stability and catalytic reaction activity can be balanced sufficiently. Accordingly, the as-prepared Cu/Zn/histidine (CuZnHis) supramolecular assemblies with optimized Cu catalytic site present a significantly enhanced SOD activity up to 37900 Unit/mg, which is at least 5.4 times higher than that of natural Cu-Zn-SOD. As a proof of concept in treating oxidative stress-related diseases, the CuZnHis assemblies promote macrophage polarization from M1 to M2 phenotype and the expression of anti-inflammatory factors, and inhibit the periodontitis in male animal models. Superoxide dismutase (SOD) is an enzyme that eliminates reactive oxygen species and is used in the treatment of oxidative stress-related diseases, but its catalytic activity is constrained by the metal ion coordination with rigid amino-acid residues. Here, the authors report Cu/Zn/histidine supramolecular assemblies with optimized Cu catalytic site and SOD activity up to 37900 Unit/mg, which is at least 5.4 times higher than that of natural Cu-Zn-SOD.