The redox-active Cu-FomA complex: the mode that provides coordination of Cu^II/Cu^I ions during the reduction/oxidation...

Colorectal cancer (CRC) is the third most commonly diagnosed form of cancer worldwide. Recent studies have indicated a strong correlation between microbial imbalance and the development of CRC. An abundance of Fusobacterium nucleatum, an anaerobic Gram-negative bacterium, has been considered a biomarker of CRC progression. Several investigations have also proposed that binding copper ions to various bacterial proteins enhances the Cu^II + e^- ⇄ Cu^I redox cycle, which consequently promotes uncontrolled production of reactive oxygen species (ROS) and propels colorectal carcinogenesis. In this work, a multidisciplinary approach was applied to study the molecular relation of copper with the peptide models of FomA, a protein expressed by Fusobacterium nucleatum. The main goal was to investigate all the factors that tune the Cu^II + e^- ⇄ Cu^I equilibrium. A linear peptide Fom1 (Ac-KGHGNGEEGTPTVHNE-NH₂) and cyclic peptide Fom2 (cyclo-(KGHGNGEEGTPTVHNE)) were used as ligands. The coordination of Cu^I was deduced from the NMR data. The conditional dissociation constants KcondD defined the stability of Cu^I complexes. The electrochemical activity of Cu^II and Cu^I compounds was analysed using cyclic voltammetry. A quasi-reversible redox conversion Cu^II-peptide + e^- ⇄ Cu^I-peptide was revealed for all studied systems. In the presence of ascorbic acid (HAsc), Cu^II complexes were immediately reduced to Cu^I species; however, their re-oxidation was kinetically sluggish. The HAsc-induced redox cycle provoked the metal-catalyzed oxidation (MCO) effect. That in the end prevented coordination of the re-appearing Cu^II ion to its initial binding site. The toxicity of the FomA-Cu^II/Cu^I complexes and their role in CRC progression were briefly discussed.