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

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-NH 2 ) 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 K condD 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.