The redox-active Cu-FomA complex: the mode that provides coordination of CuII/CuI 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(-) reversible arrow 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(-) reversible arrow 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(-) reversible arrow 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.

Automated summary

Colorectal cancer is the third most commonly diagnosed form of cancer worldwide. Recent studies have shown a strong correlation between microbial imbalance and the development of colorectal cancer. An abundance of the bacterium Fusobacterium nucleatum has been identified as a biomarker for colorectal cancer progression. Furthermore, binding copper ions to bacterial proteins has been found to promote the production of reactive oxygen species, leading to colorectal carcinogenesis. This study investigated the molecular relation of copper with a protein expressed by Fusobacterium nucleatum and found that conditional dissociation constants and electrochemical activity affect the stability of copper complexes.