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

Abstract

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 CuII + e- ⇄ CuI 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 CuII + e- ⇄ CuI equilibrium. A linear peptide Fom1 (Ac-KGHGNGEEGTPTVHNE-NH2) and cyclic peptide Fom2 (cyclo-(KGHGNGEEGTPTVHNE)) were used as ligands. The coordination of CuI was deduced from the NMR data. The conditional dissociation constants KcondD defined the stability of CuI complexes. The electrochemical activity of CuII and CuI compounds was analysed using cyclic voltammetry. A quasi-reversible redox conversion CuII-peptide + e- ⇄ CuI-peptide was revealed for all studied systems. In the presence of ascorbic acid (HAsc), CuII complexes were immediately reduced to CuI 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 CuII ion to its initial binding site. The toxicity of the FomA-CuII/CuI complexes and their role in CRC progression were briefly discussed.