COPPER SELENO-METALLOCHAPERONES

Copper serves as an important catalytic cofactor in enzymes that perform fundamental biological functions. The ability of copper to readily switch between +1 and +2 oxidation states enables catalytic functionality in essential redox chemistry, but may also cause high toxicity by producing reactive oxygen species (ROS).

Copper metallochaperones and transporters are intracellular proteins that specifically bind Cu(I), inhibit their oxidation, and deliver them to the target proteins via protein-protein interactions, thus protecting the cellular environment from harmful copper-mediated reactions. The active sites of these proteins contain a conserved sequence: MH/TCXXC. Most of those proteins have been characterized by NMR and crystallography; however their mechanism of action is yet unclear.

Menkes disorder and Wilson disease are both caused by a genetic mutation at the Cu(I) ATPases ATP7a and ATP7b, respectively. Whereas Menkes disorder is a lethal disease, Wilson disease is a chronic one, due to chelation therapy by several clinically approved Cu(I) binding drugs. The most common compounds used today are D-penicillamine and trientine (TETA), both are not Cu(I) selective and induce severe side effects. This encourages the investigation of new potential therapeutic agents.

Previously, a group of peptides containing the conserved binding sequence MH/TCXXC of the copper metallochaperones were studied. The structures of some peptide-Cu(I) complexes were determined by NMR, which raised important questions about structure-function relationships.

Here we present the affinity, kinetics and biological activities of selenopeptide analogs of the conserved binding sequence MH/TCXXC of the copper metallochaperones, in which the Cysteine (Cys, C) residues have been replaced with Selenocysteine (Sec, U).