Aldehydes release zinc from proteins. A pathway from oxidative stress/lipid peroxidation to cellular functions of zinc

Abstract

Oxidative stress, lipid peroxidation, hyperglycemia-induced glycations and environmental exposures increase the cellular concentrations of aldehydes. A novel aspect of the molecular actions of aldehydes, e.g. acetaldehyde and acrolein, is their reaction with the cysteine ligands of zinc sites in proteins and concomitant zinc release. Stoichiometric amounts of acrolein release zinc from zinc-thiolate coordination sites in proteins such as metallothionein and alcohol dehydrogenase. Aldehydes also release zinc intracellularly in cultured human hepatoma (HepG2) cells and interfere with zinc-dependent signaling processes such as gene expression and phosphorylation. Thus both acetaldehyde and acrolein induce the expression of metallothionein and modulate protein tyrosine phosphatase activity in a zinc-dependent way. Since minute changes in the availability of cellular zinc have potent effects, zinc release is a mechanism of amplification that may account for many of the biological effects of aldehydes. The zinc-releasing activity of aldehydes establishes relationships among cellular zinc, the functions of endogenous and xenobiotic aldehydes, and redox stress, with implications for pathobiochemical and toxicologic mechanisms.