Cadmium – glutathione solution structures provide new insights into heavy metal detoxification

Abstract

Cadmium is a heavy metal and a pollutant that can be found in large quantities in the environment from industrial waste. Its toxicity for living organisms could arise from its ability to alter thiol‐containing cellular components. Glutathione is an abundant tripeptide (γ‐Glu‐Cys‐Gly) that is described as the first line of defence against cadmium in many cell types. NMR experiments for structure and dynamics determination, molecular simulations, competition reactions for metal chelation by different metabolites (γ‐Glu‐Cys‐Gly, α‐Glu‐Cys‐Gly and γ‐Glu‐Cys) combined with biochemical and genetics experiments have been performed to propose a full description of bio‐inorganic reactions occurring in the early steps of cadmium detoxification processes. Our results give unambiguous information about the spontaneous formation, under physiological conditions, of the Cd(GS)2 complex, about the nature of ligands involved in cadmium chelation by glutathione, and provide insights on the structures of Cd(GS)2 complexes in solution at different pH. We also show that γ‐Glu‐Cys, the precursor of glutathione, forms a stable complex with cadmium, but biological studies of the first steps of cadmium detoxification reveal that this complex does not seem to be relevant for this purpose.

The Bioinorganic Chemistry of Cadmium in the Context of Its Toxicity

“…GSH is an abundant intracellular reductant with good chelating properties for Cd 2+ [76,77]. Thus cells capable of producing pumps exporting GSH compounds are more likely to remove chelated forms of cadmium.…”

Mitochondria targeting by environmental stressors: Implications for redox cellular signaling

“…Metals of relevance for human health such as cadmium (Cd), mercury (Hg), lead (Pb) and Arsenic (As) have also been shown to bind with high affinity to thiol/selenol residues in peptides [64–68] and proteins, with their binding being normally sufficient to inhibit the enzymes’ activities. Most enzymes catalyzing ROS detoxification are dependent on either an active site thiol or selenol – glutathione peroxidase and peroxiredoxin isoenzymes are classic examples.…”

Probing the coordination properties of glutathione with transition metal ions (Cr2+,Mn2+,Fe2+,Co2+, Ni2+,Cu2+,Zn2+,Cd2+,Hg2+) by density functional theory

“…Different experimental techniques have been devoted to investigate the metal complexes of GSH, such as electron paramagnetic resonance (EPR) [26,27], NMR [28,29], X-ray diffraction (X-ray) [30,31] and ESI-MS [32]. Nevertheless, it is difficult to explain the structures of the complexes at the atomic and electronic level.…”