Non-native Proteins as Newly-Identified Targets of Heavy Metals and Metalloids
Heavy metal ions such as Cd2+, Hg2+ and Pb2+ as well as metalloid arsenic(III) species very efficiently inhibit the refolding of chemically denatured proteins (IC50 values in nanomolar range). In their presence, the proteins misfold and aggregate. Denatured proteins appear to be much more susceptible to form high-affinity pluridentate complexes with heavy metals and metalloids than native proteins. In a denatured protein, the potential ligands of metal ions, the most important ones being cysteine and histidine residues, are more easily accessible for the toxic agents; moreover, denatured proteins with more flexible and motile backbones are more likely than folded native proteins to tolerate the formation of pluridentate protein–metal complexes with their defined geometry. In cells, the interference of metals with nascent and other non-native forms of proteins might manifest itself both in a quantitative deficiency of the affected proteins and the formation of proteotoxic aggregates. Possibly, the toxic effects of heavy metals and metalloids arise not only from their interaction with specific, particularly susceptible native proteins but also from a general derailing of protein folding . The toxic scope of heavy metals and metalloids thus could be more pleiotropic and extensive than assumed so far.
KeywordsHeavy Metal Arsenic Trioxide Leuconostoc Mesenteroides Heavy Metal Poisoning Folding Inhibition
This work was supported in part by a grant from the Swiss National Science Foundation (3100A0-109290) to PG. We thank J.H.R. Kägi for valuable discussions.
- Fraústo da Silva JJR, Williams RJP (1993) The biological chemistry of the elements: the inorganic chemistry of life. Clarendon Press, OxfordGoogle Scholar
- Hu H (2005) Heavy metal poisoning. In: Kasper DL et al (eds) Harrison’s principles of internal medicine, 16th edn. McGraw-Hill, New York, pp 2577–2580Google Scholar
- Kägi JHR, Hapke H-J (1984) Biochemical interactions of mercury, cadmium and lead. In: Nriagu JO (ed) Changing metal cycles and human health. Springer, Berlin, pp 237–250Google Scholar
- Kosnett MJ (2007) Heavy metal intoxication and chelators. In: Katzung BG (ed) Basic and clinical pharmacology, 10th edn. McGraw-Hill, New York, pp 945–957Google Scholar
- Means GE, Feeney RE (1971) Chemical modification of proteins. Holden-Day, San FranciscoGoogle Scholar
- Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH (2008) Alzheimer’s disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci 28:3–9PubMedCrossRefGoogle Scholar