Reactions of the Zn Proteome with Cd²⁺ and Other Xenobiotics: Trafficking and Toxicity

Abstract

Understanding the molecular basis of inorganic chemical toxicity has lagged behind the proliferation of detailed mechanisms that explain the biochemical toxicology of many organic xenobiotics. In this perspective, general barriers to explicating the bioinorganic chemistry of toxic metals are considered, followed by a detailed examination of these issues in relation to the toxicology of Cd. The hypothesis is evaluated that Cd damages cells by replacing Zn in key Zn proteins. An emerging methodology to assess the speciation of metals among cell proteins is described. Then, a more general hypothesis is suggested, namely, that the Zn proteome is also the toxicological target of other metals such as Pb as well as NO and reactive oxygen species. The latter may damage cells by altering the structure and function of Zn binding sites that include thiol ligands. In the process, labilized Zn may also perturb cell biochemistry. Lastly, reactions of metal chelating ligands with the Zn proteome, including formation of ligand-Zn protein adducts, provide other potential avenues of biochemical toxicity.

Metal Exchange in the Interprotein ZnII‐Binding Site of the Rad50 Hook Domain: Structural Insights into CdII‐Induced DNA‐Repair Inhibition

“…Its detrimental effects on human health are known, but a clear mechanism connecting cadmium's intake and its indirect genotoxicity is still elusive, which seems to be dictated by a multivalent effect occurring as a result of binding of the Cd II ion by its cellular targets . Cd II as a softer Lewis acid than Zn II readily displaces it in cysteine(Cys)‐rich zinc‐binding proteins and biomolecules, which solitarily introduces an enormous toxic effect inside a cell . Zn II fluctuations, which impact the exchangeable zinc quota, interfere with redox homeostasis, and deregulate cellular metalloproteome .…”

“…[6] Cd II as as ofter Lewis acid than Zn II readily displaces it in cysteine(Cys)-rich zinc-binding proteins and biomolecules, which solitarily introduces an enormoust oxic effect inside ac ell. [7] Zn II fluctuations, which impact the exchangeable zinc quota, [8] interfere with redox homeostasis, and deregulate cellular metalloproteome. [9] Furthermore, because Cd II binds preferentially to thiol-containing and other nucleophilic ligands, it interacts with aw ide spectrum of redox signaling and reactive oxygen scavenger proteins, inten-sifyingZ n II -displacement effects.…”

Cell organelles as targets of mammalian cadmium toxicity

“…thiol (SH) groups), cadmium disrupts cellular functions and may lead to death or disease (Moulis 2010;Thévenod and Lee 2013b). The molecular interactions of cadmium with proteins involve metal substitution reactions with many zinc-proteins, such as enzymes or transcription factors (Maret and Moulis 2013;Petering 2017), substitution for calcium in cellular signaling, interaction with SH-dependent redox systems, and impacting levels of second messengers, growth and transcription factors (Templeton and Liu 2010;Thévenod 2009;Thévenod and Lee 2013b). Cadmium does not undergo Fenton chemistry in biological systems, yet it does initiate reactive oxygen species (ROS) formation, indirectly through depletion of endogenous redox scavengers, inhibiting anti-oxidative enzymes or the mitochondrial electron transport chain (ETC), and/ or displacing redox active metals, such as iron or copper (Cuypers et al 2010).…”

Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications

“…By binding to essential side groups of biomolecules (e.g., SH groups) and/or displacing essential metals from macromolecules, Cd disrupts cellular functions with subsequent death or disease ( Moulis, 2010 ; Thévenod and Lee, 2013 ). Cd interacts with proteins by substituting for zinc ions, as in enzymes or transcription factors ( Maret and Moulis, 2013 ; Petering, 2017 ), or replacing calcium in cellular signal transduction, interfering with thiol-dependent redox systems, and modifying second messenger levels, growth and transcription factors ( Thévenod, 2009 ; Thévenod and Lee, 2013 ). Cd is not a transition-metal ion undergoing Fenton chemistry, yet in biological systems, it indirectly increases ROS and RNS.…”