Dynamic Protein Adduct Formation by Methylmercury: Molecular Targets, Ligand Exchange, and Toxicological Consequences

Methylmercury (MeHg) is a highly toxic environmental contaminant that preferentially interacts with sulfur- and selenium-containing biomolecules. Although MeHg exposure is associated with disruption of redox homeostasis, calcium signaling, mitochondrial function, and neuronal processes, the molecular mechanisms linking MeHg chemistry to these diverse biological effects remain incompletely understood. A central feature of MeHg chemistry is its high affinity for thiol and selenol groups and its ability to undergo ligand exchange reactions with low-molecular-weight and protein thiols and selenols. Importantly, these interactions can be reversible, suggesting that MeHg toxicity may depend not only on its accumulation in cells but also on the dynamic formation and redistribution of MeHg–S and MeHg–Se adducts. In this review, we summarize the chemical basis of MeHg interactions with sulfur- and selenium-containing biomolecules, focusing on ligand exchange, reversibility, and the differential reactivity of thiols and selenols. We then discuss molecular targets of MeHg, particularly reactive cysteine and selenocysteine residues of cytosolic protein, and their potential links to cellular dysfunction and toxicity. Recent approaches for identifying MeHg-modified biomolecules, including adductomics, are also considered. Finally, we highlight unresolved questions regarding target selectivity, adduct dynamics, and the relationship between molecular modification and biological/toxicological outcomes.