Research on metallothionein (MT), unlike studies on any other metalloprotein, captures best the difficulties that investigators faced, and continue to face, when relating protein structure to protein function. This article discusses the structural complexity of the family of human MTs with the goal of providing a background for future investigations of their functions in health and disease by molecular and atomic spectroscopies. The analytical (bio)chemist needs to overcome formidable challenges in terms of sample preparation and speciation. MTs are expressed tissue- and isoprotein-specifically; their expression responds to a variety of physiological and environmental stimuli; they are present as closely related products of at least ten different genes, several of which can be expressed simultaneously at considerably different levels in a given tissue; they have additional polymorphic forms, variable metal load, oxidation states, and degrees of polymerization; they react with different metals and thiol-modifying agents; they are localized in the extracellular and intracellular space and re-distribute subcellularly. Results from the application of highly sensitive fluorimetric techniques suggest that the active form of the zinc/thiolate clusters in MT is not the one described by X-ray crystallography or NMR spectroscopy and that the thiol chemistry is the central aspect of MT's mechanism of action. MT is not saturated with zinc ions under normal physiological conditions, and it exists to variable extent in the apoform (thionein) and in partially oxidized forms (thionin). The complexity of human MTs calls for metallomics and metalloproteomics approaches that integrate the knowledge from several scientific disciplines. Any interpretation of MT functions is based on the linkage between the metal ions and their sulfur ligands from the cysteines. Studies on the antioxidant or reactive species-scavenging properties of the cysteine sulfurs of MT need to take the effects on zinc metabolism into account, while any studies with transition metal ions need to consider the effect of metal binding on the reactivity of the cysteine sulfurs.
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