The Bioinorganic Chemistry of Mammalian Metallothioneins

Abstract

The functions, purposes, and roles of metallothioneins have been the subject of speculations since the discovery of the protein over 60 years ago. This article guides through the history of investigations and resolves multiple contentions by providing new interpretations of the structure-stability-function relationship. It challenges the dogma that the biologically relevant structure of the mammalian proteins is only the one determined by X-ray diffraction and NMR spectroscopy. The terms metallothionein and thionein are ambiguous and insufficient to understand biological function. The proteins need to be seen in their biological context, which limits and defines the chemistry possible. They exist in multiple forms with different degrees of metalation and types of metal ions. The homoleptic thiolate coordination of mammalian metallothioneins is important for their molecular mechanism. It endows the proteins with redox activity and a specific pH dependence of their metal affinities. The proteins, therefore, also exist in different redox states of the sulfur donor ligands. Their coordination dynamics allows a vast conformational landscape for interactions with other proteins and ligands. Many fundamental signal transduction pathways regulate the expression of the dozen of human metallothionein genes. Recent advances in understanding the control of cellular zinc and copper homeostasis are the foundation for suggesting that mammalian metallothioneins provide a highly dynamic, regulated, and uniquely biological metal buffer to control the availability, fluctuations, and signaling transients of the most competitive Zn­(II) and Cu­(I) ions in cellular space and time.

Metallothionein and Cadmium Toxicology—Historical Review and Commentary

“…This and later research demonstrated that MTs are low molecular weight (about 6500 Da varying depending on the metal content), cysteine-rich metal-binding proteins. A wide variety of organisms contain these proteins, including bacteria, fungi and all eukaryotes, i.e., plant and animal species [10,14].…”

“…We have continuously contributed to the knowledge about cadmium toxicology also in the last four decades and the present review and commentary summarizes our findings and gives our views on the role of metallothionein in cadmium toxicology as applied to risk assessment. Other reviews give detailed chemical properties of metallothionein [10] and detailed molecular pathways of importance for Cd kinetics and toxicity [11], not yet fully used in risk assessment.…”

An Appraisal of the Field of Metallomics and the Roles of Metal Ions in Biochemistry and Cell Signaling

“…Zinc remains in the +2 oxidation state, i.e., Zn 2+ . The cellular availability of zinc(II) ions is controlled by membrane transporters and by release from vesicular stores or from metallothioneins, which are relatively small cysteine sulfur-rich proteins that contain up to seven bound zinc(II) ions and are highly dynamic in their metal binding and regulation [30]. In the process of zinc dissociation from metallothionein, redox reactions do have a role.…”

Bert Vallee—A 20th Century Adventure(r) in Zincology

“…It is also interesting that the discovery of the MTs has been the result of a search for cadmium proteins rather than zinc proteins as a comprehensive review of the 60+ years of research on mammalian MTs summarizes [21]. There are quite a few instances where thiophilic metals in proteins and enzymes can exchange for each other depending on their specific binding constants.…”