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The Bioinorganic Chemistry of Mammalian Metallothioneins

Research output: Contribution to journalArticlepeer-review

Artur Krȩżel, Wolfgang Maret

Original languageEnglish
Pages (from-to)14594-14648
Number of pages55
JournalChemical Reviews
Issue number23
Early online date15 Oct 2021
Accepted/In press2021
E-pub ahead of print15 Oct 2021
Published8 Dec 2021

Bibliographical note

Funding Information: We recognize the centennial of the birthday of Bert L. Vallee and the passing of Milan Vašák in 2019. Research in A.K.’s laboratory was supported by the National Science Center of Poland under Opus Grant No. 2018/31/B/NZ1/00567. Publication of this article was supported financially by the Excellence Initiative - Research University (IDUB) program for the University of Wrocław. W.M. thanks his colleagues at King’s College London, Professors C. Hogstrand and S. Sturzenbaum, Professor N. Bury, University of Suffolk, and Professor P. Kille, Cardiff University, for engaging discussions on all matters of metallothioneinology over the past decade. Publisher Copyright: © 2021 American Chemical Society. All rights reserved.

King's Authors


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.

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