Vašák, M.

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INTRODUCTIONMetallothioneins: chemical and biological challengesM. Vasˇa´kReceived: 26 July 2011 / Accepted: 8 August 2011 / Published online: 9 September 2011 SBIC 2011Metallothioneins (MTs) belong to a superfamily of intrigu-ing low-molecular mass cysteine- and metal-rich proteins,present in all living organisms. The first MT was discoveredby the late Bert L. Vallee in 1957 [1]. His work and its impacton life sciences has been discussed by Williams [2] in the InMemoriam published in this journal last year. This SpecialIssue is dedicated to him in appreciation of his outstandingcontributions not only to the field of zinc biochemistry butalso to the MT field.Metallothioneins, in addition to carbonic anhydrase indiatoms, are the only biological compounds in whichcadmium accumulates naturally, the other metallic com-ponents usually being copper and zinc. In fact, zinc and/orcopper are the principal metal constituents of MTs undernormal physiological conditions. The binding of thesemetal ions is achieved through the formation of sulfur-based metal–thiolate clusters. Metallothioneins are intra-cellular proteins, but in higher organisms they can alsooccur in the extracellular space, suggesting that they mayplay different biological roles depending on their locali-zation. The majority of the MT literature has focused onvertebrate MTs in terms of their structure, function andgene regulation. Several biological roles have been ascri-bed to these MTs, including their involvement in zinc andcopper homeostasis, the protection against environmentalheavy metals and oxidative stress, the control of redoxstatus of the cell, the antiapoptotic role, and recently in theprotection and regeneration of the mammalian brain fol-lowing neurological injury and disease. Thus, it isincreasingly clear that MTs can have multiple biologicalfunctions. The studies of vertebrate MTs led to the notionthat the knowledge obtained is transferable to MTs fromother phyla. However, in recent years, the characterizationof bacterial and plant MTs led to unforeseen molecularproperties including the participation of both cysteine andhistidine in metal coordination.This Special Issue of the Journal of Biological Inor-ganic Chemistry compiles a set of reviews and researcharticles that reflect the current knowledge regarding thechemistry and biology of MTs from various organisms,their evolutionary biology and their role in disease. Manyof the foremost scientists in this field have contributedexcellent overview articles. The first contribution by Cap-devila and Atrian [3] discusses the unclear points of MTevolution, leading to the present problems in interpretingMT diversity and heterogeneity in terms of its molecularevolution along with new evolutionary aspects. In theoverview by Palacios et al. [4], the same team proposes anew classification of the MT systems in which the metalbinding preference of recombinant MTs from diverseorganisms toward the physiological relevant zinc andcopper ions is considered. Five contributions focus on MTsfrom lower organisms, namely plants, Drosophila andinvertebrates. Blindauer [5], in her review, discusses thepast and current views and challenges of studying thediverse family of bacterial MTs. This review also providesThis article is part of a JBIC special issue on metallothioneins.M. Vasˇa´kDepartment of Biochemistry,University of Zu¨rich,Winterthurerstrasse 190,8057 Zurich, SwitzerlandPresent Address:M. Vasˇa´k (&)Department of Inorganic Chemistry,University of Zu¨rich,Winterthurerstrasse 190,8057 Zurich, Switzerlande-mail: mvasak@bioc.uzh.ch123J Biol Inorg Chem (2011) 16:975–976DOI 10.1007/s00775-011-0832-5new insights into why some bacteria might have evolved tosequester surplus metals in these proteins while othersexport the excess across the plasma-membrane. Gutie´rrezet al. [6] give an overview on ciliate MTs (Tetrahymenaspecies), including a description of the peculiarities of theirprimary sequences, functional insights and their applica-tions as biosensors in environmental toxicology. Freisinger[7] reviews the structural features of plant MTs derivedfrom their sequences and biophysical data, with specialemphasis given to the structural and functional aspects oflinker sequences typical for these MTs. Drosophila mela-nogaster represents the well-known model organism inmolecular genetics. In an original research article byAtanesyan et al. [8], a new fifth member of the DrosophilaMT gene family (MtnE) was identified and its transcrip-tional regulation studied. The molecular and cellularmechanisms of the multifunctional MTs from two distinctinvertebrates, nematodes and snails, are compared in thereview by Ho¨ckner et al. [9]. Another group of contribu-tions focuses on the chemistry and biology of vertebrateMTs and their role in disease. Vasˇa´k and Meloni [10], intheir review, after a brief summary of the historical mile-stones of the mammalian MT-1/MT-2 research, discuss theadvances in the structure, chemistry and biological func-tions of the more recently discovered mammalian MT-3and MT-4 isoforms. The review by Maret [11] summarizesimportant aspects of redox biochemistry of mammalianMTs in relation to their function in redox-dependent zincmetabolism. Namdarghanbari et al. [12] provide a com-prehensive review of the role of mammalian MT-1/MT-2in toxicology, cancer and chemotherapy. A paper byManso et al. [13] first provides an overview of the generalaspects of the inflammatory responses along with thefunction of MTs in neuroinflammation of the central ner-vous system. This is followed by the first data obtained onan Alzheimer disease mouse model treated with humanMT-2A. West et al. [14] provide a comprehensive reviewof the extracellular roles of MTs in the brain and theirinteractions with the lipoprotein receptor-related proteins.Mammalian MTs represent the major Zn-binding proteinsin the cell. Zinc has emerged not only as a major regulatorof neuronal physiology but also as an importantintracellular signaling agent similar to calcium. The reviewby Fukada et al. [15] describes the role of abnormal zinchomeostasis in multiple diseases and the role of this ion incellular signaling.Overall, despite an extensive literature following thediscovery of MTs more than 50 years ago, this class ofproteins is still attracting considerable interest of researchersfrom many fields. I hope that the review articles presented inthis Special Issue will help stimulate further study into thebiological functions and bioinorganic chemistry of MTs andpossibly uncover unexpected features of these importantproteins. I wish to thank the members of the JBIC editorialboard for making this Special Issue possible and DeborahSchoenholz for her help in organizing this issue.References1. Margoshes M, Vallee BL (1957) J Am Chem Soc 79:4813–48142. Williams RJP (2010) J Biol Inorg Chem 15:1175–11763. Capdevila M, Atrian S (2011) J Biol Inorg Chem. doi:10.1007/s00775-011-0798-34. Palacios O, Atrian S, Capdevila M (2011) J Biol Inorg Chem. doi:10.1007/s00775-011-0827-25. Blindauer C (2011) J Biol Inorg Chem. doi:10.1007/s00775-011-0790-y6. Gutie´rrez JC, Amaro F, Diaz S, de Francisco P, Cubas L, Martin-Gonzalez A (2011) J Biol Inorg Chem. doi:10.1007/s00775-011-0820-97. Freisinger E (2011) J Biol Inorg Chem. doi:10.1007/s00775-011-0801-z8. Atanesyan L, Gu¨nther V, Georgiev O, Celniker SE, Schaffner W(2011) J Biol Inorg Chem. doi:10.1007/s00775-011-0825-49. Ho¨ckner M, Dallinger R, Stu¨rzenbaum SR (2011) J Biol InorgChem. doi:10.1007/s00775-011-0826-310. Vasˇa´k M, Meloni G (2011) J Biol Inorg Chem. doi:10.1007/s00775-011-0799-211. Maret W (2011) J Biol Inorg Chem. doi:10.1007/s00775-011-0800-012. Namdarghanbari M, Wobig W, Krezoski S, Tabatabai N, PeteringDH (2011) J Biol Inorg Chem. doi:10.1007/s00775-011-0823-613. Manso Y, Adlard PA, Carrasco J, Vasˇa´k M, Hidalgo J (2011) JBiol Inorg Chem. doi:10.1007/s00775-011-0802-y14. West AK, Leung J, Chung R (2011) J Biol Inorg Chem. doi:10.1007/s00775-011-0817-415. Fukada T, Yamasaki S, Keigo N, Murakami M, Hirano T (2011) JBiol Inorg Chem. doi:10.1007/s00775-011-0797-4976 J Biol Inorg Chem (2011) 16:975–976123

Metallothioneins: chemical and biological challenges

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Metallothioneins: chemical and biological challenges

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