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Special Issue "Thiophilic Metals: An Ancient Love for Sulfur at the Heart of Biochemistry"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 31 July 2021.

Special Issue Editors

Prof. Dr. Claus Jacob
E-Mail Website
Guest Editor
Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, D-66123 Saarbruecken, Germany
Interests: bioorganic chemistry; catalytic sensor/effector agents; epistemology; intracellular diagnostics; nanotechnology; natural products; reactive sulfur and selenium species; redox regulation via the cellular thiolstat
Special Issues and Collections in MDPI journals
Prof. Dr. Wolfgang Maret
E-Mail Website
Guest Editor
Departments of Biochemistry and Nutritional Sciences, King’s College London, 150 Stamford Street, London SE1 9NH, United Kingdom

Special Issue Information

Dear Colleagues,

Thiophilic metal ions, such as zinc, copper, iron, and molybdenum, are present in virtually all organisms where they fulfil a multitude of functions and often bind to sulfur as their ligands. The resulting medley of metal binding and exchange on the one side and redox activity of some of these metals and sulfur ligands on the other leads to a truly complex chemistry that is reflected in their biochemistry. This Special Issue will consider the current state of such thiophilic metal ions in biology, with a focus on their chemistry, trafficking, exchange, biological actions, and redox control. Some of this bioinorganic chemistry is established, other aspects are still speculative and in need of investigation. This includes evolutionary aspects; sulfur cycles controlling such thiophilic metals in the geosphere and biosphere; and selenophilic metals and interactions with other chalcogens, such as tellurium and polonium. This Special Issue is dedicated to Bert L. Vallee, the discoverer of the metallothioneins, on occasion of his 100th birthday in 2019.

Prof. Dr. Claus Jacob
Prof. Dr. Wolfgang Maret
Guest Editors

Manuscript Submission Information

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Published Papers (2 papers)

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Research

Open AccessArticle
Probing the Structure and Function of the Cytosolic Domain of the Human Zinc Transporter ZnT8 with Nickel(II) Ions
Int. J. Mol. Sci. 2021, 22(6), 2940; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062940 - 14 Mar 2021
Viewed by 473
Abstract
The human zinc transporter ZnT8 provides the granules of pancreatic β-cells with zinc (II) ions for assembly of insulin hexamers for storage. Until recently, the structure and function of human ZnTs have been modelled on the basis of the 3D structures of bacterial [...] Read more.
The human zinc transporter ZnT8 provides the granules of pancreatic β-cells with zinc (II) ions for assembly of insulin hexamers for storage. Until recently, the structure and function of human ZnTs have been modelled on the basis of the 3D structures of bacterial zinc exporters, which form homodimers with each monomer having six transmembrane α-helices harbouring the zinc transport site and a cytosolic domain with an α,β structure and additional zinc-binding sites. However, there are important differences in function as the bacterial proteins export an excess of zinc ions from the bacterial cytoplasm, whereas ZnT8 exports zinc ions into subcellular vesicles when there is no apparent excess of cytosolic zinc ions. Indeed, recent structural investigations of human ZnT8 show differences in metal binding in the cytosolic domain when compared to the bacterial proteins. Two common variants, one with tryptophan (W) and the other with arginine (R) at position 325, have generated considerable interest as the R-variant is associated with a higher risk of developing type 2 diabetes. Since the mutation is at the apex of the cytosolic domain facing towards the cytosol, it is not clear how it can affect zinc transport through the transmembrane domain. We expressed the cytosolic domain of both variants of human ZnT8 and have begun structural and functional studies. We found that (i) the metal binding of the human protein is different from that of the bacterial proteins, (ii) the human protein has a C-terminal extension with three cysteine residues that bind a zinc(II) ion, and (iii) there are small differences in stability between the two variants. In this investigation, we employed nickel(II) ions as a probe for the spectroscopically silent Zn(II) ions and utilised colorimetric and fluorimetric indicators for Ni(II) ions to investigate metal binding. We established Ni(II) coordination to the C-terminal cysteines and found differences in metal affinity and coordination in the two ZnT8 variants. These structural differences are thought to be critical for the functional differences regarding the diabetes risk. Further insight into the assembly of the metal centres in the cytosolic domain was gained from potentiometric investigations of zinc binding to synthetic peptides corresponding to N-terminal and C-terminal sequences of ZnT8 bearing the metal-coordinating ligands. Our work suggests the involvement of the C-terminal cysteines, which are part of the cytosolic domain, in a metal chelation and/or acquisition mechanism and, as now supported by the high-resolution structural work, provides the first example of metal-thiolate coordination chemistry in zinc transporters. Full article
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Open AccessArticle
Characterization and Reconstitution of Human Lipoyl Synthase (LIAS) Supports ISCA2 and ISCU as Primary Cluster Donors and an Ordered Mechanism of Cluster Assembly
Int. J. Mol. Sci. 2021, 22(4), 1598; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041598 - 05 Feb 2021
Viewed by 405
Abstract
Lipoyl synthase (LIAS) is an iron–sulfur cluster protein and a member of the radical S-adenosylmethionine (SAM) superfamily that catalyzes the final step of lipoic acid biosynthesis. The enzyme contains two [4Fe–4S] centers (reducing and auxiliary clusters) that promote radical formation and sulfur transfer, [...] Read more.
Lipoyl synthase (LIAS) is an iron–sulfur cluster protein and a member of the radical S-adenosylmethionine (SAM) superfamily that catalyzes the final step of lipoic acid biosynthesis. The enzyme contains two [4Fe–4S] centers (reducing and auxiliary clusters) that promote radical formation and sulfur transfer, respectively. Most information concerning LIAS and its mechanism has been determined from prokaryotic enzymes. Herein, we detail the expression, isolation, and characterization of human LIAS, its reactivity, and evaluation of natural iron–sulfur (Fe–S) cluster reconstitution mechanisms. Cluster donation by a number of possible cluster donor proteins and heterodimeric complexes has been evaluated. [2Fe–2S]-cluster-bound forms of human ISCU and ISCA2 were found capable of reconstituting human LIAS, such that complete product turnover was enabled for LIAS, as monitored via a liquid chromatography–mass spectrometry (LC–MS) assay. Electron paramagnetic resonance (EPR) studies of native LIAS and substituted derivatives that lacked the ability to bind one or the other of LIAS’s two [4Fe–4S] clusters revealed a likely order of cluster addition, with the auxiliary cluster preceding the reducing [4Fe–4S] center. These results detail the trafficking of Fe–S clusters in human cells and highlight differences with respect to bacterial LIAS analogs. Likely in vivo Fe–S cluster donors to LIAS are identified, with possible connections to human disease states, and a mechanistic ordering of [4Fe–4S] cluster reconstitution is evident. Full article
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