Editorial: Metals in cells themed issue

The complement of metals required by enzymes differs between organisms, and fluctuates within organisms, but a recent approximation was that 47% of all enzymes (for which structures are known) need one or more metal ions to function. The metals found in enzymes are typically iron, copper, zinc, manganese, magnesium, molybdenum, cobalt, calcium and a few others such as nickel. The ten articles of this themed issue encompass the main components of metal homeostasis, the control of metals in biological systems. Representative metals and molecules have been selected. Metal-transporters underpin metal homeostasis and feature throughout. It is intended that this themed issue will alert new readers to the sub-discipline, triggering new hypotheses and creative approaches to, for example, the discovery of natural products involved in metal homeostasis and the roles of metal homeostasis in natural product synthesis.

In this issue, our guest editors Nigel Robinson and Emma Raven (NPR editorial board) have gathered together key researchers in the area of metals in cells. The issue commences with an article on metal scavenging by Robert Hider and Xiaole Kong (DOI: 10.1039/b906679a) followed by two on metal sensing – the first by Jeffrey Iwig and Peter Chivers (DOI: 10.1039/b906683g) and the second by Deenah Osman and Jennifer Cavet (DOI: 10.1039/b906682a). We then have three on metallochaperones – by Deborah Zamble et al. (DOI: 10.1039/b906688h), Lucia Banci et al. (DOI: 10.1039/b906678k) and Megan McEvoy et al. (DOI: 10.1039/b906681k). These are followed by a review on metal sequestration by Claudia Blindauer and Oksana Leszczyszyn (DOI: 10.1039/b906685n), and one on metalloenzymes and metabolism by Jonathan Worrall and Erik Vijgenboom (DOI: 10.1039/b804465c). Two final reviews highlight technical challenges and technical opportunities – one by Peng Chen et al. (DOI: 10.1039/b906691h), and the other by Zhiguang Xiao and Anthony Wedd (DOI: 10.1039/b906690j).

The metal affinities of proteins estimated in vitro rarely match their metal requirements. Typically one or more ‘wrong’ metals bind more tightly than the ‘right’ ones, often many orders of magnitude more tightly (albeit that many values reported in the literature are erroneous). Though rarely acknowledged, this observation underlies the commonplace inclusion of metal-chelators such as EDTA in enzyme assay buffers in order to prevent tight-binding metal-contaminants from poisoning enzymes. Metal-scavengers, metal-sensors, metallochaperones and metal-storage compounds support the production of secondary metabolites by supplying the required metals to metalloenzymes and also restricting access to the wrong metals. Crucially, mechanisms of metal-homeostasis maintain a cytosol in which competitive metals such as copper and zinc, from the top of the Irving–Williams series, are tightly bound and buffered to restrain these ions from binding sites which must become occupied by less competitive metals such as manganese and magnesium. By controlling the relative availabilities of metals, cells overcome otherwise inadequate metal–protein affinities.

In some cases the availability of a metal to a protein is under the influence of a metallochaperone: a class of protein that delivers metals to specific destinations. The specificity of protein–protein contacts, and the conformational changes that ensue, control which proteins gain access to those metals carried by metallochaperones. Metallochaperones have been well characterised for nickel and for copper, and there is evidence that they also exist for other metals including iron. The nature of the interactions between metallochaperones and their partners have been the subject of intense investigations and most recently visualised from the fluorescent properties of single molecules trapped inside vesicles. A key outstanding question is how do metallochaperones acquire the correct metal? For the copper chaperone for mitochondrial cytochrome oxidase the answer involves a secondary metabolite awaiting structural characterisation. Secondary metabolites that contribute to metal ion homeostasis include siderophores with staggeringly tight affinities for ferric ions. Siderophores scavenge iron from solutions in which it is sparingly soluble to enable uptake. Copper-chelating methanobactins are released by methanotrophic bacteria arguably for a similar purpose – to scavenge copper for methane monooxygenase. Notwithstanding these examples, investigations into the mechanisms of metal homeostasis have to date mostly focussed on the contributions of gene products as opposed to secondary metabolites, as represented by the balance of this set of insightful reviews on the handling of Metals in cells.

Nigel Robinson obtained his BSc and PhD from Liverpool University, working with David Thurman on metal homeostasis. Supported by Fellowships from the Natural Environment Research Council, and the Director’s Office of Los Alamos National Laboratory, he worked with Paul Jackson at LANL (1984–1987), then held a Royal Society University Research Fellowship at Durham University. In 1994 he was appointed to the chair of Genetics at Newcastle University.
Emma Raven was born in Northamptonshire and obtained a BSc in Chemistry from the University of Leicester. Her interest in metalloproteins originated during PhD studies at Newcastle University with the late Geoff Sykes. She subsequently moved to the University of British Columbia (Vancouver) to Grant Mauk's laboratory, where she worked on a number of heme-containing proteins. In 1995 Emma joined the faculty of the University of Leicester where she is Professor of Biological Chemistry.

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