Thematic Minireview Series: Metals in Biology 2012

Abstract

Metals are present in about one-half of the protein structures available and also have critical roles in nucleic acid biochemistry. This prologue introduces the fourth of the Thematic Minireview Series on Metals in Biology, which deals with several topics involving iron, manganese, copper, and other metals. The six minireviews discuss metal transport and intracellular homeostasis, including chaperones and siderophores, maturation of the diiron active sites in hydrogenases, the balance between manganese and iron, and copper homeostasis relevant to pathogens.

Introduction

The study of biochemistry is incomplete without consideration of metals. Metals behave as superacids, alter the electrophilicity or nucleophilicity of reacting species, and promote heterolytic reactions (1). They are able to form ionic and both σ and π covalent bonds. Surveys of protein crystal structures of enzymes have led to estimates that 47% require metals and 41% contain metals in their catalytic centers (1, 2). Metals in proteins function as redox centers, transport oxygen, and utilize their ligand-binding abilities in acting as molecular sensors (“switches”) in signal transduction. Metals have critical roles in nucleic acid biochemistry as well as with proteins, e.g. binding to nucleoside triphosphates in polymerase activity. Our knowledge of metal biochemistry continues to grow but is still incomplete. In a comprehensive effort to characterize the “metalloproteome” of an archebacterial hyperthermophile, Pyrococcus furiosus, 154 of 343 chromatographic metal-containing fractions did not match any known metalloproteins (3). Tungsten-containing enzymes are known in this organism, and a number of unusual metals were found to be assimilated. Although some of these may be extraneous or even toxic, this work shows the opportunities still available in bioinorganic chemistry.

This is the fourth Thematic Minireview Series on Metals in Biology. The first two dealt with a variety of metals, including iron, copper, selenium, nickel, vanadium, and arsenic (4, 5), and the third (6) was focused on iron homeostasis. We continue here with a series of six minireviews dealing with various topics that can be collectively considered under the theme of metal homeostasis. Because of the critical roles of metals in biochemistry and the toxicity of excesses of most metals (7), metal homeostasis is generally highly regulated throughout biology. The current thematic series includes several aspects of these processes.

The first minireview, by José M. Argüello et al., deals with the topic of transport of metal across membranes in biological systems. This article reviews major modes of transport, including P_IB-ATPases, RND (resistance-nodulation-cell division) metal transporters, Ctr copper transporters, and cation diffusion facilitators. Interestingly, structures of these transmembrane transporters have recently become available.

The second minireview, by Caroline C. Philpott, deals with eukaryotic iron chaperones and intracellular iron delivery. In both yeast and mammalian cells, a cytosolic system involves the glutaredoxin- and poly(rC)-binding proteins, which bind iron-sensing iron-sulfur clusters and free iron, respectively. In yeast, the glutaredoxins are needed for formation of heme and functional two- and four-iron-sulfur clusters, and the poly(rC) proteins act as iron chaperones.

The third minireview, by Colin Correnti and Roland K. Strong, deals with mammalian siderophores and lipocalins. Siderophores are low molecular mass compounds with extremely high affinity for iron, long known in bacteria. Siderocalin, a siderophore-binding lipocalin, is a mammalian siderophore-binding protein and has an antibacterial function because it sequesters iron complexes. Searches for mammalian siderophores are discussed.

The fourth minireview in this series, by Yvain Nicolet and Juan C. Fontecilla-Camps, also deals with iron. In this article, the formation of the iron-sulfur cluster of a diiron hydrogenase is considered, particularly the assembly and nature of the small dithiolate species. The structural hydrogenase gene can be expressed in Escherichia coli if fortified with three maturase genes, but active hydrogenases appear to be produced in some organisms devoid of the mature genes (e.g. protozoa).

The focus shifts to interactions of iron with manganese in the fifth minireview, coauthored by Dafhne Aguirre and Valeria C. Culotta. Superoxide dismutase (SOD)² has long been known to be effective in protecting organisms from oxidative damage. One group of SODs uses manganese, although these SODs have similarity to iron-based SODs. However, insertion of iron into a manganese SOD inactivates it, and bacterial and yeast systems have mechanisms for dealing with the iron problem.

The sixth and last minireview in this series, by Victoria Hodgkinson and Michael J. Petris, addresses issues involving the homeostasis of another transition metal, copper. As mentioned above, most essential metals are also toxic, and copper is an excellent example. The macrophage phagosome accumulates copper during bacterial infection, which may constitute an important mechanism of killing (i.e. generating local oxidative stress). Bacteria have their own mechanisms for coping with this problem, and the homeostasis of copper can be important in determining the outcome of host-pathogen interactions.

Overall, the minireviews in this thematic series deal with a series of metals (primarily, the transition metals iron, copper, and manganese) in a variety of organisms. Aspects are important in the basic biology of prokaryotes and human medicine. We (the authors of these minireviews and I) hope that you will learn at least something new and more greatly appreciate the role of metals in biology. Even in four thematic series to date (4–6), we have covered only a small fraction of the topics in this area, and additional minireviews will deal with other interesting aspects of metals in biological systems.