Metallomics : Integrated Biometal Science

Iron dyshomeostasis is involved in many neurological disorders, particularly neurodegenerative diseases where iron accumulates in various brain regions. Identifying mechanisms of iron transport in the brain is crucial for understanding the role of iron in healthy and pathological states. In neurons, it has been suggested that iron can be transported by the axon to different brain regions in the form of labile iron; a pool of reactive and exchangeable intracellular iron. Here we report a novel approach to imaging labile ferrous iron, Fe(II), in live primary hippocampal neurons using confocal and TauSTED (Stimulated Emission Depletion) microscopy...

The increasing use of lithium (Li) in new technologies raises the question of its impact on living microorganisms. In the present study, we aimed to identify putative Li targets and resistance mechanisms in the yeast model Saccharomyces cerevisiae using a deletomic approach based on the screening of a collection of 4,733 knockout mutants under Li exposure. This screening highlighted 60 mutants resistant to Li and 124 mutants sensitive to Li. Through functional enrichment analyses, transport systems and catabolite repression were identified as playing a central role in cell resistance to toxic concentrations of Li...

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Histatin-5 (Hist-5) is an antimicrobial peptide found in human saliva that functions to defend the oral cavity from microbial infections, such as those caused by the fungal pathogen Candida albicans (C. albicans). Hist-5 can bind Cu in multiple oxidation states, Cu2+ and Cu+ in vitro, and supplemental Cu2+ has been shown to improve the fungicidal activity of the peptide against C. albicans in culture. However, the exact role of Cu on the antifungal activity of Hist-5 and whether direct peptide-Cu interactions occur intracellularly has yet to be fully determined...

The molecular mechanism of aluminum toxicity in biological systems is not completely understood. Saccharomyces cerevisiae is one of the most used model organisms in the study of environmental metal toxicity. Using an unbiased metallomic approach in yeast, we found that aluminum treatment caused phosphorus deprivation, and the lack of phosphorus increased as the pH of the environment decreased compared to the control strain. By screening the PHO pathway in yeast with the synthetic lethality of a new phosphorus-restricted aluminum-sensitive gene, we observed that pho84Δ mutation conferred severe growth defect to aluminum under low-phosphorus conditions, and the addition of phosphate alleviated this sensitivity...

Stresses caused by deficiency/excess of mineral nutrients or of pollution of toxic metals have already become a primary factor in limiting crop production worldwide. Genes involved in minerals and toxic metals accumulation/tolerance could be potential candidates for improving crop plants with enhanced nutritional efficiency and environmental adaptability. In this study, we first generated a high-quality yeast expression cDNA library of Brassica napus (Westar), and 46 genes mediating excess micronutrients and toxic metals detoxification were screened using the yeast genetic complementation system, including 11, 5, 6, 14, 6, 5 genes involved in cadmium (Cd), zinc (Zn), iron (Fe), manganese (Mn), boron (B), copper (Cu) tolerance respectively...

Selenomethionine (SeMet) as a methionine analog can be incorporated into protein. In turkeys, we recently found that selenium (Se) as selenite is not metabolized to SeMet but rather to selenosugars (seleno-N-acetyl galactosamine) bound to protein as well as to selenocysteine (Sec) in selenoproteins. To characterize the metabolism of SeMet, we fed rats graded levels of SeMet from 0 to 5 μg Se/g in a Se-deficient diet for 4 wk, and investigated the fate and accumulation of liver Se using HPLC coupled with Se-specific (ICP MS) and molecule specific (Orbitrap MS/MS) detection...

Using HPLC coupled with selenium-specific (ICP MS) and molecule specific (Orbitrap MS/MS) detection, we previously found that far more selenium (Se) is present as selenosugar (seleno-N-acetyl galactosamine) in Se-adequate turkey liver than is present as selenocysteine (Sec) in true selenoproteins, and that selenosugars account for half of the Se in high-Se turkey liver. To expand these observations to mammals, we studied Se metabolism in rats fed graded levels of selenite from 0 to 5 μg Se/g for 4 weeks...

The naturally occurring stable isotopes of potassium (41K/39K, expressed as δ41K) have the potential to make significant contributions to vertebrate and human biology. The utility of K stable isotopes is however conditioned by the understanding of the dietary and biological factors controlling natural variability of δ41K. This paper reports a systematic study of K isotopes in extant terrestrial endothermic vertebrates. δ41K has been measured in 158 samples of tissues, biofluids and excreta from 40 individuals of four vertebrate species (rat, guinea pig, pig and quail) reared in two controlled feeding experiments...

All bacteria possess homeostastic mechanisms that control the availability of micronutrient metals within the cell. Cross-talks between different metal homeostasis pathways within the same bacterial organism have been reported widely. In addition, there have been previous suggestions that some metal uptake transporters can promote adventitious uptake of the wrong metal. This work describes the cross-talk between Cu and the Zn and Mn homeostasis pathways in Group A Streptococcus (GAS). Using a ∆copA mutant strain that lacks the primary Cu efflux pump and thus traps excess Cu in the cytoplasm, we show that growth in the presence of supplemental Cu promotes downregulation of genes that contribute to Zn or Mn uptake...

The abandoned Allchar Mine in the Republic of North Macedonia is a globally unique deposit with the highest known grades of thallium (Tl) and arsenic (As) mineralisation. We aimed to determine the distribution of As and Tl in whole dehydrated shoots of the three Viola taxa using synchrotron μXRF analysis. Additionally, soil and plant organ samples were collected from all three Viola taxa at the Allchar site and analysed using ICP-AES. Concentrations of Tl were extremely high in all three Viola taxa (up to 58,900 mg kg-1), but concentrations of As were highly variable with V...

Heme oxygenase-1 (HO-1) catalyzes the first and rate-limiting enzymatic step of heme degradation, producing carbon monoxide, biliverdin and free iron. Most iron is derived from aged erythrocytes by the decomposition of heme, which happened mainly in macrophages. However, the role of HO-1 on iron metabolism and function of macrophage is unclear. The present study investigated the effect of HO-1 on iron metabolism in macrophages, and explored the role of HO-1 on inflammatory response, polarization and migration of macrophages...

Metallothioneins (MTs) are small, Cys-rich proteins present in various but not all organisms, from bacteria to humans. They participate in zinc and copper metabolism, toxic metals detoxification and protection against reactive species. Structurally, they contain one or multiple domains, capable of binding a variable number of metal ions. For experimental convenience, biochemical characterization of MTs is mainly performed on Cd(II)-loaded proteins, frequently omitting or limiting Zn(II) binding features and related functions...

Relative to healthy controls, lighter copper isotopic compositions have been observed in the serum of breast cancer and end-stage liver disease patients, raising the possibility that Cu isotope ratios could be used as a tracer for disease progression. Here, we assess the potential of natural Cu isotopic variations (expressed as δ65Cu) as diagnostic tools for cancer progression and/or liver failure by performing a first-order analysis of Cu isotopic cycling in the human body. Using a box model, we simulate the kinetics of Cu mass transfer throughout significant reservoirs in the body, allowing isotopic fractionation to occur during Cu uptake/release from these reservoirs...

The sea is a generally iron-poor environment and brown algae were recognized in recent years for having a unique, ferritin-free iron storage system. Kelp (Laminaria digitata) and the filamentous brown alga Ectocarpus siliculosus were investigated using X-ray microprobe imaging and nanoprobe XRF tomography to explore the localization of iron, arsenic, strontium and zinc, and µXANES to study Fe binding. Fe distribution in frozen-hydrated environmental samples of both algae shows higher accumulation in the cortex with symplastic subcellular localisation...

Currently, clinical analysis of male infertility mainly relies on parameters of semen and sperm cells. However, the high diagnostic failure rates indicate that the current assessment methods are not sufficient and a new approach to evaluating sperm function still needs to be developed. Here we explored the feasibility of single-cell inductively coupled plasma mass spectrometry (sc-ICP-MS)-derived profiles to determine the elemental characteristics in viable capacitated sperm under normal and deficient conditions...

Metallothioneins (MTs) are small proteins present in all kingdoms of life. Their high cysteine content enables them to bind metal ions, such as Zn2+, Cd2+, and Cu+, providing means for detoxification and metal homeostasis. Three MT isoforms with distinct metal binding preferences are present in the Roman Snail Helix pomatia. Here, we use NMR to follow the evolution of Cd2+ and Cu+ binding from the reconstructed ancestral Stylommatophora MT to the three Helix pomatia MT (HpMT) isoforms. Information obtained from [15 N,1H, ]-HSQC spectra and T2 relaxation times are combined to describe the conformational stability of the MT-metal complexes...

Anemia of inflammation (or inflammation-associated anemia) decreases the quality of life in billions of patients suffering from various inflammatory diseases, such as infection, autoimmune diseases, and cancer, associated with a prolonged state of immune activation. While proper utilization of iron, a nutrient metal essential for erythropoiesis, is important for the prevention of anemia, the alteration of body iron homeostasis upon inflammation, which can contribute to the development of anemia, is not completely understood...

Metallothioneins (MT) are regulators of the metals Zn(II) and Cu(I) and act as antioxidants in many organisms, including humans [1-3]. Isoform 3 (MT3) is expressed constitutively in central nervous tissue and has been shown to have additional biological functions, including the inhibition of neuronal growth, the regulation of apoptosis, and cytoskeleton modulation. To facilitate these functions, protein-protein interactions likely occur. These interactions may then impact the metalation status of the MT and the recipient metalloprotein...

The importance of cellular low molecular weight (LMW) ligands in metalloenzyme maturation is largely unexplored. Maturation of NiSOD requires post-translational N-terminal processing of the proenzyme, SodN, by its cognate protease, SodX. Here we provide evidence for the participation of L-histidine in the protease-dependent maturation of Nickel-dependent Superoxide Dismutase (NiSOD) from Streptomyces coelicolor. In vitro studies using purified proteins cloned from S. coelicolor and overexpressed in E. coli support a model where a ternary complex formed between the substrate (SodN), the protease (SodX) and L-Histidine creates a novel Ni-binding site that is capable of the N-terminal processing of SodN and specifically incorporates Ni into the apo-NiSOD product...