Metallomics最新文献

Iron dyshomeostasis in neurons, involving iron accumulation and abnormal redox balance, is implicated in neurodegeneration. In particular, labile iron, a highly reactive pool of intracellular iron, plays a prominent role in iron-induced neurological damage. However, the mechanisms governing the detoxification and transport of labile iron within neurons are not fully understood. This study investigates the storage and transport of labile ferrous iron Fe(II) in cultured primary rat hippocampal neurons. Iron distribution was studied using live cell fluorescence microscopy with a selective labile Fe(II) fluorescent dye, and synchrotron X-ray fluorescence microscopy (SXRF) for total iron distribution. Fluorescent labeling of the axon initial segment and of lysosomes allowed iron distribution to be correlated with these subcellular compartments. The results show that labile Fe(II) is stored in lysosomes within somas, axons, and dendrites and that lysosomal labile Fe(II) is transported retrogradely and anterogradely along axons and dendrites. In addition, SXRF imaging of total iron confirms iron uptake and iron distribution in the form of iron-rich dots in the soma and neurites. These results suggest that after exposure to Fe(II), labile Fe(II) is stored in lysosomes and can be transported along dendrites and axons. These storage and transport mechanisms could be associated with the detoxification of reactive Fe(II) in lysosomes, which protects cellular structures from oxidative stress. They could also be associated with the metabolic functions of iron in the soma, axons, and dendrites. In this case, easily exchangeable Fe(II) is transported in lysosomes to the neuronal compartments where iron is required.

Six Hyp (A through F) proteins synthesize the NiFe(CN)2CO cofactor found in all [NiFe]-hydrogenases. The Fe(CN)2CO moiety of this cofactor is assembled on a separate scaffold complex comprising HypC and HypD. HypE and HypF generate the cyanide ligands from carbamoyl phosphate by converting the carbamoyl moiety to a thiocyanate associated with HypE's C-terminal cysteine residue, within a conserved 'PRIC' motif. Here, we identify amino acid residue D98 in the central cleft of HypD to be required for biosynthesis of the Fe(CN)2CO moiety and for optimal interaction of HypD with HypE. Construction of a D98A amino acid variant of HypD caused near-complete loss of hydrogenase activity in anaerobically grown Escherichia coli cells, while exchange of the structurally proximal, but non-conserved, residue S356 on HypD, did not. Native mass spectrometric analysis of the anaerobically purified HypC-HypDD98A scaffold complex revealed only a low amount of the bound Fe(CN)2CO group. Western blotting experiments revealed that purified scaffold complexes between either HypC or HybG (a paralogue of HypC) with HypD-D98A showed a strongly impaired interaction with HypE. Examination of the HypCDE complex crystal structure from Thermococcus kodakarensis revealed that D98 of HypD lies within a cleft through which the C-terminus of HypE can access the bound iron ion on HypCD. Alphafold3 predictions suggest that the D98 residue interacts with the arginine residue of the 'PRIC' motif at the C-terminus of HypE to position the modified terminal cysteine residue precisely for delivery of cyanide to the iron ion associated with the HypCD complex.

The large subunit of all [NiFe]-hydrogenases in bacteria and archaea has a heterobimetallic NiFe(CN)2CO cofactor coordinated by four cysteine residues. The iron ion has two cyanides and a carbon monoxide as diatomic ligands. Six ancillary Hyp (ABCDEF) proteins are necessary for anaerobic synthesis of this cofactor, while under oxic conditions at least one further protein, HypX, is required for CO synthesis. The Fe(CN)2CO moiety of the cofactor is synthesized on a separate HypCD scaffold complex. Nickel is inserted into the apo-large subunit only after Fe(CN)2CO has been introduced. Recent biochemical and structural studies have significantly advanced our understanding of cofactor biosynthesis for these important metalloenzymes. Despite these gains in mechanistic insight, many questions still remain, the most pressing of which is the origin of the CO ligand in anaerobic microorganisms. This minireview provides an overview of the current status of this research field and highlights recent advances and unresolved issues.

Zinc (Zn²⁺) plays a pivotal role in T-cell activation by modulating the interactions between the co-receptors CD4 and CD8α and the Src-family kinase Lck. A central structural feature in this regulation is the zinc clasp, a Zn²⁺-mediated CD4/CD8α-Lck receptor interface that stabilizes these complexes during T cell receptor signaling. Recent findings reveal that the stability of CD4-Lck and CD8α-Lck complexes is differentially regulated by Zn²⁺, which acts as a dynamic signaling molecule during T-cell activation. Here, we discuss the structural dynamics of these interactions and the impact of Zn²⁺ on CD4 dimerization, palmitoylation, and membrane interactions, which are crucial for effective T-cell responses. These mechanisms underscore a broader framework in which zinc biology intersects with co-receptor-Lck coupling to guide T-cell development, lineage fidelity, and functional specialization. Beyond immunobiology, zinc-dependent protein-protein interactions offer promising opportunities for biotechnological innovation, particularly in the design of molecular systems that exploit zinc-mediated structural control.

Selenoneine (SEN), a selenium analog of ergothioneine (EGT), is widely distributed in marine fish and is a strong radical scavenger. Electron spin resonance spectrometry showed that SEN monomer and dimer directly scavenged ·OH generated by irradiating hydrogen peroxide (H2O2) with ultraviolet light. The radical scavenging capacity was stronger for SEN monomer, dimer, and EGT in that order. Mass spectrometry analyses revealed that the monomer and dimer were oxidized to SEN seleninic acid (SEN-seleninic acid) in the presence of H2O2, and that SEN-seleninic acid was reduced to SEN monomer by reduced glutathione (GSH). These reactions proceeded at physiological concentrations of H2O2 and GSH. Our findings suggest that SEN scavenges ·OH directly by a rapid, repetitive nonenzymatic reaction via self-oxidation and by its reduction back to SEN.

Administration of the cadmium-metallothionein (Cd-MT) complex has been known to cause acute nephrotoxicity due to free Cd ions during the breakdown of the Cd-MT protein in renal cells. However, the fate of the renal Cd after Cd-MT administration remains elusive. We applied Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) to visualize Cd distribution in the kidneys of mice administered Cd-MT. In the initial several hours, Cd was detected predominantly in the renal cortex. Elevated urinary β2-microglobulin and glucose within a day and rapid induction of MT-I mRNA indicated the generation of toxic free Cd ions. Unexpectedly, however, the Cd distribution changed drastically: from the cortex to the boundary of the cortex and outer medulla until 3 days. From 3 to 18 h, renal Cd concentrations decreased rapidly, accompanied by a large amount of urinary Cd excretion. These results suggest that the injected Cd-MT was transiently distributed in the surface nephrons in the cortex, and the free Cd ions derived from the decomposed Cd-MT were released into the lumen of proximal tubules and then partly reabsorbed at the boundary of the cortex and outer medulla, where the S3-segment proximal tubules exist abundantly. Thus, the LA-ICP-MS revealed dynamic changes in Cd distribution, suggesting the intra-renal transport of the Cd-MT-derived free Cd ions in the kidneys.

Volcanic ash is a significant source of micronutrients including iron (Fe), copper (Cu), and zinc (Zn) in oligotrophic tropical waters. These bioactive metals enhance primary productivity, influencing local and global biogeochemical cycles. This study explores how volcanic ash exposure affects trace metal uptake and photophysiological response, and how redox-sensitive metal stable isotope measurements in the tissues of the scleractinian coral Stylophora pistillata can provide crucial information on coral health. Controlled coral culture experiments were conducted in which coral nubbins were exposed to varying intensity and duration of volcanic ash. Throughout the experiment, coral symbionts showed enhanced photosynthetic performance irrespective of intensity or duration of ash exposure. Stable isotopes, such as δ65Cu and δ56Fe, in the coral tissue are marked by systematic variations, not associated with intensity or duration of ash exposure. Instead, we suggest biologically modulated redox-sensitive fractionation associated with ash exposure, linked to the coral host's oxidative stress state. This is evidenced by significant correlations between δ65Cu in coral hosts and photophysiology, with lighter Cu isotope ratios associated with higher photosynthetic performances. Hence, we propose that δ65Cu, and more generally redox-sensitive isotopic ratios (i.e. δ56Fe), in coral hosts serves as an indicator of the physiological state of symbiotic corals.

In an attempt to treat neglected diseases such as leishmaniasis and fungal infections, three novel copper(II) hybrid have been developed: [Cu(dppz)(CTZ)(NO3)](NO3) (1), [Cu(dppz)(KTZ)(H2O)(NO3)](NO3) (2), and [Cu(dppz)(FLZ)(NO3)]2(NO3)2 (3). They were synthesized by coordinating antifungal imidazole based drugs and dipyridophenazine as ligands to copper(II) under mild conditions and in good yields. These coordination compounds were characterized by various analytical and spectroscopic techniques which confirmed the coordination of both ligands to the metal, and the monodentate (1) or bidentate (2 and 3) coordination of the nitrate and as counterion. These copper hybrids were stable in solid state, in dimethyl sulfoxide (DMSO) and the DMSO-water mixture. DNA interactions were studied using absorption and fluorescence titrations, viscosity measurements, and electrophoresis assays. Complexes 1 and 2 formed strong interaction with DNA. The activity against Leishmania was the highest with complex 3, unlike against Sporothrix brasiliensis, where the free imidazole-based drugs (ITZ and KTZ) performed better.

In this paper, we critically examine the key challenges associated with the development of inorganic drugs, a field that remains underrepresented despite its significant therapeutic potential. Currently, most clinically approved pharmaceuticals are organic compounds, a trend driven by multiple interconnected factors that have historically limited the adoption and regulatory approval of metal(loid)-based entities. These challenges include issues related to stability, selectivity, pharmacokinetics, and potential toxicity, which require systematic investigation and innovative solutions. Nevertheless, the profound clinical impact of approved inorganic drugs-particularly transition metal(loid)-based agents for both therapeutic and diagnostic applications-is well-established. The success of these compounds underscores the need for expanded research efforts and optimized clinical protocols to fully harness the advantages of metal-based pharmaceuticals. In this context, we explore emerging strategies to overcome current limitations and accelerate the development of next-generation inorganic drugs. These include the rational design of metal-based therapeutics, the integration of advanced metallomics and metalloproteomics, and the application of AI-driven predictive modeling to improve drug selectivity, bioavailability, and safety. By overcoming these challenges through an interdisciplinary approach, metal-based medicine will advance significantly, expanding its impact across a wide range of therapeutic applications.

Chelation therapy is a promising approach to mitigating health risks associated with toxic metal exposure, which contributes to cardiovascular disease, neurotoxicity, and other chronic conditions. disodium ethylene diamine tetraacetic acid (EDTA) is widely used, but its optimal dosing strategy remains unclear. This study evaluates the dose-dependent efficacy of EDTA in mobilizing toxic metals, including lead (Pb), cadmium (Cd), and gadolinium (Gd), while minimizing the loss of essential metals like copper (Cu) and manganese (Mn) to optimize therapeutic safety and efficacy. Ten volunteers (≥50 years) received 3 infusions at doses of 0.5, 1, and 3 g of EDTA over 30 min, 1 h, and 3 h, respectively. Urine and blood samples were analyzed pre- and post-infusion to assess pharmacokinetics of metal chelation. Urinary Pb excretion increased by 2200% at 0.5 g, with only a marginal gain at higher doses (3300%), supporting low-dose EDTA efficacy. Urinary Cd clearance required 3 g EDTA due to its strong tissue binding. Notably, Gd excretion increased by up to 78 000% even at 0.5 g EDTA, highlighting EDTA's potential to reduce long-term Gd burden post-MRI. Urinary excretion of essential metals varied, with Mn and Zn loss increasing at higher EDTA doses, underscoring the need for dose optimization while Cu and Ca only showed a clear increase urinary excretion at 3 g EDTA. Overall, a 0.5 g EDTA dose effectively mobilized Pb and Gd while minimizing essential metal depletion, reducing infusion time to 30 min, and improving patient compliance. These findings align with TACT and TACT 2 studies, reinforcing EDTA's long-term benefits in Pb reduction and supporting low-dose EDTA as a safe, efficient, and well-tolerated detoxification strategy.