Bioessential Metals Research Articles

Transferrin-inspired iron delivery across the cell membrane using [(L2Fe)2(μ-O)] (L = chlorquinaldol) to harness anticancer activity of ferroptosis.

Although iron is a bio-essential metal, dysregulated iron acquisition and metabolism result in production of reactive oxygen species (ROS) due to the Fenton catalytic reaction, which activates ferroptotic cell death pathways. The lipophilic Fe(III)-chelator chlorquinaldol (L; i.e., 5,7-dichloro-8-hydroxy-2-methylquinoline) strongly favors the formation of a highly stable binuclear Fe(III) complex [(L2Fe)2(μ-O)] (1) that can mimic the function of the Fe(III)-transferrin complex in terms of the strong binding to Fe(III) and facile release of Fe(II) when the metal center is reduced. It should be noted that the cellular uptake of 1 is not transferrin receptor-mediated but enhanced by the high lipophilicity of chlorquinaldol. Once 1 is transported across the cell membrane, Fe(III) can be reduced by ferric reductase or other cellular antioxidants to be released as Fe(II), which triggers the Fenton catalytic reaction, thus harnessing the anticancer activity of iron. As the result, this transferrin-inspired iron-delivery strategy significantly reduces the cytotoxicity of 1 in normal human embryonic kidney cells (HEK 293) and the hemolytic activity of 1 in human red blood cells (hRBCs), giving rise to the unique tumor-specific anticancer activity of this Fe(III) complex.

Chemical conditions on Hycean worlds.

Traditionally, the search for life on exoplanets has been predominantly focused on rocky exoplanets. The recently proposed Hycean worlds have the potential to significantly expand and accelerate the search for life elsewhere. Hycean worlds are a class of habitable sub-Neptunes with planet-wide oceans and H2-rich atmospheres. Their broad range of possible sizes and temperatures lead to a wide habitable zone and high potential for discovery and atmospheric characterization using transit spectroscopy. Over a dozen candidate Hycean planets are already known to be transiting nearbyM dwarfs, making them promising targets for atmospheric characterization with the James Webb Space Telescope (JWST). In this work, we investigate possible chemical conditions on a canonical Hycean world, focusing on (a) the present and primordial molecular composition of the atmosphere, and (b) the inventory of bioessential elements for the origin and sustenance of life in the ocean. Based on photochemical and kinetic modeling for a range of conditions, we discuss the possible chemical evolution and observable present-day composition of its atmosphere. In particular, for reduced primordial conditions the early atmospheric evolution passes through a phase that is rich in organic molecules that could provide important feedstock for prebiotic chemistry. We investigate avenues for delivering bioessential metals to the ocean, considering the challenging lack of weathering from a rocky surface and the ocean separated from the rocky core by a thick icy mantle. Based on ocean depths from internal structure modelling and elemental estimates for the early Earth's oceans, we estimate the requirements for bioessential metals in such a planet. We find that the requirements can be met for plausible assumptions about impact history and atmospheric sedimentation, and supplemented by other steady state sources. We discuss the observational prospects for atmospheric characterisation of Hycean worlds with JWST and future directions of this new paradigm in the search for life on exoplanets.

Metal complexation, FT-IR characterization, and plankton abundance in the marine surface microlayer of coastal areas in the Eastern Mediterranean

Barely any data exist on metal speciation in the marine surface microlayer (SML), a rather complex environment, the study of which contributes to enhancement of knowledge on metal speciation and its effect to the ocean. Metal speciation is significant since life requires a wide variety of trace metals that are essential for the growth of the organisms. Ligand concentrations (L) of copper (Cu), zinc (Zn), and cadmium (Cd) were studied by anodic stripping voltammetry (ASV) in the SML of coastal areas within the Aegean Sea in the Eastern Mediterranean. Complexing capacities in the SML in decreasing order ranged for Cu from 29 to 201 nM (median 101 nM), for Zn 24–149 nM (45 nM), and for Cd 1.0–1.5 nM (1.4 nM). Average enrichment factors (EFs) of SML samples compared to subsurface ones (SSW) were calculated equal to 0.9 ± 0.8, 1.2 ± 0.5, and 1.7 ± 1.6 for LZn, LCu, and LCd, respectively. In five out of the six total paired samples of SML and SSW, lower concentrations of LZn were measured in the SML, which is not the case for LCu and LCd. Due to elevated dissolved Zn concentrations in the SML, its complexation is incomplete, contrary to those of Cu and Cd, which are fully complexed. These trace metals are essential nutrients for biological functions, hence any differences on their concentration and chemical speciation may directly influence the distribution of phytoplankton species in the upper water column and neuston. EFs of SML relatively to subsurface water ranged in average between 1.2 and 2.4 for total organic carbon (TOC), chlorophyll a (Chla), and plankton, being generally >2 for most of the amino acids detected, demonstrating a relative enrichment of the SML in organic matter. A significant correlation was found between Cu ligands and dinoflagellates <20 μm, confirming older findings supporting that marine dinoflagellates of Gymnodinium genera produce Cu ligands. New insights are provided in the study and the importance of investigating bio-essential metal ions (Cu, Zn, Cd) and their organic complexes in the SML is pointed. Data on Zn and Cd complexing capacities in the SML are the first published so far.

Surface water oxygenation and bioproductivity – A link provided by combined chromium and cadmium isotopes in Early Cambrian metalliferous black shales (Nanhua Basin, South China)

The intrinsic link between atmospheric oxygenation, surface seawater redox and bioproductivity in the upper water column of oceans offers to combine cadmium with chromium isotopes in marine archives to deduce information on past controls of biological metal and nutrient cycling. We here use a novel approach in combining chromium and cadmium isotope signatures in metalliferous and organic matter (OM) rich shales from the Early Cambrian Niutitang formation (south China) to reconstruct the surface water redox and cycling of bioessential metals, in a period directly following the Cambrian animal evolution. The inventory of authigenic Cd in the black shales is controlled by their sulfide abundance, whereas authigenic Cr is dominantly controlled by iron(oxy-)hydroxides and OM. Cadmium isotopes measured on bulk sediments and 3 N HNO3 leachates exhibit ε114Cd values from −1.5 to +4.5, with MoNi rich sulfidic shales revealing elevated values > + 2.5. Chromium isotopes define δ53Cr values from +0.4 to +1.7‰, with V-rich non-sulfidic shales yielding more positively fractionated signatures than MoNi rich sulfidic shales. The negative δ53Cr-ε114Cd correlation trend recorded in the black shales suggests a high-ε114Cd sulfide endmember of authigenic Cd preserved in anoxic bottom conditions. The other endmember is constituted by OM with the isotopically heavy Cr and light Cd signals reflecting efficient phytoplankton uptake in the photic zone. The endmembers constrain the Cd and Cr isotope signatures of surface waters in the Early Cambrian Nanhua Basin to ε114Cd of ~ +7 to +17, and to δ53Cr of ~ + 0.7 to +1.9‰. These values are compatible with those of modern ocean surface waters and attest to a Cambrian surface ocean water sustaining elevated primary bioproductivity in the aftermath of late Ediacaran snowball Earth glaciations. Our study emphasizes the potential of the CrCd double tracer in studies aimed at the reconstruction of paleoproductivity and (bio)geochemical metal cycling in marine paleo-basins.

Trace Metal and Cd Isotope Systematics of the Basal Datangpo Formation, Yangtze Platform (South China) Indicate Restrained (Bio)Geochemical Metal Cycling in Cryogenian Seawater

The behaviour of bioavailable trace metals and their stable isotopes in the modern oceans is controlled by uptake into phototrophic organisms and adsorption on and incorporation into marine authigenic minerals. Among other bioessential metals, Cd and its stable isotopes have recently been used in carbonate lithologies as novel tracer for changes in the paleo primary productivity and (bio)geochemical cycling. However, many marine sediments that were deposited during geologically highly relevant episodes and which, thus, urgently require study for a better understanding of the paleo environment are rather composed of a mixture of organic matter (OM), and detrital and authigenic minerals. In this study, we present Cd concentrations and their isotopic compositions as well as trace metal concentrations from sequential leachates of OM-rich shales of the Cryogenian basal Datangpo Formation, Yangtze Platform (South China). Our study shows variable distribution of conservative and bioavailable trace metals as well as Cd isotope compositions between sequential leachates of carbonate, OM, sulphide, and silicate phases. We show that the Cd isotope compositions obtained from OM leachates can be used to calculate the ambient Cryogenian surface seawater of the restricted Nanhua Basin by applying mass balance calculations. By contrast, early diagenetic Mn carbonates and sulphides incorporated the residual Cd from dissolved organic matter that was in isotopic equilibrium with deep/pore waters of the Nanhua Basin. Our model suggests that the Cd isotopic composition of surface seawater at that time reached values of modern oxygenated surface oceans. However, the deep water Cd isotope composition was substantially heavier than that of modern fully oxygenated oceans and rather resembles deep waters with abundant sulphide precipitation typical for modern oxygen minimum zones. This argues for incomplete recycling of Cd and other bioavailable metals shortly after the Sturtian glaciation in the redox stratified Cryogenian Nanhua Basin. Our study highlights the importance of sequential leaching procedures when dealing with impure authigenic sediments such as OM-rich carbonates, mudstones, or shales to achieve reliable trace metal concentrations and Cd isotope compositions as proxies for (bio)geochemical metal cycling in past aquatic systems.

Cd isotopes trace periodic (bio)geochemical metal cycling at the verge of the Cambrian animal evolution

Abstract Cadmium (Cd) isotopes are an emerging proxy for biological controlled metal and nutrient cycling in the modern oceans, but its potential as a geochemical proxy in ancient environments is still uncertain yet. Sequential leaching experiments of organic matter (OM)-rich shales from the early Cambrian Niutitang Formation (Fm.) were performed in order to understand the cycling of bioessential metals short after the Cambrian animal evolution. Carbonate, OM, sulphide and silicate leachates of OM-rich shales show an overall Cd isotope variation of 6 e112Cd/110Cd (e112Cd) units, indicating preferential incorporation of light Cd isotopes in the order sulphide > OM > carbonate > silicate. Carbonate leachates not only show negative correlations of e112Cd with bulk-rock total organic carbon (TOC) and δ13Corg but also show co-variations with redox-sensitive elements and bioessential metal concentrations, indicating a combined redox and primary productivity evolution of the early Cambrian Nanhua Basin on the Yangtze. Together with increased Cd/Zn ratios and decreasing total organic carbon (TOC) and redox-sensitive elements (RSE) concentrations in the upper Niutitang, this argues for an increase in essential metal availability for primary producers. Coinciding with the transition from a highly unstable ecosystem shortly after the Precambrian/Cambrian boundary to a more habitable environment increased nutrient uptake, oxygen availability and enhanced dissolved organic carbon (DOC) recycling match with the diversification of early metazoan fossil findings at the studied local. Our findings demonstrate that Cd isotopes in combination with trace metals can be used to infer changes in biogeochemical metal cycling in paleoenvironments and further allow establishing Cd isotope systematics as a reliable paleoproductivity proxy in the search for Earth’s earliest phototrophic life.

Study of complexation of dopamine analogues with bioactive metals by cyclic voltammetry

Dopamine analogues are reported to have remarkable biological activities. Levodopa and carbidopa are the active ingredients of drugs used for the treatment of Parkinson and Alzheimer diseases. Methyldopa is another molecule belonging to the same class of compounds and is used as hypertensive drug. Concurrent ingestion of the metal ions can cause marked changes in the bioavailability of these drug molecules. In the present study, interaction of dopamine analogues with the bioessential metals like iron, copper, and aluminum is investigated. These bioessential metals have a significant role in the normal functioning of the brain and nerves. The work is aimed to establish a convenient, simple, and fast method through which the complexation of dopamine analogues with different bioactive metals can be explored. For this purpose, cyclic voltammetric probe is used and electrochemical parameters of electroactive drug in the presence and absence of metal ion are served as an analytical tool. It was found that the drug molecule undergoes coupled chemical reaction with the metal ions, and this interaction is pH dependent. Electrochemical behavior of the drug molecule was found to be changed in the presence of the metal ion.

Biological relevance of CuFeO2 nanoparticles: Antibacterial and anti-inflammatory activity, genotoxicity, DNA and protein interactions

Heterometal oxide nanoparticles of bioessential metals are shedding new light to nanoparticle-inspired bioapplications. Pairing bioreactive elements like copper and iron can affect the redox dynamic and biological profile of the nanomaterial. Given the complexity of physicochemical properties, biological activity and toxicity concerns, extensive exploration is demanded, especially when active and less active oxidation states participate as in case of cuprous-ferric delafossite CuFeO2 (copper(I)-iron(III)), a less widespread nanomaterial. In that vein, CuFeO2 nanoparticles were synthesized and biological profile was evaluated in comparison with cuprous oxide (Cu2O NPs) counterpart, an already established antimicrobial agent. Interactions with bacteria, proteins and DNA were examined. Cu2O NPs exhibited stronger antibacterial activity (IC50 < 25 μg/ml) than CuFeO2 NPs (IC50 > 100 μg/ml). In vitro exposure of nanoparticles on plasmid DNA unveiled toxicity in the form of DNA damage for Cu2O and enhanced biocompatibility for CuFeO2 NPs. Genotoxicity estimated by the frequency of sister chromatid exchanges, cytostaticity based on the proliferating rate indices and cytotoxicity based on the mitotic indices at human peripheral lymphocyte cultures were all significantly lower in the case of CuFeO2 NPs. Furthermore, through in vitro albumin denaturation assay, CuFeO2 NPs showed better performance in protein denaturation protection, correlating in superior anti-inflammatory activity than Cu2O and similar to acetylsalicylic acid. Synergy of copper(I)-iron(III) in nanoscale is apparent and gives rise to fruitful bioapplications and perspectives.

Facile Synthesis of Mg2+‐Doped Carbon Dots as Novel Biomaterial Inducing Cell Osteoblastic Differentiation

AbstractCarbon dots (CDs), as an emerging fluorescent nanomaterial with low toxicity, has been widely applied in various bio‐related fields. However, investigations on their capabilities in guiding osteogenic differentiation are rarely seen, which has great significance in osteoporosis therapy and bone regeneration. Herein, for the first time, a new kind of Mg2+‐doped CDs is facilely synthesized through a one‐step hydrothermal method from metal gluconate salts. The CDs can serve as nanocarrier of Mg2+ ions entering into cells, and the bioessential metal ions subsequently stimulate osteoblastic differentiation by improving alkaline phosphatase (ALP) activity and upregulation related mRNA expression. Noteworthy, the raw material has almost negligible performance on osteoblastic differentiation compared to Mg‐CDs, which is due to the ultrasmall sizes of CDs and the efficient uptake by cells. Moreover, benefitting from the fluorescence properties, Mg‐CDs can also be applied as cell labeling agents. This work proposes a new strategy to synthesize multifunctional metal ion‐doped CDs, which might had great potential in serving as promising nanodrugs for bone loss therapy.

Delayed euxinia in Paleoproterozoic intracontinental seas: Vital havens for the evolution of eukaryotes?

Increased flux of sulfate to the oceans in the aftermath of the Great Oxidation Event (GOE) ∼2.4billionyears ago (Ga) caused major changes in seawater chemistry, which eventually contributed to the cessation of iron formation deposition ∼1.8Ga. It is generally accepted that this engendered heterogeneous stratified redox conditions, with anoxic and sulfidic (euxinic) conditions in shallow open-marine environments and anoxic ferruginous conditions in deeper environments. However, the redox evolution of intracontinental marine basins following the cessation of iron formation deposition remains poorly understood.Here, we report contrasting paleoredox conditions in two shale units of the lower McArthur Basin, northern Australia, soon after the cessation of iron formation deposition ∼1.84Ga. Our data shows that the ∼1.78Ga McDermott Formation was deposited in a sulfur-limited, anoxic shallow-marine environment, whereas the younger ∼1.73Ga Wollogorang Formation was deposited in a euxinic shallow-marine environment. This implies a delay in the development of euxinia in a shallow intracontinental basin following the onset of euxinia in the open marine realm. Since bioessential metals are sequestered by pyrite deposition under euxinic conditions, protracted low-sulfidic conditions in 1.78Ga intracontinental shallow environments could have provided vital niches for nitrogen-fixing prokaryotes and eukaryotes. Thus the ability for localized Paleoproterozoic intracontinental basins to remain non-euxinic after the onset of euxinia in shallow open-marine shelves highlights the importance of intracontinental environments to the evolution and diversification of microbial life, perhaps throughout the wider Proterozoic.

Novel bio-essential metal based complexes linked by heterocyclic ligand: Synthesis, structural elucidation, biological investigation and docking analysis

New series of bio-essential metal based complexes linked by Schiff base ligand (L) and 2,2′-bipyridine (bpy) have been synthesized and characterized by diverse spectral techniques such as elemental analysis, magnetic susceptibility, molar conductivity measurements, FT-IR, UV–Vis., 1H NMR, 13C NMR, EPR and Mass. The spectral data suggest that the metal complexes espouse octahedral geometry around the metal ions. Interactions of the complexes with CT DNA have been explored by electronic absorption, ethidium bromide displacement assay, viscosity measurements, cyclic voltammetry and differential pulse voltammetry in order to evaluate the possible DNA-binding mode and to calculate the corresponding DNA-binding constants. The DNA interaction studies propose that the intercalative mode of interaction and the complexes exhibit oxidative cleavage of pUC19 DNA in the presence of hydrogen peroxide as activator. The synthesized Schiff base ligand and its metal complexes have been screened for anti-microbial activity by micro dilution method against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), two Gram-negative bacteria (Escherichia coli and Salmonella typhi) and three fungi strains (Fusarium solani, Aspergillus niger and Candida albicans) revealing that the complexes are good anti-pathogenic agents than the ligand. Moreover, molecular docking analysis has been performed to confirm the nature of binding of the complexes with DNA.

Coupled sulfur, iron and molybdenum isotope data from black shales of the Teplá-Barrandian unit argue against deep ocean oxygenation during the Ediacaran

The Earth’s atmosphere and hydrosphere changed from an Archean anoxic to a modern oxygenated world in two major steps, the Paleoproterozoic Great Oxidation Event (2.4–2.3 billion years ago) and the Neoproterozoic Oxidation Event (0.8–0.5 billion years ago). Both events had a strong influence on the availability of redox sensitive and bio-essential metals within the ocean and are, thus, strongly linked to fundamental biological innovations and diversification. Biological diversification during the Precambrian–Cambrian transition between 555 and 540 million years ago may have been driven by ocean–atmosphere oxygenation. The exact timing and the extent of (deep) ocean oxygenation within this time period remains unresolved though.Here we present major and trace element compositions as well as Mo, S and Fe isotopic data of organic-rich black shales from the Teplá-Barrandian unit, Czech Republic. New in situ zircon U–Pb ages provide a maximum depositional age of 559.8±3.8 million years. Black shales with strong metal enrichment show low δ56Fe values due to the dominance of authigenic pyrite-Fe with δ56Fe values around −0.6‰ over detrital Fe with δ56Fe values around 0.1‰. Samples with lower authigenic metal enrichment show relatively low Mo/TOC ratios and increasing δ34S values, which is interpreted to reflect basinal restriction and longer seawater renewal times. In analogy to the modern Black Sea, the accompanied depletion of basinal Moaq due to near quantitative Mo removal might have led to the preservation of the seawater δ98Mo in the respective black shales. Our best estimate for this seawater Mo isotopic composition <560 million years ago is +1.2‰ in δ98Mo, which is nearly identical to seawater δ98Mo values inferred from Mid-Proterozoic black shales. The lack of higher δ98Mo values in black shales (and seawater) argues against contemporaneous Mn oxide formation in well oxygenated deep sea settings, which would preferentially adsorb isotopically light Mo leaving behind an isotopically heavy ocean. By contrast, the deep ocean might have remained ferruginous with the hydrothermal Fe still outbalancing surficial oxygen production. Our results therefore contribute to a growing data set, which suggests limited deep water oxygenation during major biological innovations in the late Ediacaran period.

High Molybdenum availability for evolution in a Mesoproterozoic lacustrine environment.

Trace metal data for Proterozoic marine euxinic sediments imply that the expansion of nitrogen-fixing cyanobacteria and diversification of eukaryotes were delayed while the availability of bioessential metals such as molybdenum in the ocean was limited. However, there is increasing recognition that the Mesoproterozoic evolution of nitrogen fixation and eukaryotic life may have been promoted in marginal marine and terrestrial environments, including lakes, rather than in the deep ocean. Molybdenum availability is critical to life in lakes, just as it is in the oceans. It is, therefore, important to assess molybdenum availability to the lacustrine environment in the Mesoproterozoic. Here we show that the flux of molybdenum to a Mesoproterozoic lake was 1 to 2 orders of magnitude greater than typical fluxes in the modern and ancient marine environment. Thus, there was no barrier to availability to prevent evolution in the terrestrial environment, in contrast to the nutrient-limited Mesoproterozoic oceans.

Investigation of Iron Complex Formation of Anti-Hypertensive Drug: Methyldopa

The drug administered for any disease may play an unwanted function in biological system. They may have multiple counter effects, one of which is their interaction to bioactive metals. Iron is most common bio essential metal and is reported to interact with antihypertensive drug methyldopa. In the present study, above said complex is analyzed by UV-Visible spectrophotometry. Formation constant of the complex is calculated by using mole ratio method and single point statistical method which is in the range of 1010, values are also calculated which are independent of pH like formation constant. Absorbance maxima were found to be dependent on pH. At lower pH complex shows two broad bands centered at 430 nm and 730 nm. With the rise in pH later peak shifts toward lower wavelength, so 615 nm is selected for further studies. Molar extinction coefficient of the complex is explored by serial dilution method. At all wavelengths it increases with increase in pH. Mole ratio and slope ratio methods are used for exploring stoichiometry. Metal to ligand combining ratio in the complex is 1:2 at pH 4.0 and pH 4.5 while 1:3 at pH 5.0 and pH 5.5.

Hydrolytic Activity of Amyloid-beta and its Inhibition with Short Peptides

The main component of the amyloid plaque is insoluble Aβ1-42 (Aβ42), which adopts a structure rich in antiparallel β-pleated sheets. Recently, increasing awareness of Aβ intermediates as molten-globule states has paralleled insight into the biological activities of the Aβ conformer. The molten-globule state of Aβ42 displays a less ordered, metastable conformation that is stabilized by the formation of fibrils. The molten-globule state of the protein has many biological properties and understanding the mechanisms of its formation is an important step in devising a therapeutic strategy for Alzheimers disease. There have been many studies of the biological properties of Aβ42 such as self-aggregation, binding to other proteins such as apolipoprotein E, cytotoxicity for neuronal cells, vasoconstriction, oxidative activity with superoxide-mediated singlet-oxygen intermediate and proteolytic activity against casein. Recent studies demonstrated that α-1 anti-chymotrypsin, a member of the serine protease inhibitor (serpin) family is also involved in the amyloid plaque. In this review, we focused on the serine protease-like activity of Aβ42 for casein substrate and the effect of bio-essential metal ions for the activity and also suggest its inhibition with Aβ42 derivatives; Aβ15-22 (QKLVFFAE) which is a potential fragment to prevent Aβ self-aggregation. Consequently, we suggest that the short peptides of this kind may be of use in the therapy of Alzheimers disease. Keywords: alzheimers disease, guanidine hydrochloride, molten-globule, ab peptides, serine protease-like activity, selfaggregation, metal ions, eight-residue derivatives

Production of a molybdophore during metal-targeted dissolution of silicates by soil bacteria

Although many bioessential metals are scarce in natural water and rock systems, microbial secretion of high-affinity ligands for metal extraction from solid phases has only been documented for Fe. However, we have discovered that Mo is extracted from a silicate by a high-affinity ligand (a possible “molybdophore”) secreted by an N 2-fixing soil bacterium. The putative molybdophore, aminochelin, is secreted as a siderophore under Fe-depleted conditions, but is also secreted under Fe-sufficient, Mo-depleted conditions. Presumably, molybdophore production facilitates uptake of Mo for use in Mo enzymes. In contrast, an Fe-requiring soil bacterium without a special Mo requirement only enhances the release of Fe from the silicate. Fractionation of Mo stable isotopes during uptake to cells may provide a “fingerprint” for the importance of chelating ligands in such systems. Many such metal-specific ligands secreted by prokaryotes for extraction of bioessential metals, their effects on Earth materials, and their possible utility in the recovery of economic metals remain to be discovered.

Dramatic Aggregation of Alzheimer Aβ by Cu(II) Is Induced by Conditions Representing Physiological Acidosis

The cortical deposition of Abeta is an event that occurs in Alzheimer's disease, Down's syndrome, head injury, and normal aging. Previously, in appraising the effects of different neurochemical factors that impact upon the solubility of Abeta, we observed that Zn2+ was the predominant bioessential metal to induce the aggregation of soluble Abeta at pH 7.4 in vitro and that this reaction is totally reversible with chelation. We now report that unlike other biometals tested at maximal biological concentrations, marked Cu2+-induced aggregation of Abeta1-40 emerged as the solution pH was lowered from 7.4 to 6.8 and that the reaction was completely reversible with either chelation or alkalinization. This interaction was comparable to the pH-dependent effect of Cu2+ on insulin aggregation but was not seen for aprotinin or albumin. Abeta1-40 bound three to four Cu2+ ions when precipitated at pH 7.0. Rapid, pH-sensitive aggregation occurred at low nanomolar concentrations of both Abeta1-40 and Abeta1-42 with submicromolar concentrations of Cu2+. Unlike Abeta1-40, Abeta1-42 was precipitated by submicromolar Cu2+ concentrations at pH 7.4. Rat Abeta1-40 and histidine-modified human Abeta1-40 were not aggregated by Zn2+, Cu2+, or Fe3+, indicating that histidine residues are essential for metal-mediated Abeta assembly. These results indicate that H+-induced conformational changes unmask a metal-binding site on Abeta that mediates reversible assembly of the peptide. Since a mildly acidic environment together with increased Zn2+ and Cu2+ are common features of inflammation, we propose that Abeta aggregation by these factors may be a response to local injury. Cu2+, Zn2+, and Fe3+ association with Abeta explains the recently reported enrichment of these metal ions in amyloid plaques in Alzheimer's disease.