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Chemico-biological Interactions Nov 2022In total, twenty elements appear to be essential for the correct functioning of the human body, half of which are metals and half are non-metals. Among those metals that... (Review)
Review
In total, twenty elements appear to be essential for the correct functioning of the human body, half of which are metals and half are non-metals. Among those metals that are currently considered to be essential for normal biological functioning are four main group elements, sodium (Na), potassium (K), magnesium (Mg), and calcium (Ca), and six d-block transition metal elements, manganese (Mn), iron (Fe), cobalt (Co), copper (Cu), zinc (Zn) and molybdenum (Mo). Cells have developed various metallo-regulatory mechanisms for maintaining a necessary homeostasis of metal-ions for diverse cellular processes, most importantly in the central nervous system. Since redox active transition metals (for example Fe and Cu) may participate in electron transfer reactions, their homeostasis must be carefully controlled. The catalytic behaviour of redox metals which have escaped control, e.g. via the Fenton reaction, results in the formation of reactive hydroxyl radicals, which may cause damage to DNA, proteins and membranes. Transition metals are integral parts of the active centers of numerous enzymes (e.g. Cu,Zn-SOD, Mn-SOD, Catalase) which catalyze chemical reactions at physiologically compatible rates. Either a deficiency, or an excess of essential metals may result in various disease states arising in an organism. Some typical ailments that are characterized by a disturbed homeostasis of redox active metals include neurological disorders (Alzheimer's, Parkinson's and Huntington's disorders), mental health problems, cardiovascular diseases, cancer, and diabetes. To comprehend more deeply the mechanisms by which essential metals, acting either alone or in combination, and/or through their interaction with non-essential metals (e.g. chromium) function in biological systems will require the application of a broader, more interdisciplinary approach than has mainly been used so far. It is clear that a stronger cooperation between bioinorganic chemists and biophysicists - who have already achieved great success in understanding the structure and role of metalloenzymes in living systems - with biologists, will access new avenues of research in the systems biology of metal ions. With this in mind, the present paper reviews selected chemical and biological aspects of metal ions and their possible interactions in living systems under normal and pathological conditions.
Topics: Calcium; Catalase; Chromium; Cobalt; Copper; Humans; Ions; Iron; Magnesium; Manganese; Metalloproteins; Molybdenum; Potassium; Sodium; Superoxide Dismutase; Zinc
PubMed: 36152810
DOI: 10.1016/j.cbi.2022.110173 -
Current Environmental Health Reports Sep 2023Biomarkers are commonly used in epidemiological studies to assess metals and metalloid exposure and estimate internal dose, as they integrate multiple sources and routes... (Review)
Review
PURPOSE OF REVIEW
Biomarkers are commonly used in epidemiological studies to assess metals and metalloid exposure and estimate internal dose, as they integrate multiple sources and routes of exposure. Researchers are increasingly using multi-metal panels and innovative statistical methods to understand how exposure to real-world metal mixtures affects human health. Metals have both common and unique sources and routes of exposure, as well as biotransformation and elimination pathways. The development of multi-element analytical technology allows researchers to examine a broad spectrum of metals in their studies; however, their interpretation is complex as they can reflect different windows of exposure and several biomarkers have critical limitations. This review elaborates on more than 500 scientific publications to discuss major sources of exposure, biotransformation and elimination, and biomarkers of exposure and internal dose for 12 metals/metalloids, including 8 non-essential elements (arsenic, barium, cadmium, lead, mercury, nickel, tin, uranium) and 4 essential elements (manganese, molybdenum, selenium, and zinc) commonly used in multi-element analyses.
RECENT FINDINGS
We conclude that not all metal biomarkers are adequate measures of exposure and that understanding the metabolic biotransformation and elimination of metals is key to metal biomarker interpretation. For example, whole blood is a good biomarker of exposure to arsenic, cadmium, lead, mercury, and tin, but it is not a good indicator for barium, nickel, and uranium. For some essential metals, the interpretation of whole blood biomarkers is unclear. Urine is the most commonly used biomarker of exposure across metals but it should not be used to assess lead exposure. Essential metals such as zinc and manganese are tightly regulated by homeostatic processes; thus, elevated levels in urine may reflect body loss and metabolic processes rather than excess exposure. Total urinary arsenic may reflect exposure to both organic and inorganic arsenic, thus, arsenic speciation and adjustment for arsebonetaine are needed in populations with dietary seafood consumption. Hair and nails primarily reflect exposure to organic mercury, except in populations exposed to high levels of inorganic mercury such as in occupational and environmental settings. When selecting biomarkers, it is also critical to consider the exposure window of interest. Most populations are chronically exposed to metals in the low-to-moderate range, yet many biomarkers reflect recent exposures. Toenails are emerging biomarkers in this regard. They are reliable biomarkers of long-term exposure for arsenic, mercury, manganese, and selenium. However, more research is needed to understand the role of nails as a biomarker of exposure to other metals. Similarly, teeth are increasingly used to assess lifelong exposures to several essential and non-essential metals such as lead, including during the prenatal window. As metals epidemiology moves towards embracing a multi-metal/mixtures approach and expanding metal panels to include less commonly studied metals, it is important for researchers to have a strong knowledge base about the metal biomarkers included in their research. This review aims to aid metals researchers in their analysis planning, facilitate sound analytical decision-making, as well as appropriate understanding and interpretation of results.
Topics: Pregnancy; Female; Humans; Cadmium; Arsenic; Manganese; Selenium; Nickel; Barium; Uranium; Tin; Zinc; Mercury; Biomarkers
PubMed: 37337116
DOI: 10.1007/s40572-023-00402-x -
Current Opinion in Chemical Biology Feb 2022Inorganic metals supplement the chemical repertoire of organic molecules, especially proteins. This requires the correct metals to associate with proteins at metalation.... (Review)
Review
Inorganic metals supplement the chemical repertoire of organic molecules, especially proteins. This requires the correct metals to associate with proteins at metalation. Protein mismetalation typically occurs when excesses of unbound metals compete for a binding site ex vivo. However, in biology, excesses of metal-binding sites typically compete for limiting amounts of exchangeable metals. Here, we summarise mechanisms of metal homeostasis that sustain optimal metal availabilities in biology. We describe recent progress to understand metalation by comparing the strength of metal binding to a protein versus the strength of binding to competing sites inside cells.
Topics: Biology; Cobalt; Copper; Manganese; Metals; Zinc
PubMed: 34763208
DOI: 10.1016/j.cbpa.2021.102095 -
The Journal of Biological Chemistry Oct 2014The metal binding preferences of most metalloproteins do not match their metal requirements. Thus, metallation of an estimated 30% of metalloenzymes is aided by metal... (Review)
Review
The metal binding preferences of most metalloproteins do not match their metal requirements. Thus, metallation of an estimated 30% of metalloenzymes is aided by metal delivery systems, with ∼ 25% acquiring preassembled metal cofactors. The remaining ∼ 70% are presumed to compete for metals from buffered metal pools. Metallation is further aided by maintaining the relative concentrations of these pools as an inverse function of the stabilities of the respective metal complexes. For example, magnesium enzymes always prefer to bind zinc, and these metals dominate the metalloenzymes without metal delivery systems. Therefore, the buffered concentration of zinc is held at least a million-fold below magnesium inside most cells.
Topics: Bacillus subtilis; Bacterial Proteins; Biological Transport; Clostridium; Cyanobacteria; Escherichia coli; Helicobacter pylori; Iron; Kinetics; Magnesium; Manganese; Metalloproteins; Models, Molecular; Thermodynamics; Zinc
PubMed: 25160626
DOI: 10.1074/jbc.R114.588145 -
FEBS Letters Jan 2023Metalation, the acquisition of metals by proteins, must avoid mis-metalation with tighter binding metals. This is illustrated by four selected proteins that require... (Review)
Review
Metalation, the acquisition of metals by proteins, must avoid mis-metalation with tighter binding metals. This is illustrated by four selected proteins that require different metals: all show similar ranked orders of affinity for bioavailable metals, as described in a universal affinity series (the Irving-Williams series). Crucially, cellular protein metalation occurs in competition with other metal binding sites. The strength of this competition defines the intracellular availability of each metal: its magnitude has been estimated by calibrating a cells' set of DNA-binding, metal-sensing, transcriptional regulators. This has established that metal availabilities (as free energies for forming metal complexes) are maintained to the inverse of the universal series. The tightest binding metals are least available. With these availabilities, correct metalation is achieved.
Topics: Metals; Metalloproteins; Bacterial Proteins; Cobalt; Copper
PubMed: 36124565
DOI: 10.1002/1873-3468.14500 -
The Biochemical Journal Mar 2021Metal ions play many critical roles in biology, as structural and catalytic cofactors, and as cell regulatory and signalling elements. The metal-protein affinity,... (Review)
Review
Metal ions play many critical roles in biology, as structural and catalytic cofactors, and as cell regulatory and signalling elements. The metal-protein affinity, expressed conveniently by the metal dissociation constant, KD, describes the thermodynamic strength of a metal-protein interaction and is a key parameter that can be used, for example, to understand how proteins may acquire metals in a cell and to identify dynamic elements (e.g. cofactor binding, changing metal availabilities) which regulate protein metalation in vivo. Here, we outline the fundamental principles and practical considerations that are key to the reliable quantification of metal-protein affinities. We review a selection of spectroscopic probes which can be used to determine protein affinities for essential biological transition metals (including Mn(II), Fe(II), Co(II), Ni(II), Cu(I), Cu(II) and Zn(II)) and, using selected examples, demonstrate how rational probe selection combined with prudent experimental design can be applied to determine accurate KD values.
Topics: Animals; Catalysis; Humans; Metals; Protein Binding; Proteins; Thermodynamics
PubMed: 33710331
DOI: 10.1042/BCJ20200838 -
Metal Ions in Life Sciences Apr 2017Heavy metal exposure has long been associated with metallothionein (MT) regulation and its functions. MT is a ubiquitous, cysteine-rich protein that is involved in... (Review)
Review
Heavy metal exposure has long been associated with metallothionein (MT) regulation and its functions. MT is a ubiquitous, cysteine-rich protein that is involved in homeostatic metal response for the essential metals zinc and copper, as well as detoxification of heavy metals; the most commonly proposed being cadmium. MT binds in vivo to a number of metals in addition to zinc, cadmium and copper, such as bismuth. In vitro, metallation with a wide range of metals (especially mercury, arsenic, and lead) has been reported using a variety of analytical methods. To fully understand MT and its role with lead metabolism, we will describe how MT interacts with a wide variety of metals that bind in vitro. In general, affinity to the metal-binding cysteine residues of MT follows that of metal binding to thiols: Zn(II) < Pb(II) < Cd (II) < Cu(I) < Ag(I) < Hg(II) < Bi(III). To introduce the metal binding properties that we feel directly relate to the metallation of metallothionein by Pb(II), we will explore MT's interactions with metals long known as toxic, particularly, Cd(II), Hg(II), and As(III), along with xenobiotic metals, and how these metal-binding studies complement those of lead binding. Lead's effects on an organism's physiological functions are not fully understood, but it is known that chronic exposure inflicts amongst other factors pernicious anemia and developmental issues in the brain, especially in children who are more vulnerable to its toxic effects. Understanding the interaction of lead with metallothioneins throughout the biosphere, from bacteria, to algae, to fish, to humans, is important in determining pathways for lead to enter and damage physiologically significant protein function, and thereby its toxicity.
Topics: Animals; Humans; Lead; Lead Poisoning; Metallothionein; Protein Binding
PubMed: 28731302
DOI: 10.1515/9783110434330-009 -
Frontiers in Cellular and Infection... 2022Metal such as iron, zinc, manganese, and nickel are essential elements for bacteria. These nutrients are required in crucial structural and catalytic roles in biological... (Review)
Review
Metal such as iron, zinc, manganese, and nickel are essential elements for bacteria. These nutrients are required in crucial structural and catalytic roles in biological processes, including precursor biosynthesis, DNA replication, transcription, respiration, and oxidative stress responses. While essential, in excess these nutrients can also be toxic. The immune system leverages both of these facets, to limit bacterial proliferation and combat invaders. Metal binding immune proteins reduce the bioavailability of metals at the infection sites starving intruders, while immune cells intoxicate pathogens by providing metals in excess leading to enzyme mismetallation and/or reactive oxygen species generation. In this dynamic metal environment, maintaining metal homeostasis is a critical process that must be precisely coordinated. To achieve this, bacteria utilize diverse metal uptake and efflux systems controlled by metalloregulatory proteins. Recently, small regulatory RNAs (sRNAs) have been revealed to be critical post-transcriptional regulators, working in conjunction with transcription factors to promote rapid adaptation and to fine-tune bacterial adaptation to metal abundance. In this mini review, we discuss the expanding role for sRNAs in iron homeostasis, but also in orchestrating adaptation to the availability of other metals like manganese and nickel. Furthermore, we describe the sRNA-mediated interdependency between metal homeostasis and oxidative stress responses, and how regulatory networks controlled by sRNAs contribute to survival and virulence.
Topics: Bacteria; Gene Expression Regulation, Bacterial; Ions; Iron; Manganese; Metals; Nickel; Transcription Factors; Virulence
PubMed: 35865816
DOI: 10.3389/fcimb.2022.952948 -
International Journal of Nanomedicine 2022Across the planet, outbreaks of bacterial illnesses pose major health risks and raise concerns. Photodynamic, photothermal, and metal ion release effects of transition... (Review)
Review
Across the planet, outbreaks of bacterial illnesses pose major health risks and raise concerns. Photodynamic, photothermal, and metal ion release effects of transition metal-based nanocomposites (TMNs) were recently shown to be highly effective in reducing bacterial resistance and upsurges in outbreaks. Surface plasmonic resonance, photonics, crystal structures, and optical properties of TMNs have been used to regulate metal ion release, produce oxidative stress, and generate heat for bactericidal applications. The superior properties of TMNs provide a chance to investigate and improve their antimicrobial actions, perhaps leading to therapeutic interventions. In this review, we discuss three alternative antibacterial strategies based on TMNs of photodynamic therapy, photothermal therapy, and metal ion release and their mechanistic actions. The scientific community has made significant efforts to address the safety, effectiveness, toxicity, and biocompatibility of these metallic nanostructures; significant achievements and trends have been highlighted in this review. The combination of therapies together has borne significant results to counter antimicrobial resistance (4-log reduction). These three antimicrobial pathways are separated into subcategories based on recent successes, highlighting potential needs and challenges in medical, environmental, and allied industries.
Topics: Nanocomposites; Anti-Bacterial Agents; Anti-Infective Agents; Transition Elements; Metals
PubMed: 36605560
DOI: 10.2147/IJN.S392081 -
Scientific Reports Oct 2020α-Synuclein is an intrinsically disordered protein that can self-aggregate and plays a major role in Parkinson's disease (PD). Elevated levels of certain metal ions are...
α-Synuclein is an intrinsically disordered protein that can self-aggregate and plays a major role in Parkinson's disease (PD). Elevated levels of certain metal ions are found in protein aggregates in neurons of people suffering from PD, and environmental exposure has also been linked with neurodegeneration. Importantly, cellular interactions with metal ions, particularly Ca, have recently been reported as key for α-synuclein's physiological function at the pre-synapse. Here we study effects of metal ion interaction with α-synuclein at the molecular level, observing changes in the conformational behaviour of monomers, with a possible link to aggregation pathways and toxicity. Using native nano-electrospray ionisation ion mobility-mass spectrometry (nESI-IM-MS), we characterize the heterogeneous interactions of alkali, alkaline earth, transition and other metal ions and their global structural effects on α-synuclein. Different binding stoichiometries found upon titration with metal ions correlate with their specific binding affinity and capacity. Subtle conformational effects seen for singly charged metals differ profoundly from binding of multiply charged ions, often leading to overall compaction of the protein depending on the preferred binding sites. This study illustrates specific effects of metal coordination, and the associated electrostatic charge patterns, on the complex structural space of the intrinsically disordered protein α-synuclein.
Topics: Calcium; Copper; Intrinsically Disordered Proteins; Ion Mobility Spectrometry; Mass Spectrometry; Metals; Potassium; Protein Conformation; Sodium; Zinc; alpha-Synuclein
PubMed: 33004902
DOI: 10.1038/s41598-020-73207-9