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Current Opinion in Chemical Biology Apr 2020Metals play an essential role in biological systems and are required as structural or catalytic co-factors in many proteins. Disruption of the homeostatic control and/or... (Review)
Review
Metals play an essential role in biological systems and are required as structural or catalytic co-factors in many proteins. Disruption of the homeostatic control and/or spatial distributions of metals can lead to disease. Imaging technologies have been developed to visualize elemental distributions across a biological sample. Measurement of elemental distributions by imaging mass spectrometry and imaging X-ray fluorescence are increasingly employed with technologies that can assess histological features and molecular compositions. Data from several modalities can be interrogated as multimodal images to correlate morphological, elemental, and molecular properties. Elemental and molecular distributions have also been axially resolved to achieve three-dimensional volumes, dramatically increasing the biological information. In this review, we provide an overview of recent developments in the field of metal imaging with an emphasis on multimodal studies in two and three dimensions. We specifically highlight studies that present technological advancements and biological applications of how metal homeostasis affects human health.
Topics: Animals; Biosensing Techniques; Coenzymes; Homeostasis; Humans; Mass Spectrometry; Metalloproteins; Metals; Models, Theoretical; Molecular Imaging; Multimodal Imaging; Optical Imaging
PubMed: 32087551
DOI: 10.1016/j.cbpa.2020.01.008 -
Biology Letters Apr 2022Intracellular ligands that bind heavy metals (HMs) and thereby minimize their detrimental effects to cellular metabolism are attracting great interest for a number of...
Intracellular ligands that bind heavy metals (HMs) and thereby minimize their detrimental effects to cellular metabolism are attracting great interest for a number of applications including bioremediation and development of HM-biosensors. Metallothioneins (MTs) are short, cysteine-rich, genetically encoded proteins involved in intracellular metal-binding and play a key role in detoxification of HMs. We searched approximately 700 genomes and transcriptomes of non-ciliate protists for novel putative MTs by similarity and structural analyses and found 21 unique proteins playing a potential role as MTs. Most putative MTs derive from heterokonts and dinoflagellates and share common features such as (i) a putative metal-binding domain in proximity of the N-terminus, (ii) two putative MT-specific domains near the C-terminus and (iii) one to three CTCGXXCXCGXXCXCXXC patterns. Although the biological function of these proteins has not been experimentally proven, knowledge of their genetic sequences adds useful information on proteins that are potentially involved in HM-binding and can contribute to the design of future biomolecular assays on HM-microbe interactions and MT-based biosensors.
Topics: Computational Biology; Metallothionein; Metals, Heavy
PubMed: 35414221
DOI: 10.1098/rsbl.2022.0039 -
The FEBS Journal Jul 2017The high-potential iron-sulfur protein (HiPIP) is a small (~ 80 residues) soluble metalloprotein functioning as an electron carrier in photosynthetic bacteria. HiPIP has... (Review)
Review
The high-potential iron-sulfur protein (HiPIP) is a small (~ 80 residues) soluble metalloprotein functioning as an electron carrier in photosynthetic bacteria. HiPIP has one Fe S cluster at its molecular center. Its electronic structure is important for understanding electron transport. We recently succeeded in determining an ultra-high-resolution structure and analyzing the charge-density of HiPIP by using X-ray diffraction data at 0.48 Å resolution. The distribution of valence electrons in the iron-sulfur cluster and in the protein environment were clearly visualized, which is the first successful case for metalloproteins. In addition, a topological analysis of the charge density provided information about the electronic structure of the cluster.
Topics: Bacteria; Bacterial Proteins; Crystallography, X-Ray; Electron Transport; Electrons; Iron-Sulfur Proteins; Photosynthesis; Photosynthetic Reaction Center Complex Proteins; Protein Conformation
PubMed: 28165666
DOI: 10.1111/febs.14036 -
International Journal of Molecular... Jan 2016A significant number of chemical elements are either essential for life with known functions, or present in organisms with poorly defined functional outcomes. We do not... (Review)
Review
A significant number of chemical elements are either essential for life with known functions, or present in organisms with poorly defined functional outcomes. We do not know all the essential elements with certainty and we know even less about the functions of apparently non-essential elements. In this article, I discuss a basis for a biological periodic system of the elements and that biochemistry should include the elements that are traditionally part of inorganic chemistry and not only those that are in the purview of organic chemistry. A biological periodic system of the elements needs to specify what "essential" means and to which biological species it refers. It represents a snapshot of our present knowledge and is expected to undergo further modifications in the future. An integrated approach of biometal sciences called metallomics is required to understand the interactions of metal ions, the biological functions that their chemical structures acquire in the biological system, and how their usage is fine-tuned in biological species and in populations of species with genetic variations (the variome).
Topics: Animals; Computational Biology; Diet; Humans; Metalloproteins; Metals; Micronutrients
PubMed: 26742035
DOI: 10.3390/ijms17010066 -
Journal of the American Chemical Society Feb 2021Dinuclear iron centers with a bridging hydroxido or oxido ligand form active sites within a variety of metalloproteins. A key feature of these sites is the ability of...
Dinuclear iron centers with a bridging hydroxido or oxido ligand form active sites within a variety of metalloproteins. A key feature of these sites is the ability of the protein to control the structures around the Fe centers, which leads to entatic states that are essential for function. To simulate this controlled environment, artificial proteins have been engineered using biotin-streptavidin (Sav) technology in which Fe complexes from adjacent subunits can assemble to form [Fe-(μ-OH)-Fe] cores. The assembly process is promoted by the site-specific localization of the Fe complexes within a subunit through the designed mutation of a tyrosinate side chain to coordinate the Fe centers. An important outcome is that the Sav host can regulate the Fe···Fe separation, which is known to be important for function in natural metalloproteins. Spectroscopic and structural studies from X-ray diffraction methods revealed uncommonly long Fe···Fe separations that change by less than 0.3 Å upon the binding of additional bridging ligands. The structural constraints imposed by the protein host on the di-Fe cores are unique and create examples of active sites having entatic states within engineered artificial metalloproteins.
Topics: Biomimetic Materials; Biotin; Iron; Metalloproteins; Models, Molecular; Molecular Conformation; Streptavidin
PubMed: 33528256
DOI: 10.1021/jacs.0c12564 -
Journal of Biological Inorganic... Aug 2014The ferritin superfamily contains several protein groups that share a common fold and metal coordinating ligands. The different groups utilize different dinuclear... (Review)
Review
The ferritin superfamily contains several protein groups that share a common fold and metal coordinating ligands. The different groups utilize different dinuclear cofactors to perform a diverse set of reactions. Several groups use an oxygen-activating di-iron cluster, while others use di-manganese or heterodinuclear Mn/Fe cofactors. Given the similar primary ligand preferences of Mn and Fe as well as the similarities between the binding sites, the basis for metal specificity in these systems remains enigmatic. Recent data for the heterodinuclear cluster show that the protein scaffold per se is capable of discriminating between Mn and Fe and can assemble the Mn/Fe center in the absence of any potential assembly machineries or metal chaperones. Here we review the current understanding of the assembly of the heterodinuclear cofactor in the two different protein groups in which it has been identified, ribonucleotide reductase R2c proteins and R2-like ligand-binding oxidases. Interestingly, although the two groups form the same metal cluster they appear to employ partly different mechanisms to assemble it. In addition, it seems that both the thermodynamics of metal binding and the kinetics of oxygen activation play a role in achieving metal specificity.
Topics: Catalytic Domain; Iron; Manganese; Metalloproteins; Models, Molecular
PubMed: 24771036
DOI: 10.1007/s00775-014-1140-7 -
Chemical Communications (Cambridge,... Oct 2022There is growing interest in the design of bimetallic cooperative complexes, which have emerged due to their potential for bond activation and catalysis, a feature... (Review)
Review
There is growing interest in the design of bimetallic cooperative complexes, which have emerged due to their potential for bond activation and catalysis, a feature widely exploited by nature in metalloenzymes, and also in the field of heterogeneous catalysis. Herein, we discuss the widespread opportunities derived from combining two metals in close proximity, ranging from systems containing multiple M-M bonds to others in which bimetallic cooperation occurs even in the absence of M⋯M interactions. The choice of metal pairs is crucial for the reactivity of the resulting complexes. In this context, we describe the prospects of combining not only transition metals but also those of the main group series, which offer additional avenues for cooperative pathways and reaction discovery. Emphasis is given to mechanisms by which bond activation occurs across bimetallic structures, which is ascribed to the precise synergy between the two metal atoms. The results discussed herein indicate a future landscape full of possibilities within our reach, where we anticipate that bimetallic synergism will have an important impact in the design of more efficient catalytic processes and the discovery of new catalytic transformations.
Topics: Catalysis; Metalloproteins; Metals; Transition Elements
PubMed: 36128973
DOI: 10.1039/d2cc04296g -
American Journal of Physiology. Renal... Nov 2023The transmembrane protein SLC22A17 [or the neutrophil gelatinase-associated lipocalin/lipocalin-2 (LCN2)/24p3 receptor] is an atypical member of the SLC22 family of... (Review)
Review
The transmembrane protein SLC22A17 [or the neutrophil gelatinase-associated lipocalin/lipocalin-2 (LCN2)/24p3 receptor] is an atypical member of the SLC22 family of organic anion and cation transporters: it does not carry typical substrates of SLC22 transporters but mediates receptor-mediated endocytosis (RME) of LCN2. One important task of the kidney is the prevention of urinary loss of proteins filtered by the glomerulus by bulk reabsorption of multiple ligands via megalin:cubilin:amnionless-mediated endocytosis in the proximal tubule (PT). Accordingly, overflow, glomerular, or PT damage, as in Fanconi syndrome, results in proteinuria. Strikingly, up to 20% of filtered proteins escape the PT under physiological conditions and are reabsorbed by the distal nephron. The renal distal tubule and collecting duct express SLC22A17, which mediates RME of filtered proteins that evade the PT but with limited capacity to prevent proteinuria under pathological conditions. The kidney also prevents excretion of filtered essential and nonessential transition metals, such as iron or cadmium, respectively, that are largely bound to proteins with high affinity, e.g., LCN2, transferrin, or metallothionein, or low affinity, e.g., microglobulins or albumin. Hence, increased uptake of transition metals may cause nephrotoxicity. Here, we assess the literature on SLC22A17 structure, topology, tissue distribution, regulation, and assumed functions, emphasizing renal SLC22A17, which has relevance for physiology, pathology, and nephrotoxicity due to the accumulation of proteins complexed with transition metals, e.g., cadmium or iron. Other putative renal functions of SLC22A17, such as its contribution to osmotic stress adaptation, protection against urinary tract infection, or renal carcinogenesis, are discussed.
Topics: Humans; Lipocalin-2; Metalloproteins; Cadmium; Iron; Metallothionein; Kidney Tubules, Proximal; Proteinuria; Nephrosis; Endocytosis; Low Density Lipoprotein Receptor-Related Protein-2; Organic Cation Transport Proteins
PubMed: 37589051
DOI: 10.1152/ajprenal.00020.2023 -
Journal of Inorganic Biochemistry Jun 2021The recent pandemic caused by the novel coronavirus resulted in the greatest global health crisis since the Spanish flu pandemic of 1918. There is limited knowledge of...
The recent pandemic caused by the novel coronavirus resulted in the greatest global health crisis since the Spanish flu pandemic of 1918. There is limited knowledge of whether SARS-CoV-2 is physically associated with human metalloproteins. Recently, high-confidence, experimentally supported protein-protein interactions between SARS-CoV-2 and human proteins were reported. In this work, 58 metalloproteins among these human targets have been identified by a structure-based approach. This study reveals that most human metalloproteins interact with the recently discovered SARS-CoV-2 orf8 protein, whose antibodies are one of the principal markers of SARS-CoV-2 infections. Furthermore, this work provides sufficient evidence to conclude that Zn plays an important role in the interplay between the novel coronavirus and humans. First, the content of Zn-binding proteins in the involved human metalloproteome is significantly higher than that of the other metal ions. Second, a molecular linkage between the identified human Zn-binding proteome with underlying medical conditions, that might increase the risk of severe illness from the SARS-CoV-2 virus, has been found. Likely perturbations of host cellular metal homeostasis by SARS-CoV-2 infection are highlighted.
Topics: COVID-19; Carrier Proteins; Host-Pathogen Interactions; Humans; Metalloproteins; Nervous System Diseases; SARS-CoV-2; Viral Proteins
PubMed: 33813307
DOI: 10.1016/j.jinorgbio.2021.111423 -
Journal of Biological Inorganic... Sep 2016Binuclear non-heme iron enzymes activate O2 to perform diverse chemistries. Three different structural mechanisms of O2 binding to a coupled binuclear iron site have... (Review)
Review
Binuclear non-heme iron enzymes activate O2 to perform diverse chemistries. Three different structural mechanisms of O2 binding to a coupled binuclear iron site have been identified utilizing variable-temperature, variable-field magnetic circular dichroism spectroscopy (VTVH MCD). For the μ-OH-bridged Fe(II)2 site in hemerythrin, O2 binds terminally to a five-coordinate Fe(II) center as hydroperoxide with the proton deriving from the μ-OH bridge and the second electron transferring through the resulting μ-oxo superexchange pathway from the second coordinatively saturated Fe(II) center in a proton-coupled electron transfer process. For carboxylate-only-bridged Fe(II)2 sites, O2 binding as a bridged peroxide requires both Fe(II) centers to be coordinatively unsaturated and has good frontier orbital overlap with the two orthogonal O2 π* orbitals to form peroxo-bridged Fe(III)2 intermediates. Alternatively, carboxylate-only-bridged Fe(II)2 sites with only a single open coordination position on an Fe(II) enable the one-electron formation of Fe(III)-O2 (-) or Fe(III)-NO(-) species. Finally, for the peroxo-bridged Fe(III)2 intermediates, further activation is necessary for their reactivities in one-electron reduction and electrophilic aromatic substitution, and a strategy consistent with existing spectral data is discussed.
Topics: Catalytic Domain; Nonheme Iron Proteins; Quantum Theory
PubMed: 27369780
DOI: 10.1007/s00775-016-1372-9