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The Journal of Biological Chemistry Oct 2014Mononuclear iron enzymes can tightly bind non-activating metals. How do cells avoid mismetallation? The model bacterium Escherichia coli may control its metal pools so... (Review)
Review
Mononuclear iron enzymes can tightly bind non-activating metals. How do cells avoid mismetallation? The model bacterium Escherichia coli may control its metal pools so that thermodynamics favor the correct metallation of each enzyme. This system is disrupted, however, by superoxide and hydrogen peroxide. These species oxidize ferrous iron and thereby displace it from many iron-dependent mononuclear enzymes. Ultimately, zinc binds in its place, confers little activity, and imposes metabolic bottlenecks. Data suggest that E. coli compensates by using thiols to extract the zinc and by importing manganese to replace the catalytic iron atom. Manganese resists oxidants and provides substantial activity.
Topics: Cations, Divalent; Escherichia coli; Escherichia coli Proteins; Gene Expression; Hydrogen Peroxide; Iron; Manganese; Metalloproteins; Oxidation-Reduction; Oxidative Stress; Structure-Activity Relationship; Superoxides; Zinc
PubMed: 25160623
DOI: 10.1074/jbc.R114.588814 -
Frontiers in Cellular and Infection... 2022Transition metals are essential for metalloprotein function among all domains of life. Humans utilize nutritional immunity to limit bacterial infections, employing... (Review)
Review
Transition metals are essential for metalloprotein function among all domains of life. Humans utilize nutritional immunity to limit bacterial infections, employing metalloproteins such as hemoglobin, transferrin, and lactoferrin across a variety of physiological niches to sequester iron from invading bacteria. Consequently, some bacteria have evolved mechanisms to pirate the sequestered metals and thrive in these metal-restricted environments. , the causative agent of the sexually transmitted infection gonorrhea, causes devastating disease worldwide and is an example of a bacterium capable of circumventing human nutritional immunity. production of specific outer-membrane metallotransporters, is capable of extracting iron directly from human innate immunity metalloproteins. This review focuses on the function and expression of each metalloprotein at gonococcal infection sites, as well as what is known about how the gonococcus accesses bound iron.
Topics: Gonorrhea; Hemoglobins; Humans; Iron; Lactoferrin; Metalloproteins; Neisseria gonorrhoeae
PubMed: 36189345
DOI: 10.3389/fcimb.2022.1017348 -
International Journal of Molecular... May 2020Sulfur is an essential element required for plant growth. It can be found as a thiol group of proteins or non-protein molecules, and as various sulfur-containing small... (Review)
Review
Sulfur is an essential element required for plant growth. It can be found as a thiol group of proteins or non-protein molecules, and as various sulfur-containing small biomolecules, including iron-sulfur (Fe/S) clusters, molybdenum cofactor (Moco), and sulfur-modified nucleotides. Thiol-mediated redox regulation has been well investigated, whereas biosynthesis pathways of the sulfur-containing small biomolecules have not yet been clearly described. In order to understand overall sulfur transfer processes in plant cells, it is important to elucidate the relationships among various sulfur delivery pathways as well as to investigate their interactions. In this review, we summarize the information from recent studies on the biosynthesis pathways of several sulfur-containing small biomolecules and the proteins participating in these processes. In addition, we show characteristic features of gene expression in at the early stage of sulfate depletion from the medium, and we provide insights into sulfur transfer processes in plant cells.
Topics: Biosynthetic Pathways; Carbon-Sulfur Lyases; Coenzymes; Iron-Sulfur Proteins; Metalloproteins; Molybdenum Cofactors; Plants; Pteridines; Sulfhydryl Compounds; Sulfur; Sulfurtransferases
PubMed: 32423011
DOI: 10.3390/ijms21103470 -
Molecules (Basel, Switzerland) Apr 2022The multiscaling quantum mechanics/molecular mechanics (QM/MM) approach was introduced in 1976, while the extensive acceptance of this methodology started in the 1990s.... (Review)
Review
The multiscaling quantum mechanics/molecular mechanics (QM/MM) approach was introduced in 1976, while the extensive acceptance of this methodology started in the 1990s. The combination of QM/MM approach with molecular dynamics (MD) simulation, otherwise known as the QM/MM/MD approach, is a powerful and promising tool for the investigation of chemical reactions' mechanism of complex molecular systems, drug delivery, properties of molecular devices, organic electronics, etc. In the present review, the main methodologies in the multiscaling approaches, i.e., density functional theory (DFT), semiempirical methodologies (SE), MD simulations, MM, and their new advances are discussed in short. Then, a review on calculations and reactions on metalloproteins is presented, where particular attention is given to nitrogenase that catalyzes the conversion of atmospheric nitrogen molecules N₂ into NH₃ through the process known as nitrogen fixation and the FeMo-cofactor.
Topics: Metalloproteins; Molecular Dynamics Simulation; Nitrogenase; Quantum Theory
PubMed: 35566011
DOI: 10.3390/molecules27092660 -
Methods in Enzymology 2022Carotenoids are a family of pigment compounds, a subset of which are precursors for vitamin A biosynthesis. These pigments are derived from isopentenyl pyrophosphate...
Carotenoids are a family of pigment compounds, a subset of which are precursors for vitamin A biosynthesis. These pigments are derived from isopentenyl pyrophosphate (IPP), with geranylgeranyl diphosphate being the first metabolite unique to carotenoid biosynthesis in plants, algae, fungi, some bacteria, and arthropods. This chapter highlights the metal-dependent enzymes involved in synthesizing carotenoids in plants and the current state of knowledge of their cofactors and mechanisms. Emphasis is given to spectroscopic methods used to characterize metal centers. The recently discovered heme-dependent isomerase Z-ISO is presented as a case study in how to interrogate a metalloenzyme. Use of UV-vis, electron paramagnetic resonance, and magnetic circular dichroism spectroscopies of a metal center at various oxidation states and with external small molecule probes (CN, CO, and NO) can provide information about the nature of the metal center, the identity of its ligands, and its mechanism of action. Z-ISO is a histidine/cysteine ligated heme-dependent enzyme that is only active in the ferrous state and possesses redox-linked ligand switching. The choice and design of experiments are discussed as well as the conclusions that can be drawn.
Topics: Carotenoids; Electron Spin Resonance Spectroscopy; Heme; Metalloproteins; Oxidation-Reduction
PubMed: 35878978
DOI: 10.1016/bs.mie.2022.01.012 -
Current Opinion in Structural Biology Dec 2021An estimated half of all proteins contain a metal, with these being essential for a tremendous variety of biological functions. X-ray crystallography is the major method... (Review)
Review
An estimated half of all proteins contain a metal, with these being essential for a tremendous variety of biological functions. X-ray crystallography is the major method for obtaining structures at high resolution of these metalloproteins, but there are considerable challenges to obtain intact structures due to the effects of radiation damage. Serial crystallography offers the prospect of determining low-dose synchrotron or effectively damage free XFEL structures at room temperature and enables time-resolved or dose-resolved approaches. Complementary spectroscopic data can validate redox and or ligand states within metalloprotein crystals. In this opinion, we discuss developments in the application of serial crystallographic approaches to metalloproteins and comment on future directions.
Topics: Catalysis; Crystallography, X-Ray; Metalloproteins; Spectrum Analysis; Synchrotrons
PubMed: 34455163
DOI: 10.1016/j.sbi.2021.07.007 -
Haematologica Feb 2023Iron overload (IO) reflected by elevated ferritin is associated with increased mortality in myelodysplastic syndromes (MDS), however, ferritin is an imperfect metric....
Iron overload (IO) reflected by elevated ferritin is associated with increased mortality in myelodysplastic syndromes (MDS), however, ferritin is an imperfect metric. Elevated labile plasma iron correlates with clinical outcomes and transferrin saturation (TSAT) >80%, but is not readily measurable. The trajectory of TSAT, and its association with clinical outcomes remain undefined. Canadian MDS registry patients were evaluated. Mean TSAT, mean ferritin and transfusion dose density (TDD) were determined. Survival was evaluated by TSAT and ferritin (<50%, 50-80%, >80%), (≤500 μg/L, 501-800 μg/L, >800 μg/L). In 718 patients, median age was 74 years; 12%, 31%, 29%, 15% and 13% were IPSS-R very low, low, intermediate, high and very high. TSAT and ferritin were moderately correlated (r=0.63, P<0.0001). TSAT increased over time in transfusion- dependent patients (P=0.006). Higher TSAT and ferritin were associated with inferior 5-year overall (OS), progression- free (PFS), and leukemia-free survival (LFS) (P≤0.008) and higher TDD with inferior 5-year OS. TSAT >80% trended with inferior cardiac death-free survival (P=0.053). In univariate analysis, age, IPSS-R, blast percentage by Eastern Cooperative Oncology Group Performance Status, frailty, Charlson Comorbidity Index, iron chelation (Y/N), TDD, TSAT and ferritin were significantly associated with inferior OS. By multivariable analysis, TSAT >80% (P=0.007) remained significant for OS (R2 30.3%). In MDS, TSAT >80% and ferritin >800 μg/L portended inferior OS, PFS and LFS. TSAT may indicate the presence of oxidative stress, and is readily measurable in a clinical setting. The relationship between TSAT and cardiac death-free survival warrants further study.
Topics: Humans; Aged; Canada; Iron; Ferritins; Myelodysplastic Syndromes; Transferrins; Transferrin
PubMed: 35979720
DOI: 10.3324/haematol.2022.280723 -
Molecules (Basel, Switzerland) Jul 2019Metalloproteins and metalloenzymes play important roles in biological systems by using the limited metal ions, complexes, and clusters that are associated with the... (Review)
Review
Metalloproteins and metalloenzymes play important roles in biological systems by using the limited metal ions, complexes, and clusters that are associated with the protein matrix. The design of artificial metalloproteins and metalloenzymes not only reveals the structure and function relationship of natural proteins, but also enables the synthesis of artificial proteins and enzymes with improved properties and functions. Acknowledging the progress in rational design from single to multiple active sites, this review focuses on recent achievements in the design of artificial metalloproteins and metalloenzymes with metal clusters, including zinc clusters, cadmium clusters, iron-sulfur clusters, and copper-sulfur clusters, as well as noble metal clusters and others. These metal clusters were designed in both native and de novo protein scaffolds for structural roles, electron transfer, or catalysis. Some synthetic metal clusters as functional models of native enzymes are also discussed. These achievements provide valuable insights for deep understanding of the natural proteins and enzymes, and practical clues for the further design of artificial enzymes with functions comparable or even beyond those of natural counterparts.
Topics: Carrier Proteins; Catalysis; Catalytic Domain; Enzymes; Metalloproteins; Metals; Models, Molecular; Molecular Conformation; Molecular Structure; Protein Binding; Protein Engineering
PubMed: 31362341
DOI: 10.3390/molecules24152743 -
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 -
Molecules (Basel, Switzerland) Nov 2023The pyranopterin dithiolene ligand is remarkable in terms of its geometric and electronic structure and is uniquely found in mononuclear molybdenum and tungsten enzymes.... (Review)
Review
The pyranopterin dithiolene ligand is remarkable in terms of its geometric and electronic structure and is uniquely found in mononuclear molybdenum and tungsten enzymes. The pyranopterin dithiolene is found coordinated to the metal ion, deeply buried within the protein, and non-covalently attached to the protein via an extensive hydrogen bonding network that is enzyme-specific. However, the function of pyranopterin dithiolene in enzymatic catalysis has been difficult to determine. This focused account aims to provide an overview of what has been learned from the study of pyranopterin dithiolene model complexes of molybdenum and how these results relate to the enzyme systems. This work begins with a summary of what is known about the pyranopterin dithiolene ligand in the enzymes. We then introduce the development of inorganic small molecule complexes that model aspects of a coordinated pyranopterin dithiolene and discuss the results of detailed physical studies of the models by electronic absorption, resonance Raman, X-ray absorption and NMR spectroscopies, cyclic voltammetry, X-ray crystallography, and chemical reactivity.
Topics: Models, Molecular; Molybdenum; Ligands; Metalloproteins; Catalysis; Coenzymes
PubMed: 38005178
DOI: 10.3390/molecules28227456