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Journal of Inorganic Biochemistry Feb 2022Sulfide and transition metals often came together in Biology. The variety of possible structural combinations enabled living organisms to evolve an array of highly... (Review)
Review
Sulfide and transition metals often came together in Biology. The variety of possible structural combinations enabled living organisms to evolve an array of highly versatile metal-sulfide centers to fulfill different physiological roles. The ubiquitous iron‑sulfur centers, with their structural, redox, and functional diversity, are certainly the best-known partners, but other metal-sulfide centers, involving copper, nickel, molybdenum or tungsten, are equally crucial for Life. This review provides a concise overview of the exclusive sulfide properties as a metal ligand, with emphasis on the structural aspects and biosynthesis. Sulfide as catalyst and as a substrate is discussed. Different enzymes are considered, including xanthine oxidase, formate dehydrogenases, nitrogenases and carbon monoxide dehydrogenases. The sulfide effect on the activity and function of iron‑sulfur, heme and zinc proteins is also addressed.
Topics: Heme; Iron-Sulfur Proteins; Metalloproteins; Sulfides; Transition Elements
PubMed: 34953313
DOI: 10.1016/j.jinorgbio.2021.111687 -
Redox Biology Apr 2023Reactive sulfur species (RSS) entail a diverse family of sulfur derivatives that have emerged as important effector molecules in HS-mediated biological events. RSS... (Review)
Review
Reactive sulfur species (RSS) entail a diverse family of sulfur derivatives that have emerged as important effector molecules in HS-mediated biological events. RSS (including HS) can exert their biological roles via widespread interactions with metalloproteins. Metalloproteins are essential components along the metabolic route of oxygen in the body, from the transport and storage of O, through cellular respiration, to the maintenance of redox homeostasis by elimination of reactive oxygen species (ROS). Moreover, heme peroxidases contribute to immune defense by killing pathogens using oxygen-derived HO as a precursor for stronger oxidants. Coordination and redox reactions with metal centers are primary means of RSS to alter fundamental cellular functions. In addition to RSS-mediated metalloprotein functions, the reduction of high-valent metal centers by RSS results in radical formation and opens the way for subsequent per- and polysulfide formation, which may have implications in cellular protection against oxidative stress and in redox signaling. Furthermore, recent findings pointed out the potential role of RSS as substrates for mitochondrial energy production and their cytoprotective capacity, with the involvement of metalloproteins. The current review summarizes the interactions of RSS with protein metal centers and their biological implications with special emphasis on mechanistic aspects, sulfide-mediated signaling, and pathophysiological consequences. A deeper understanding of the biological actions of reactive sulfur species on a molecular level is primordial in HS-related drug development and the advancement of redox medicine.
Topics: Hydrogen Sulfide; Metalloproteins; Hydrogen Peroxide; Reactive Oxygen Species; Oxygen; Sulfur
PubMed: 36738685
DOI: 10.1016/j.redox.2023.102617 -
Current Opinion in Chemical Biology Apr 2015Three-helix bundles and coiled-coil motifs are well-established de novo designed scaffolds that have been investigated for their metal-binding and catalytic properties.... (Review)
Review
Three-helix bundles and coiled-coil motifs are well-established de novo designed scaffolds that have been investigated for their metal-binding and catalytic properties. Satisfaction of the primary coordination sphere for a given metal is sufficient to introduce catalytic activity and a given structure may catalyze different reactions dependent on the identity of the incorporated metal. Here we describe recent contributions in the de novo design of metalloenzymes based on three-helix bundles and coiled-coil motifs, focusing on non-heme systems for hydrolytic and redox chemistry.
Topics: Copper; Drug Design; Enzymes; Metalloproteins; Protein Structure, Secondary; Zinc
PubMed: 25579452
DOI: 10.1016/j.cbpa.2014.12.034 -
Angewandte Chemie (International Ed. in... May 2020The relationship between protein structure and function is one of the greatest puzzles within biochemistry. De novo metalloprotein design is a way to wipe the board... (Review)
Review
The relationship between protein structure and function is one of the greatest puzzles within biochemistry. De novo metalloprotein design is a way to wipe the board clean and determine what is required to build in function from the ground up in an unrelated structure. This Review focuses on protein design efforts to create de novo metalloproteins within alpha-helical scaffolds. Examples of successful designs include those with carbonic anhydrase or nitrite reductase activity by incorporating a ZnHis or CuHis site, or that recapitulate the spectroscopic properties of unique electron-transfer sites in cupredoxins (CuHis Cys) or rubredoxins (FeCys ). This work showcases the versatility of alpha helices as scaffolds for metalloprotein design and the progress that is possible through careful rational design. Our studies cover the invariance of carbonic anhydrase activity with different site positions and scaffolds, refinement of our cupredoxin models, and enhancement of nitrite reductase activity up to 1000-fold.
Topics: Drug Design; Electron Transport; Metalloproteins; Protein Conformation, alpha-Helical
PubMed: 31441170
DOI: 10.1002/anie.201907502 -
Metallomics : Integrated Biometal... Jan 2019
Topics: Animals; Computational Biology; Humans; Metalloproteins; Metals; Research Personnel
PubMed: 30632595
DOI: 10.1039/c8mt90047g -
Accounts of Chemical Research Oct 2014Natural metalloenzymes are often the most proficient catalysts in terms of their activity, selectivity, and ability to operate at mild conditions. However,... (Review)
Review
Natural metalloenzymes are often the most proficient catalysts in terms of their activity, selectivity, and ability to operate at mild conditions. However, metalloenzymes are occasionally surprising in their selection of catalytic metals, and in their responses to metal substitution. Indeed, from the isolated standpoint of producing the best catalyst, a chemist designing from first-principles would likely choose a different metal. For example, some enzymes employ a redox active metal where a simple Lewis acid is needed. Such are several hydrolases. In other cases, substitution of a non-native metal leads to radical improvements in reactivity. For example, histone deacetylase 8 naturally operates with Zn(2+) in the active site but becomes much more active with Fe(2+). For β-lactamases, the replacement of the native Zn(2+) with Ni(2+) was suggested to lead to higher activity as predicted computationally. There are also intriguing cases, such as Fe(2+)- and Mn(2+)-dependent ribonucleotide reductases and W(4+)- and Mo(4+)-dependent DMSO reductases, where organisms manage to circumvent the scarcity of one metal (e.g., Fe(2+)) by creating protein structures that utilize another metal (e.g., Mn(2+)) for the catalysis of the same reaction. Naturally, even though both metal forms are active, one of the metals is preferred in every-day life, and the other metal variant remains dormant until an emergency strikes in the cell. These examples lead to certain questions. When are catalytic metals selected purely for electronic or structural reasons, implying that enzymatic catalysis is optimized to its maximum? When are metal selections a manifestation of competing evolutionary pressures, where choices are dictated not just by catalytic efficiency but also by other factors in the cell? In other words, how can enzymes be improved as catalysts merely through the use of common biological building blocks available to cells? Addressing these questions is highly relevant to the enzyme design community, where the goal is to prepare maximally efficient quasi-natural enzymes for the catalysis of reactions that interest humankind. Due to competing evolutionary pressures, many natural enzymes may not have evolved to be ideal catalysts and can be improved for the isolated purpose of catalysis in vitro when the competing factors are removed. The goal of this Account is not to cover all the possible stories but rather to highlight how variable enzymatic catalysis can be. We want to bring up possible factors affecting the evolution of enzyme structure, and the large- and intermediate-scale structural and electronic effects that metals can induce in the protein, and most importantly, the opportunities for optimization of these enzymes for catalysis in vitro.
Topics: Biocatalysis; Humans; Metalloproteins; Metals; Models, Molecular
PubMed: 25207938
DOI: 10.1021/ar500227u -
Biomolecules Mar 2020The widespread use of uranium for civilian purposes causes a worldwide concern of its threat to human health due to the long-lived radioactivity of uranium and the high... (Review)
Review
The widespread use of uranium for civilian purposes causes a worldwide concern of its threat to human health due to the long-lived radioactivity of uranium and the high toxicity of uranyl ion (UO). Although uranyl-protein/DNA interactions have been known for decades, fewer advances are made in understanding their structural-functional impacts. Instead of focusing only on the structural information, this article aims to review the recent advances in understanding the binding of uranyl to proteins in either potential, native, or artificial metal-binding sites, and the structural-functional impacts of uranyl-protein interactions, such as inducing conformational changes and disrupting protein-protein/DNA/ligand interactions. Photo-induced protein/DNA cleavages, as well as other impacts, are also highlighted. These advances shed light on the structure-function relationship of proteins, especially for metalloproteins, as impacted by uranyl-protein interactions. It is desired to seek approaches for biological remediation of uranyl ions, and ultimately make a full use of the double-edged sword of uranium.
Topics: Carrier Proteins; Metalloproteins; Models, Molecular; Structure-Activity Relationship; Uranium Compounds
PubMed: 32187982
DOI: 10.3390/biom10030457 -
Journal of the American Chemical Society Nov 2022Many naturally occurring metalloenzymes are gated by rate-limiting conformational changes, and there exists a critical interplay between macroscopic structural...
Many naturally occurring metalloenzymes are gated by rate-limiting conformational changes, and there exists a critical interplay between macroscopic structural rearrangements of the protein and subatomic changes affecting the electronic structure of embedded metallocofactors. Despite this connection, most artificial metalloproteins (ArMs) are prepared in structurally rigid protein hosts. To better model the natural mechanisms of metalloprotein reactivity, we have developed conformationally switchable ArMs (swArMs) that undergo a large-scale structural rearrangement upon allosteric effector binding. The swArMs reported here contain a Co(dmgH)(X) cofactor (dmgH = dimethylglyoxime and X = N, HC, and Pr). We used UV-vis absorbance and energy-dispersive X-ray fluorescence spectroscopies, along with protein assays, and mass spectrometry to show that these metallocofactors are installed site-specifically and stoichiometrically via direct Co-S cysteine ligation within the glutamine binding protein (GlnBP). Structural characterization by single-crystal X-ray diffraction unveils the precise positioning and microenvironment of the metallocofactor within the protein fold. Fluorescence, circular dichroism, and infrared spectroscopies, along with isothermal titration calorimetry, reveal that allosteric Gln binding drives a large-scale protein conformational change. In swArMs containing a Co(dmgH)(CH) cofactor, we show that the protein stabilizes the otherwise labile Co-S bond relative to the free complex. Kinetics studies performed as a function of temperature and pH reveal that the protein conformational change accelerates this bond dissociation in a pH-dependent fashion. We present swArMs as a robust platform for investigating the interplay between allostery and metallocofactor regulation.
Topics: Metalloproteins; Crystallography, X-Ray; Escherichia coli; Circular Dichroism; Kinetics
PubMed: 36378237
DOI: 10.1021/jacs.2c08885 -
Biochemistry Nov 2021Metalloproteins play diverse and critical functions in all living systems, and their dysfunctional forms are closely related to many human diseases. The development of...
Metalloproteins play diverse and critical functions in all living systems, and their dysfunctional forms are closely related to many human diseases. The development of methods that enable comprehensive mapping of metalloproteome is of great interest to help elucidate crucial roles of metalloproteins in both physiology and pathology, as well as to discover new metalloproteins. We herein briefly review recent progress in the field of metalloproteomics and provide future outlooks.
Topics: Humans; Metalloproteins; Protein Interaction Mapping; Protein Interaction Maps; Proteomics
PubMed: 34406001
DOI: 10.1021/acs.biochem.1c00404 -
FEMS Microbiology Reviews Jan 2016Molybdoenzymes are widespread in eukaryotic and prokaryotic organisms where they play crucial functions in detoxification reactions in the metabolism of humans and... (Review)
Review
Molybdoenzymes are widespread in eukaryotic and prokaryotic organisms where they play crucial functions in detoxification reactions in the metabolism of humans and bacteria, in nitrate assimilation in plants and in anaerobic respiration in bacteria. To be fully active, these enzymes require complex molybdenum-containing cofactors, which are inserted into the apoenzymes after folding. For almost all the bacterial molybdoenzymes, molybdenum cofactor insertion requires the involvement of specific chaperones. In this review, an overview on the molybdenum cofactor biosynthetic pathway is given together with the role of specific chaperones dedicated for molybdenum cofactor insertion and maturation. Many bacteria are involved in geochemical cycles on earth and therefore have an environmental impact. The roles of molybdoenzymes in bioremediation and for environmental applications are presented.
Topics: Apoenzymes; Bacteria; Bacterial Proteins; Coenzymes; Environmental Microbiology; Metalloproteins; Molecular Chaperones; Molybdenum Cofactors; Pteridines
PubMed: 26468212
DOI: 10.1093/femsre/fuv043