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Biomolecules Nov 2020Transition metals interact with a large proportion of the proteome in all forms of life, and they play mandatory and irreplaceable roles. The dynamics of ligand binding... (Review)
Review
Transition metals interact with a large proportion of the proteome in all forms of life, and they play mandatory and irreplaceable roles. The dynamics of ligand binding to ions of transition metals falls within the realm of Coordination Chemistry, and it provides the basic principles controlling traffic, regulation, and use of metals in cells. Yet, the cellular environment stands out against the conditions prevailing in the test tube when studying metal ions and their interactions with various ligands. Indeed, the complex and often changing cellular environment stimulates fast metal-ligand exchange that mostly escapes presently available probing methods. Reducing the complexity of the problem with purified proteins or in model organisms, although useful, is not free from pitfalls and misleading results. These problems arise mainly from the absence of the biosynthetic machinery and accessory proteins or chaperones dealing with metal / metal groups in cells. Even cells struggle with metal selectivity, as they do not have a metal-directed quality control system for metalloproteins, and serendipitous metal binding is probably not exceptional. The issue of metal exchange in biology is reviewed with particular reference to iron and illustrating examples in patho-physiology, regulation, nutrition, and toxicity.
Topics: Animals; Binding Sites; Cell Physiological Phenomena; Humans; Metalloproteins; Metals; Protein Structure, Secondary
PubMed: 33233467
DOI: 10.3390/biom10111584 -
Journal of Inorganic Biochemistry Jun 2021Artificial metalloenzymes (ArMs) consist of an unnatural metal or cofactor embedded in a protein scaffold, and are an excellent platform for applying the concepts of... (Review)
Review
Artificial metalloenzymes (ArMs) consist of an unnatural metal or cofactor embedded in a protein scaffold, and are an excellent platform for applying the concepts of protein engineering to catalysis. In this Focused Review, we describe the application of ArMs as simple, tunable artificial models of the active sites of complex natural metalloenzymes for small-molecule activation. In this sense, ArMs expand the strategies of synthetic model chemistry to protein-based supporting ligands with potential for participation from the second coordination sphere. We focus specifically on ArMs that are structural, spectroscopic, and functional models of enzymes for activation of small molecules like CO, CO, O, N, and NO, as well as production/consumption of H. These ArMs give insight into the identities and roles of metalloenzyme structural features within and near the cofactor. We give examples of ArM work relevant to hydrogenases, acetyl-coenzyme A synthase, superoxide dismutase, heme oxygenases, nitric oxide reductase, methyl-coenzyme M reductase, copper-O enzymes, and nitrogenases.
Topics: Catalysis; Catalytic Domain; Coordination Complexes; Hydrogenase; Ligands; Metalloproteins; Metals; Models, Theoretical; Nitrogenase; Oxidoreductases; Protein Engineering
PubMed: 33873051
DOI: 10.1016/j.jinorgbio.2021.111430 -
Chemical Reviews Jun 2020The metallobiochemistry underlying the formation of the inorganic N-N-bond-containing molecules nitrous oxide (NO), dinitrogen (N), and hydrazine (NH) is essential to... (Review)
Review
The metallobiochemistry underlying the formation of the inorganic N-N-bond-containing molecules nitrous oxide (NO), dinitrogen (N), and hydrazine (NH) is essential to the lifestyles of diverse organisms. Similar reactions hold promise as means to use N-based fuels as alternative carbon-free energy sources. This review discusses research efforts to understand the mechanisms underlying biological N-N bond formation in primary metabolism and how the associated reactions are tied to energy transduction and organismal survival. These efforts comprise studies of both natural and engineered metalloenzymes as well as synthetic model complexes.
Topics: Hydrazines; Metalloproteins; Models, Molecular; Nitrogen; Nitrous Oxide
PubMed: 32108471
DOI: 10.1021/acs.chemrev.9b00629 -
Nature Communications Nov 2022Metallohydrolases are ubiquitous in nearly all subclasses of hydrolases, utilizing metal elements to activate a water molecule and facilitate its subsequent dissociation...
Metallohydrolases are ubiquitous in nearly all subclasses of hydrolases, utilizing metal elements to activate a water molecule and facilitate its subsequent dissociation of diverse chemical bonds. However, such a catalytic role of metal ions is rarely found with glycosidases that hydrolyze the glycosidic bonds in sugars. Herein, we design metalloglycosidases by constructing a hydrolytically active Zn-binding site within a barrel-shaped outer membrane protein OmpF. Structure- and mechanism-based redesign and directed evolution have led to the emergence of Zn-dependent glycosidases with catalytic proficiency of 2.8 × 10 and high β-stereoselectivity. Biochemical characterizations suggest that the Zn-binding site constitutes a key catalytic motif along with at least one adjacent acidic residue. This work demonstrates that unprecedented metalloenzymes can be tailor-made, expanding the scope of inorganic reactivities in proteinaceous environments, resetting the structural and functional diversity of metalloenzymes, and providing the potential molecular basis of unidentified metallohydrolases and novel whole-cell biocatalysts.
Topics: Metalloproteins; Binding Sites; Catalytic Domain; Catalysis; Glycoside Hydrolases; Metals
PubMed: 36369431
DOI: 10.1038/s41467-022-34713-8 -
Molecules (Basel, Switzerland) Jun 2020Artificial metalloenzymes (ArMs) comprise a synthetic metal complex in a protein scaffold. ArMs display performances combining those of both homogeneous catalysts and... (Review)
Review
Artificial metalloenzymes (ArMs) comprise a synthetic metal complex in a protein scaffold. ArMs display performances combining those of both homogeneous catalysts and biocatalysts. Specifically, ArMs selectively catalyze non-natural reactions and reactions inspired by nature in water under mild conditions. In the past few years, the construction of ArMs that possess a genetically incorporated unnatural amino acid and the directed evolution of ArMs have become of great interest in the field. Additionally, biochemical applications of ArMs have steadily increased, owing to the fact that compartmentalization within a protein scaffold allows the synthetic metal complex to remain functional in a sea of inactivating biomolecules. In this review, we present updates on: 1) the newly reported ArMs, according to their type of reaction, and 2) the unique biochemical applications of ArMs, including chemoenzymatic cascades and intracellular/ catalysis. We believe that ArMs have great potential as catalysts for organic synthesis and as chemical biology tools for pharmaceutical applications.
Topics: Catalysis; Chemistry Techniques, Synthetic; Coordination Complexes; Metalloproteins; Protein Engineering
PubMed: 32629938
DOI: 10.3390/molecules25132989 -
The FEBS Journal May 2011Metalloproteins play major roles in cell metabolism and signalling pathways. In many cases, they show moonlighting behaviour, acting in different processes, depending on... (Review)
Review
Metalloproteins play major roles in cell metabolism and signalling pathways. In many cases, they show moonlighting behaviour, acting in different processes, depending on the physiological state of the cell. To understand these multitasking proteins, we need to discover the partners with which they carry out such novel functions. Although many technological and methodological tools have recently been reported for the detection of protein interactions, specific approaches to studying the interactions involving metalloproteins are not yet well developed. The task is even more challenging for metalloproteins, because they often form short-lived complexes that are difficult to detect. In this review, we gather the different proteomic techniques and biointeractomic tools reported in the literature. All of them have shown their applicability to the study of transient and weak protein-protein interactions, and are therefore suitable for metalloprotein interactions.
Topics: Cells; Chromatography, Affinity; Mass Spectrometry; Metalloproteins; Oligonucleotide Array Sequence Analysis; Protein Binding; Proteomics; Signal Transduction
PubMed: 21352492
DOI: 10.1111/j.1742-4658.2011.08061.x -
Metallomics : Integrated Biometal... Nov 2011Nickel has long been known to be an important human toxicant, including having the ability to form carcinomas, but until recently nickel was believed to be an issue only... (Review)
Review
Nickel has long been known to be an important human toxicant, including having the ability to form carcinomas, but until recently nickel was believed to be an issue only to microorganisms living in nickel-rich serpentine soils or areas contaminated by industrial pollution. This assumption was overturned by the discovery of a nickel defense system (RcnR/RcnA) found in microorganisms that live in a wide range of environmental niches, suggesting that nickel homeostasis is a general biological concern. To date, the mechanisms of nickel toxicity in microorganisms and higher eukaryotes are poorly understood. In this review, we summarize nickel homeostasis processes used by microorganisms and highlight in vivo and in vitro effects of exposure to elevated concentrations of nickel. On the basis of this evidence we propose four mechanisms of nickel toxicity: (1) nickel replaces the essential metal of metalloproteins, (2) nickel binds to catalytic residues of non-metalloenzymes; (3) nickel binds outside the catalytic site of an enzyme to inhibit allosterically and (4) nickel indirectly causes oxidative stress.
Topics: Bacteria; Drug Resistance, Microbial; Heavy Metal Poisoning; Homeostasis; Humans; Metalloproteins; Nickel; Oxidative Stress; Poisoning; Protein Conformation; Soil Microbiology; Yeasts
PubMed: 21799955
DOI: 10.1039/c1mt00063b -
Current Opinion in Chemical Biology Dec 2013The de novo design of artificial metalloproteins from first-principles is a powerful strategy with which to establish the minimum structure required for function, as... (Review)
Review
The de novo design of artificial metalloproteins from first-principles is a powerful strategy with which to establish the minimum structure required for function, as well as to identify the important design features for tuning the chemistry of the coordinated metal ion. Herein we describe recent contributions to this field, covering metallo-porphyrin, mononuclear and multinuclear metal ion sites engineered into de novo proteins. Using miniature artificial scaffolds these examples demonstrate that complex natural protein folds are not required to mimic naturally occurring metal ion sites in proteins. More importantly progress is being made to engineer de novo metalloproteins capable of performing functions not in the repertoire of biology.
Topics: Animals; Binding Sites; Humans; Metalloproteins; Metals; Models, Molecular; Protein Conformation; Protein Engineering; Proteins
PubMed: 24183813
DOI: 10.1016/j.cbpa.2013.10.015 -
Journal of Biological Inorganic... Apr 2017Nature uses dioxygen as a key oxidant in the transformation of biomolecules. Among the enzymes that are utilized for these reactions are copper-containing... (Review)
Review
Nature uses dioxygen as a key oxidant in the transformation of biomolecules. Among the enzymes that are utilized for these reactions are copper-containing metalloenzymes, which are responsible for important biological functions such as the regulation of neurotransmitters, dioxygen transport, and cellular respiration. Enzymatic and model system studies work in tandem in order to gain an understanding of the fundamental reductive activation of dioxygen by copper complexes. This review covers the most recent advancements in the structures, spectroscopy, and reaction mechanisms for dioxygen-activating copper proteins and relevant synthetic models thereof. An emphasis has also been placed on cofactor biogenesis, a fundamentally important process whereby biomolecules are post-translationally modified by the pro-enzyme active site to generate cofactors which are essential for the catalytic enzymatic reaction. Significant questions remaining in copper-ion-mediated O-activation in copper proteins are addressed.
Topics: Animals; Catalytic Domain; Copper; Humans; Metalloproteins; Oxygen
PubMed: 27921179
DOI: 10.1007/s00775-016-1415-2 -
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