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Trends in Biotechnology Jan 2018Residing at the interface of chemistry and biotechnology, artificial metalloenzymes (ArMs) offer an attractive technology to combine the versatile reaction repertoire of... (Review)
Review
Residing at the interface of chemistry and biotechnology, artificial metalloenzymes (ArMs) offer an attractive technology to combine the versatile reaction repertoire of transition metal catalysts with the exquisite catalytic features of enzymes. While earlier efforts in this field predominantly comprised studies in well-defined test-tube environments, a trend towards exploiting ArMs in more complex environments has recently emerged. Integration of these artificial biocatalysts in enzymatic cascades and using them in whole-cell biotransformations and in vivo opens up entirely novel prospects for both preparative chemistry and synthetic biology. We highlight selected recent developments with a particular focus on challenges and opportunities in the in vivo application of ArMs.
Topics: Biocatalysis; Biotechnology; Metalloproteins; Protein Engineering
PubMed: 29061328
DOI: 10.1016/j.tibtech.2017.10.003 -
Journal of Inorganic Biochemistry Oct 2021A large fraction of metalloenzymes harbors multiple metal-centers that are electronically and/or functionally arranged within their proteinaceous environments. To... (Review)
Review
A large fraction of metalloenzymes harbors multiple metal-centers that are electronically and/or functionally arranged within their proteinaceous environments. To explore the orchestration of inorganic and biochemical components and to develop bioinorganic catalysts and materials, we have described selected examples of artificial metalloproteins having multiple metallocofactors that were grouped depending on their initial protein scaffolds, the nature of introduced inorganic moieties, and the method used to propagate the number of metal ions within a protein. They demonstrated that diverse inorganic moieties can be selectively grafted and modulated in protein environments, providing a retrosynthetic bottom-up approach in the design of versatile and proficient biocatalysts and biomimetic model systems to explore fundamental questions in bioinorganic chemistry.
Topics: Bacteria; Biocatalysis; Coenzymes; Coordination Complexes; Humans; Metalloproteins; Metals, Heavy; Protein Engineering
PubMed: 34332336
DOI: 10.1016/j.jinorgbio.2021.111552 -
Free Radical Biology & Medicine Mar 2019Mammalian cells contain thousands of metalloproteins and have evolved sophisticated systems for ensuring that metal cofactors are correctly assembled and delivered to... (Review)
Review
Mammalian cells contain thousands of metalloproteins and have evolved sophisticated systems for ensuring that metal cofactors are correctly assembled and delivered to their proper destinations. Equally critical in this process are the strategies to avoid the insertion of the wrong metal cofactor into apo-proteins and to avoid the damage that redox-active metals can catalyze in the cellular milieu. Iron and zinc are the most abundant metal cofactors in cells and iron cofactors include heme, iron-sulfur clusters, and mono- and dinuclear iron centers. Systems for the intracellular trafficking of iron cofactors are being characterized. This review focuses on the trafficking of ferrous iron cofactors in the cytosol of mammalian cells, a process that involves specialized iron-binding proteins, termed iron chaperones, of the poly rC-binding protein family.
Topics: Animals; Cytosol; Heme; Humans; Iron; Iron-Binding Proteins; Iron-Sulfur Proteins; Metalloproteins; Molecular Chaperones; Sulfur
PubMed: 30321701
DOI: 10.1016/j.freeradbiomed.2018.10.411 -
Journal of Experimental Botany Mar 2022Copper and iron proteins have a wide range of functions in living organisms. Metal assembly into metalloproteins is a complex process, where mismetalation is detrimental... (Review)
Review
Copper and iron proteins have a wide range of functions in living organisms. Metal assembly into metalloproteins is a complex process, where mismetalation is detrimental and energy consuming to cells. Under metal deficiency, metal distribution is expected to reach a metalation ranking, prioritizing essential versus dispensable metalloproteins, while avoiding interference with other metals and protecting metal-sensitive processes. In this review, we propose that post-transcriptional modulators of metalloprotein mRNA (ModMeR) are good candidates in metal prioritization under metal-limited conditions. ModMeR target high quota or redundant metalloproteins and, by adjusting their synthesis, ModMeR act as internal metal distribution valves. Inappropriate metalation of ModMeR targets could compete with metal delivery to essential metalloproteins and interfere with metal-sensitive processes, such as chloroplastic photosynthesis and mitochondrial respiration. Regulation of ModMeR targets could increase or decrease the metal flow through interconnected pathways in cellular metal distribution, helping to achieve adequate differential metal requirements. Here, we describe and compare ModMeR that function in response to copper and iron deficiencies. Specifically, we describe copper-miRNAs from Arabidopsis thaliana and diverse iron ModMeR from yeast, mammals, and bacteria under copper and iron deficiencies, as well as the influence of oxidative stress. Putative functions derived from their role as ModMeR are also discussed.
Topics: Animals; Arabidopsis; Copper; Iron; Iron Deficiencies; Mammals; Metalloproteins; Metals; Saccharomyces cerevisiae
PubMed: 34849747
DOI: 10.1093/jxb/erab521 -
Advances in Experimental Medicine and... 2018Biochemical imbalances, provoked by aging or a secondary illness, might directly affect the brain, causing severe problems, such as loss of memory or alteration of... (Review)
Review
Biochemical imbalances, provoked by aging or a secondary illness, might directly affect the brain, causing severe problems, such as loss of memory or alteration of behavior patterns. Brain disorders are usually classified as injuries (such as stroke, hematomas, and concussions), tumors, and neurodegenerative (such as Parkinson's and Alzheimer's diseases) and mental (such as depression, bipolar disorder, schizophrenia) diseases. As the pathophysiology of these illnesses is not completely established and multiple factors are involved, metallomics, a bioanalytical strategy that allows the detection of metal ions and metalloproteins in diverse biological matrices, is of extreme relevance in identifying which elements are affected by a disease and/or treatment. Thus, determining which element ions suffer disturbances in their homeostasis during the disease progress is relevant to understand the biochemical changes and propose new drug targets. In addition, it is well known that oxidative stress plays an important role in the development of pathological neurodegenerative and mental diseases, which may be caused by metal ion dyshomeostasis, so it is also important to understand endogenous antioxidant metalloprotein and metalloenzyme mechanisms in this regard. In this context, recent applications of metallomics in the study of neurodegenerative and mental disorders are discussed in this chapter, as well as future trends in this research area.
Topics: Animals; Antioxidants; Homeostasis; Humans; Mental Disorders; Metalloproteins; Metals; Neurodegenerative Diseases
PubMed: 29884960
DOI: 10.1007/978-3-319-90143-5_2 -
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 -
Methods in Molecular Biology (Clifton,... 2019A major hurdle in the studies of nitrogenase, one of the most complicated metalloenzymes known to date, is to obtain large amounts of intact, active proteins....
A major hurdle in the studies of nitrogenase, one of the most complicated metalloenzymes known to date, is to obtain large amounts of intact, active proteins. Nitrogenase and related proteins are often multimeric and consist of metal centers that are critical for their activities. Most notably, the well-studied MoFe protein of Mo-nitrogenase is a heterotetramer that houses two of the most complicated metal clusters found in nature, the P-cluster and the FeMoco (or M-cluster). The structural complexity of these proteins and the oxygen sensitivity of their associated metal clusters, along with the demand for large amounts of high-quality proteins in most downstream analyses, make large-scale, high-yield purification of fully competent nitrogenase proteins a formidable task and yet, at the same time, a prerequisite for the success of nitrogenase research. This chapter highlights several methods that have been developed over the past few decades chiefly for the purification of naturally expressed nitrogenase in the diazotroph Azotobacter vinelandii. In addition, purification and Fe-S reconstitution strategies are also outlined for the heterologously expressed nitrogenase proteins in Escherichia coli.
Topics: Azotobacter vinelandii; Bacterial Proteins; Chromatography, Gel; Chromatography, Ion Exchange; Escherichia coli; Metalloproteins; Molybdenum; Multienzyme Complexes; Nitrogenase; Protein Conformation
PubMed: 30317477
DOI: 10.1007/978-1-4939-8864-8_7 -
Chemistry (Weinheim An Der Bergstrasse,... Jun 2019The net electrostatic charge (Z) of a folded protein in solution represents a bird's eye view of its surface potentials-including contributions from tightly bound metal,... (Review)
Review
The net electrostatic charge (Z) of a folded protein in solution represents a bird's eye view of its surface potentials-including contributions from tightly bound metal, solvent, buffer, and cosolvent ions-and remains one of its most enigmatic properties. Few tools are available to the average biochemist to rapidly and accurately measure Z at pH≠pI. Tools that have been developed more recently seem to go unnoticed. Most scientists are content with this void and estimate the net charge of a protein from its amino acid sequence, using textbook values of pK . Thus, Z remains unmeasured for nearly all folded proteins at pH≠pI. When marveling at all that has been learned from accurately measuring the other fundamental property of a protein-its mass-one wonders: what are we missing by not measuring the net charge of folded, solvated proteins? A few big questions immediately emerge in bioinorganic chemistry. When a single electron is transferred to a metalloprotein, does the net charge of the protein change by approximately one elementary unit of charge or does charge regulation dominate, that is, do the pK values of most ionizable residues (or just a few residues) adjust in response to (or in concert with) electron transfer? Would the free energy of charge regulation (ΔΔG ) account for most of the outer sphere reorganization energy associated with electron transfer? Or would ΔΔG contribute more to the redox potential? And what about metal binding itself? When an apo-metalloprotein, bearing minimal net negative charge (e.g., Z=-2.0) binds one or more metal cations, is the net charge abolished or inverted to positive? Or do metalloproteins regulate net charge when coordinating metal ions? The author's group has recently dusted off a relatively obscure tool-the "protein charge ladder"-and used it to begin to answer these basic questions.
Topics: Buffers; Electron Transport; Hydrogen-Ion Concentration; Ions; Metalloproteins; Metals; Models, Molecular; Protein Conformation; Protein Folding; Proteins; Solvents; Static Electricity; Thermodynamics
PubMed: 30779227
DOI: 10.1002/chem.201900178 -
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 -
Journal of Chemical Information and... Mar 2024Metalloproteins play a fundamental role in molecular biology, contributing to various biological processes. However, the discovery of high-affinity ligands targeting...
Metalloproteins play a fundamental role in molecular biology, contributing to various biological processes. However, the discovery of high-affinity ligands targeting metalloproteins has been delayed due, in part, to a lack of suitable tools and data. Molecular docking, a widely used technique for virtual screening of small-molecule ligand interactions with proteins, often faces challenges when applied to metalloproteins due to the particular nature of the ligand metal bond. To address these limitations associated with docking metalloproteins, we introduce a knowledge-driven docking approach known as "metalloprotein bias docking" (MBD), which extends the AutoDock Bias technique. We assembled a comprehensive data set of metalloprotein-ligand complexes from 15 different metalloprotein families, encompassing Ca, Co, Fe, Mg, Mn, and Zn metal ions. Subsequently, we conducted a performance analysis of our MBD method and compared it to the conventional docking (CD) program AutoDock4, applied to various metalloprotein targets within our data set. Our results demonstrate that MBD outperforms CD, significantly enhancing accuracy, selectivity, and precision in ligand pose prediction. Additionally, we observed a positive correlation between our predicted ligand free energies and the corresponding experimental values. These findings underscore the potential of MBD as a valuable tool for the effective exploration of metalloprotein-ligand interactions.
Topics: Humans; Metalloproteins; Molecular Docking Simulation; Ligands
PubMed: 38373276
DOI: 10.1021/acs.jcim.3c01853