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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 -
International Journal of Molecular... Jul 2021Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals... (Review)
Review
Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and "prion-like disease", amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, and depression.
Topics: Ceruloplasmin; Copper; Humans; Iron; Iron Metabolism Disorders; Manganese; Manganese Poisoning; Metabolic Diseases; Metalloproteins; Neuroaxonal Dystrophies; Neurodegenerative Diseases; Oxidative Stress
PubMed: 34360586
DOI: 10.3390/ijms22157820 -
Chemistry (Weinheim An Der Bergstrasse,... Dec 2021Only two enzymes are capable of directly reducing CO : CO dehydrogenase, which produces CO at a [NiFe S ] active site, and formate dehydrogenase, which produces formate... (Review)
Review
Only two enzymes are capable of directly reducing CO : CO dehydrogenase, which produces CO at a [NiFe S ] active site, and formate dehydrogenase, which produces formate at a mononuclear W or Mo active site. Both metalloenzymes are very rapid, energy-efficient and specific in terms of product. They have been connected to electrodes with two different objectives. A series of studies used protein film electrochemistry to learn about different aspects of the mechanism of these enzymes (reactivity with substrates, inhibitors…). Another series focused on taking advantage of the catalytic performance of these enzymes to build biotechnological devices, from CO -reducing electrodes to full photochemical devices performing artificial photosynthesis. Here, we review all these works.
Topics: Carbon Dioxide; Catalysis; Electrodes; Formate Dehydrogenases; Metalloproteins
PubMed: 34506631
DOI: 10.1002/chem.202102702 -
Molecules (Basel, Switzerland) Aug 2022The transition element molybdenum (Mo) is an essential micronutrient for plants, animals, and microorganisms, where it forms part of the active center of Mo enzymes. To... (Review)
Review
The transition element molybdenum (Mo) is an essential micronutrient for plants, animals, and microorganisms, where it forms part of the active center of Mo enzymes. To gain biological activity in the cell, Mo has to be complexed by a pterin scaffold to form the molybdenum cofactor (Moco). Mo enzymes and Moco are found in all kingdoms of life, where they perform vital transformations in the metabolism of nitrogen, sulfur, and carbon compounds. In this review, I recall the history of Moco in a personal view, starting with the genetics of Moco in the 1960s and 1970s, followed by Moco biochemistry and the description of its chemical structure in the 1980s. When I review the elucidation of Moco biosynthesis in the 1990s and the early 2000s, I do it mainly for eukaryotes, as I worked with plants, human cells, and filamentous fungi. Finally, I briefly touch upon human Moco deficiency and whether there is life without Moco.
Topics: Animals; Coenzymes; Eukaryota; Humans; Metalloproteins; Molybdenum; Molybdenum Cofactors; Plants; Pterins
PubMed: 35956883
DOI: 10.3390/molecules27154934 -
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 -
Physical Chemistry Chemical Physics :... Jul 2022Paramagnetic NMR data contain extremely accurate long-range information on metalloprotein structures and, when used in the frame of integrative structural biology... (Review)
Review
Paramagnetic NMR data contain extremely accurate long-range information on metalloprotein structures and, when used in the frame of integrative structural biology approaches, they allow for the retrieval of structural details to a resolution that is not achievable using other techniques. Paramagnetic data thus represent an extremely powerful tool to refine protein models in solution, especially when coupled to X-ray or cryoelectron microscopy data, to monitor the formation of complexes and determine the relative arrangements of their components, and to highlight the presence of conformational heterogeneity. More recently, theoretical and computational advancements in quantum chemical calculations of paramagnetic NMR observables are progressively opening new routes in structural biology, because they allow for the determination of the structure within the coordination sphere of the metal center, thus acting as a loupe on sites that are difficult to observe but very important for protein function.
Topics: Biology; Cryoelectron Microscopy; Magnetic Resonance Spectroscopy; Metalloproteins; Molecular Conformation
PubMed: 35849063
DOI: 10.1039/d2cp01838a -
International Journal of Molecular... Dec 2022Metal chelation can provide structural stability and form reactive centers in metalloproteins. Approximately one third of known protein structures are metalloproteins,... (Review)
Review
Metal chelation can provide structural stability and form reactive centers in metalloproteins. Approximately one third of known protein structures are metalloproteins, and metal binding, or the lack thereof, is often implicated in disease, making it necessary to be able to study these systems in detail. Peptide-metal complexes are both present in nature and can provide a means to focus on the binding region of a protein and control experimental variables to a high degree. Structural studies of peptide complexes with metal ions by nuclear magnetic resonance (NMR) were surveyed for all the essential metal complexes and many non-essential metal complexes. The various methods used to study each metal ion are presented together with examples of recent research. Many of these metal systems have been individually reviewed and this current overview of NMR studies of metallopeptide complexes aims to provide a basis for inspiration from structural studies and methodology applied in the field.
Topics: Coordination Complexes; Magnetic Resonance Spectroscopy; Metals; Peptides; Metalloproteins; Ions
PubMed: 36555599
DOI: 10.3390/ijms232415957 -
Chemical Reviews Jul 2022One of the hallmark advances in our understanding of metalloprotein function is showcased in our ability to design new, non-native, catalytically active protein... (Review)
Review
One of the hallmark advances in our understanding of metalloprotein function is showcased in our ability to design new, non-native, catalytically active protein scaffolds. This review highlights progress and milestone achievements in the field of metalloprotein design focused on reports from the past decade with special emphasis on designs couched within common subfields of bioinorganic study: heme binding proteins, monometal- and dimetal-containing catalytic sites, and metal-containing electron transfer sites. Within each subfield, we highlight several of what we have identified as significant and important contributions to either our understanding of that subfield or metalloprotein design as a discipline. These reports are placed in context both historically and scientifically. General suggestions for future directions that we feel will be important to advance our understanding or accelerate discovery are discussed.
Topics: Binding Sites; Catalysis; Catalytic Domain; Electrons; Metalloproteins; Models, Molecular
PubMed: 35763791
DOI: 10.1021/acs.chemrev.1c01025