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Emerging Trends in Metal Biochemistry
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Emerging Trends in Metal Biochemistry

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (30 April 2019) | Viewed by 58372

Special Issue Editor

Prof. Dr. Vinzenz M. Unger

E-Mail Website
Guest Editor
Department of Molecular Biosciences, Northwestern University, Hogan 2-100, 2205 Tech Drive, Evanston, IL 60208, USA
Interests: copper ions; membrane proteins; biophysics; membrane-associated scaffolds; electron microscopy; digital image reconstruction

Special Issue Information

Dear Colleagues,

Stereotypically, “biochemistry” is associated with the properties and roles of proteins, nucleic acids, carbohydrates, lipids and the thousands of chemical reactions that occur within the chemical engine that keeps cells alive. Often missing from this picture are the myriad contributions of metal ions that are woven so deeply into the chemistry of life that imbalances in their homeostasis invariably derail cellular function, often with lethal consequences. What makes metals universally useful and indispensable within biology are their distinct chemical behaviors that allow them to support every aspect of life. In fact, there is not one cellular function that does not—in one way or another—rely on the presence of metal ions, be it through passive screening of electrostatics on biopolymer surfaces, direct regulation of biopolymer dynamics, stabilization of protein domains, catalysis, generation of voltages, or cellular signalling. Yet despite its fundamental importance, the biochemistry of metals at large remains understudied and underappreciated—metals, in short, are often taken for granted. However, as life sciences advance, new and sometimes unexpected roles of metals are discovered at an accelerating pace, slowly but surely moving a spotlight onto this exciting field within biochemistry.

Through a mix of review and original articles, the scope of this Special Issue is to highlight recent and emerging trends in the biochemistry of five pivotal metals: calcium, copper, iron, manganese, and zinc. The goal is to share passion for metals by providing an integrated view that spans from cell to systems biology, from biophysics to pharmacology, pathology and clinical applications, showcasing how study of metal biochemistry will make increasingly important contributions to our understanding of life’s mysteries.

Prof. Dr. Vinzenz M. Unger
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • calcium
  • copper
  • iron
  • manganese
  • zinc
  • metal homeostasis
  • metal biology
  • metal pharmacology
  • clinical imaging of metals
  • bio-inorganic chemistry
  • metalloproteins
  • metalloprotein structure
  • trace metals
  • crystallography
  • electron microscopy
  • PET imaging
  • X-ray fluorescent microscopy
  • Fe-S cluster
  • signaling
  • neurotransmission
  • neurodegenerative disease
  • metals in plants
  • reactive oxygen species

 

Published Papers (10 papers)

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Research

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26 pages, 6665 KiB  
Article
Emerging Approaches to Investigate the Influence of Transition Metals in the Proteinopathies
by Frederik Lermyte, James Everett, Jake Brooks, Francesca Bellingeri, Kharmen Billimoria, Peter J. Sadler, Peter B. O’Connor, Neil D. Telling and Joanna F. Collingwood
Cells 2019, 8(10), 1231; https://doi.org/10.3390/cells8101231 - 10 Oct 2019
Cited by 20 | Viewed by 4418
Abstract
Transition metals have essential roles in brain structure and function, and are associated with pathological processes in neurodegenerative disorders classed as proteinopathies. Synchrotron X-ray techniques, coupled with ultrahigh-resolution mass spectrometry, have been applied to study iron and copper interactions with amyloid β (1–42) [...] Read more.
Transition metals have essential roles in brain structure and function, and are associated with pathological processes in neurodegenerative disorders classed as proteinopathies. Synchrotron X-ray techniques, coupled with ultrahigh-resolution mass spectrometry, have been applied to study iron and copper interactions with amyloid β (1–42) or α-synuclein. Ex vivo tissue and in vitro systems were investigated, showing the capability to identify metal oxidation states, probe local chemical environments, and localize metal-peptide binding sites. Synchrotron experiments showed that the chemical reduction of ferric (Fe3+) iron and cupric (Cu2+) copper can occur in vitro after incubating each metal in the presence of Aβ for one week, and to a lesser extent for ferric iron incubated with α-syn. Nanoscale chemical speciation mapping of Aβ-Fe complexes revealed a spatial heterogeneity in chemical reduction of iron within individual aggregates. Mass spectrometry allowed the determination of the highest-affinity binding region in all four metal-biomolecule complexes. Iron and copper were coordinated by the same N-terminal region of Aβ, likely through histidine residues. Fe3+ bound to a C-terminal region of α-syn, rich in aspartic and glutamic acid residues, and Cu2+ to the N-terminal region of α-syn. Elucidating the biochemistry of these metal-biomolecule complexes and identifying drivers of chemical reduction processes for which there is evidence ex-vivo, are critical to the advanced understanding of disease aetiology. Full article
(This article belongs to the Special Issue Emerging Trends in Metal Biochemistry)
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19 pages, 2207 KiB  
Article
The Zinc Transporter Zip7 Is Downregulated in Skeletal Muscle of Insulin-Resistant Cells and in Mice Fed a High-Fat Diet
by Shaghayegh Norouzi, John Adulcikas, Darren C Henstridge, Sabrina Sonda, Sukhwinder Singh Sohal and Stephen Myers
Cells 2019, 8(7), 663; https://doi.org/10.3390/cells8070663 - 01 Jul 2019
Cited by 12 | Viewed by 4994
Abstract
Background: The zinc transporter Zip7 modulates zinc flux and controls cell signaling molecules associated with glucose metabolism in skeletal muscle. The present study evaluated the role of Zip7 in cell signaling pathways involved in insulin-resistant skeletal muscle and mice fed a high-fat diet. [...] Read more.
Background: The zinc transporter Zip7 modulates zinc flux and controls cell signaling molecules associated with glucose metabolism in skeletal muscle. The present study evaluated the role of Zip7 in cell signaling pathways involved in insulin-resistant skeletal muscle and mice fed a high-fat diet. Methods: Insulin-resistant skeletal muscle cells were prepared by treatment with an inhibitor of the insulin receptor, HNMPA-(AM)3 or palmitate, and Zip7 was analyzed along with pAkt, pTyrosine and Glut4. Similarly, mice fed normal chow (NC) or a high-fat diet (HFD) were also analyzed for protein expression of Glut4 and Zip7. An overexpression system for Zip7 was utilized to determine the action of this zinc transporter on several genes implicated in insulin signaling and glucose control. Results: We identified that Zip7 is upregulated by glucose in normal skeletal muscle cells and downregulated in insulin-resistant skeletal muscle. We also observed (as expected) a decrease in pAkt and Glut4 in the insulin-resistant skeletal muscle cells. The overexpression of Zip7 in skeletal muscle cells led to the modulation of key genes involved in the insulin signaling axis and glucose metabolism including Akt3, Dok2, Fos, Hras, Kras, Nos2, Pck2, and Pparg. In an in vivo mouse model, we identified a reduction in Glut4 and Zip7 in the skeletal muscle of mice fed a HFD compared to NC controls. Conclusions: These data suggest that Zip7 plays a role in skeletal muscle insulin signaling and is downregulated in an insulin-resistant, and HFD state. Understanding the molecular mechanisms of Zip7 action will provide novel opportunities to target this transporter therapeutically for the treatment of insulin resistance and type 2 diabetes. Full article
(This article belongs to the Special Issue Emerging Trends in Metal Biochemistry)
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28 pages, 8886 KiB  
Article
The Copper(II)-Assisted Connection between NGF and BDNF by Means of Nerve Growth Factor-Mimicking Short Peptides
by Irina Naletova, Cristina Satriano, Adriana Pietropaolo, Fiorenza Gianì, Giuseppe Pandini, Viviana Triaca, Giuseppina Amadoro, Valentina Latina, Pietro Calissano, Alessio Travaglia, Vincenzo Giuseppe Nicoletti, Diego La Mendola and Enrico Rizzarelli
Cells 2019, 8(4), 301; https://doi.org/10.3390/cells8040301 - 01 Apr 2019
Cited by 25 | Viewed by 4858
Abstract
Nerve growth factor (NGF) is a protein necessary for development and maintenance of the sympathetic and sensory nervous systems. We have previously shown that the NGF N-terminus peptide NGF(1-14) is sufficient to activate TrkA signaling pathways essential for neuronal survival and to induce [...] Read more.
Nerve growth factor (NGF) is a protein necessary for development and maintenance of the sympathetic and sensory nervous systems. We have previously shown that the NGF N-terminus peptide NGF(1-14) is sufficient to activate TrkA signaling pathways essential for neuronal survival and to induce an increase in brain-derived neurotrophic factor (BDNF) expression. Cu2+ ions played a critical role in the modulation of the biological activity of NGF(1-14). Using computational, spectroscopic, and biochemical techniques, here we report on the ability of a newly synthesized peptide named d-NGF(1-15), which is the dimeric form of NGF(1-14), to interact with TrkA. We found that d-NGF(1-15) interacts with the TrkA-D5 domain and induces the activation of its signaling pathways. Copper binding to d-NGF(1-15) stabilizes the secondary structure of the peptides, suggesting a strengthening of the noncovalent interactions that allow for the molecular recognition of D5 domain of TrkA and the activation of the signaling pathways. Intriguingly, the signaling cascade induced by the NGF peptides ultimately involves cAMP response element-binding protein (CREB) activation and an increase in BDNF protein level, in keeping with our previous result showing an increase of BDNF mRNA. All these promising connections can pave the way for developing interesting novel drugs for neurodegenerative diseases. Full article
(This article belongs to the Special Issue Emerging Trends in Metal Biochemistry)
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15 pages, 2906 KiB  
Article
Metabolic Signature of Dietary Iron Overload in a Mouse Model
by Chiara Volani, Giuseppe Paglia, Sigurdur V. Smarason, Peter P. Pramstaller, Egon Demetz, Christa Pfeifhofer-Obermair and Guenter Weiss
Cells 2018, 7(12), 264; https://doi.org/10.3390/cells7120264 - 11 Dec 2018
Cited by 31 | Viewed by 4466
Abstract
Iron is an essential co-factor for several metabolic processes, including the Krebs cycle and mitochondrial oxidative phosphorylation. Therefore, maintaining an appropriate iron balance is essential to ensure sufficient energy production and to avoid excessive reactive oxygen species formation. Iron overload impairs mitochondrial fitness; [...] Read more.
Iron is an essential co-factor for several metabolic processes, including the Krebs cycle and mitochondrial oxidative phosphorylation. Therefore, maintaining an appropriate iron balance is essential to ensure sufficient energy production and to avoid excessive reactive oxygen species formation. Iron overload impairs mitochondrial fitness; however, little is known about the associated metabolic changes. Here we aimed to characterize the metabolic signature triggered by dietary iron overload over time in a mouse model, where mice received either a standard or a high-iron diet. Metabolic profiling was assessed in blood, plasma and liver tissue. Peripheral blood was collected by means of volumetric absorptive microsampling (VAMS). Extracted blood and tissue metabolites were analyzed by liquid chromatography combined to high resolution mass spectrometry. Upon dietary iron loading we found increased glucose, aspartic acid and 2-/3-hydroxybutyric acid levels but low lactate and malate levels in peripheral blood and plasma, pointing to a re-programming of glucose homeostasis and the Krebs cycle. Further, iron loading resulted in the stimulation of the urea cycle in the liver. In addition, oxidative stress was enhanced in circulation and coincided with increased liver glutathione and systemic cysteine synthesis. Overall, iron supplementation affected several central metabolic circuits over time. Hence, in vivo investigation of metabolic signatures represents a novel and useful tool for getting deeper insights into iron-dependent regulatory circuits and for monitoring of patients with primary and secondary iron overload, and those ones receiving iron supplementation therapy. Full article
(This article belongs to the Special Issue Emerging Trends in Metal Biochemistry)
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14 pages, 2057 KiB  
Article
Carvacrol Attenuates Hippocampal Neuronal Death after Global Cerebral Ischemia via Inhibition of Transient Receptor Potential Melastatin 7
by Dae Ki Hong, Bo Young Choi, A Ra Kho, Song Hee Lee, Jeong Hyun Jeong, Beom Seok Kang, Dong Hyeon Kang, Kyoung-Ha Park and Sang Won Suh
Cells 2018, 7(12), 231; https://doi.org/10.3390/cells7120231 - 26 Nov 2018
Cited by 24 | Viewed by 3703
Abstract
Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production [...] Read more.
Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production of reactive oxygen species and neurodegeneration. Carvacrol inhibits transient receptor potential melastatin 7 (TRPM7), which regulates the homeostasis of extracellular metal ions, such as calcium and zinc. In the present study, we test whether carvacrol displays any neuroprotective effects after global cerebral ischemia (GCI), via a blockade of zinc influx. To test our hypothesis, we used eight-week-old male Sprague–Dawley rats, and a GCI model was induced by bilateral common carotid artery occlusion (CCAO), accompanied by blood withdrawal from the femoral artery. Ischemic duration was defined as a seven-minute electroencephalographic (EEG) isoelectric period. Carvacrol (50 mg/kg) was injected into the intraperitoneal space once per day for three days after the onset of GCI. The present study found that administration of carvacrol significantly decreased the number of degenerating neurons, microglial activation, oxidative damage, and zinc translocation after GCI, via downregulation of TRPM7 channels. These findings suggest that carvacrol, a TRPM7 inhibitor, may have therapeutic potential after GCI by reducing intracellular zinc translocation. Full article
(This article belongs to the Special Issue Emerging Trends in Metal Biochemistry)
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Review

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45 pages, 2695 KiB  
Review
Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases
by George J. Kontoghiorghes and Christina N. Kontoghiorghe
Cells 2020, 9(6), 1456; https://doi.org/10.3390/cells9061456 - 12 Jun 2020
Cited by 84 | Viewed by 6970
Abstract
Iron is essential for all living organisms. Many iron-containing proteins and metabolic pathways play a key role in almost all cellular and physiological functions. The diversity of the activity and function of iron and its associated pathologies is based on bond formation with [...] Read more.
Iron is essential for all living organisms. Many iron-containing proteins and metabolic pathways play a key role in almost all cellular and physiological functions. The diversity of the activity and function of iron and its associated pathologies is based on bond formation with adjacent ligands and the overall structure of the iron complex in proteins or with other biomolecules. The control of the metabolic pathways of iron absorption, utilization, recycling and excretion by iron-containing proteins ensures normal biologic and physiological activity. Abnormalities in iron-containing proteins, iron metabolic pathways and also other associated processes can lead to an array of diseases. These include iron deficiency, which affects more than a quarter of the world’s population; hemoglobinopathies, which are the most common of the genetic disorders and idiopathic hemochromatosis. Iron is the most common catalyst of free radical production and oxidative stress which are implicated in tissue damage in most pathologic conditions, cancer initiation and progression, neurodegeneration and many other diseases. The interaction of iron and iron-containing proteins with dietary and xenobiotic molecules, including drugs, may affect iron metabolic and disease processes. Deferiprone, deferoxamine, deferasirox and other chelating drugs can offer therapeutic solutions for most diseases associated with iron metabolism including iron overload and deficiency, neurodegeneration and cancer, the detoxification of xenobiotic metals and most diseases associated with free radical pathology. Full article
(This article belongs to the Special Issue Emerging Trends in Metal Biochemistry)
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23 pages, 1620 KiB  
Review
Genetic Disorders Associated with Metal Metabolism
by Muhammad Umair and Majid Alfadhel
Cells 2019, 8(12), 1598; https://doi.org/10.3390/cells8121598 - 09 Dec 2019
Cited by 29 | Viewed by 9111
Abstract
Genetic disorders associated with metal metabolism form a large group of disorders and mostly result from defects in the proteins/enzymes involved in nutrient metabolism and energy production. These defects can affect different metabolic pathways and cause mild to severe disorders related to metal [...] Read more.
Genetic disorders associated with metal metabolism form a large group of disorders and mostly result from defects in the proteins/enzymes involved in nutrient metabolism and energy production. These defects can affect different metabolic pathways and cause mild to severe disorders related to metal metabolism. Some disorders have moderate to severe clinical consequences. In severe cases, these elements accumulate in different tissues and organs, particularly the brain. As they are toxic and interfere with normal biological functions, the severity of the disorder increases. However, the human body requires a very small amount of these elements, and a deficiency of or increase in these elements can cause different genetic disorders to occur. Some of the metals discussed in the present review are copper, iron, manganese, zinc, and selenium. These elements may play a key role in the pathology and physiology of the nervous system. Full article
(This article belongs to the Special Issue Emerging Trends in Metal Biochemistry)
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17 pages, 813 KiB  
Review
Structural Consequences of Copper Binding to the Prion Protein
by Giulia Salzano, Gabriele Giachin and Giuseppe Legname
Cells 2019, 8(8), 770; https://doi.org/10.3390/cells8080770 - 25 Jul 2019
Cited by 36 | Viewed by 4959
Abstract
Prion, or PrPSc, is the pathological isoform of the cellular prion protein (PrPC) and it is the etiological agent of transmissible spongiform encephalopathies (TSE) affecting humans and animal species. The most relevant function of PrPC is its ability [...] Read more.
Prion, or PrPSc, is the pathological isoform of the cellular prion protein (PrPC) and it is the etiological agent of transmissible spongiform encephalopathies (TSE) affecting humans and animal species. The most relevant function of PrPC is its ability to bind copper ions through its flexible N-terminal moiety. This review includes an overview of the structure and function of PrPC with a focus on its ability to bind copper ions. The state-of-the-art of the role of copper in both PrPC physiology and in prion pathogenesis is also discussed. Finally, we describe the structural consequences of copper binding to the PrPC structure. Full article
(This article belongs to the Special Issue Emerging Trends in Metal Biochemistry)
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25 pages, 2972 KiB  
Review
Live-Cell Imaging of Physiologically Relevant Metal Ions Using Genetically Encoded FRET-Based Probes
by Helmut Bischof, Sandra Burgstaller, Markus Waldeck-Weiermair, Thomas Rauter, Maximilian Schinagl, Jeta Ramadani-Muja, Wolfgang F. Graier and Roland Malli
Cells 2019, 8(5), 492; https://doi.org/10.3390/cells8050492 - 22 May 2019
Cited by 64 | Viewed by 8818
Abstract
Essential biochemical reactions and processes within living organisms are coupled to subcellular fluctuations of metal ions. Disturbances in cellular metal ion homeostasis are frequently associated with pathological alterations, including neurotoxicity causing neurodegeneration, as well as metabolic disorders or cancer. Considering these important aspects [...] Read more.
Essential biochemical reactions and processes within living organisms are coupled to subcellular fluctuations of metal ions. Disturbances in cellular metal ion homeostasis are frequently associated with pathological alterations, including neurotoxicity causing neurodegeneration, as well as metabolic disorders or cancer. Considering these important aspects of the cellular metal ion homeostasis in health and disease, measurements of subcellular ion signals are of broad scientific interest. The investigation of the cellular ion homeostasis using classical biochemical methods is quite difficult, often even not feasible or requires large cell numbers. Here, we report of genetically encoded fluorescent probes that enable the visualization of metal ion dynamics within individual living cells and their organelles with high temporal and spatial resolution. Generally, these probes consist of specific ion binding domains fused to fluorescent protein(s), altering their fluorescent properties upon ion binding. This review focuses on the functionality and potential of these genetically encoded fluorescent tools which enable monitoring (sub)cellular concentrations of alkali metals such as K+, alkaline earth metals including Mg2+ and Ca2+, and transition metals including Cu+/Cu2+ and Zn2+. Moreover, we discuss possible approaches for the development and application of novel metal ion biosensors for Fe2+/Fe3+, Mn2+ and Na+. Full article
(This article belongs to the Special Issue Emerging Trends in Metal Biochemistry)
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14 pages, 960 KiB  
Review
Switching on Endogenous Metal Binding Proteins in Parkinson’s Disease
by Fleur A. McLeary, Alexandre N. Rcom-H’cheo-Gauthier, Michael Goulding, Rowan A. W. Radford, Yuho Okita, Peter Faller, Roger S. Chung and Dean L. Pountney
Cells 2019, 8(2), 179; https://doi.org/10.3390/cells8020179 - 19 Feb 2019
Cited by 22 | Viewed by 5194
Abstract
The formation of cytotoxic intracellular protein aggregates is a pathological signature of multiple neurodegenerative diseases. The principle aggregating protein in Parkinson’s disease (PD) and atypical Parkinson’s diseases is α-synuclein (α-syn), which occurs in neural cytoplasmic inclusions. Several factors have been found to trigger [...] Read more.
The formation of cytotoxic intracellular protein aggregates is a pathological signature of multiple neurodegenerative diseases. The principle aggregating protein in Parkinson’s disease (PD) and atypical Parkinson’s diseases is α-synuclein (α-syn), which occurs in neural cytoplasmic inclusions. Several factors have been found to trigger α-syn aggregation, including raised calcium, iron, and copper. Transcriptional inducers have been explored to upregulate expression of endogenous metal-binding proteins as a potential neuroprotective strategy. The vitamin-D analogue, calcipotriol, induced increased expression of the neuronal vitamin D-dependent calcium-binding protein, calbindin-D28k, and this significantly decreased the occurrence of α-syn aggregates in cells with transiently raised intracellular free Ca, thereby increasing viability. More recently, the induction of endogenous expression of the Zn and Cu binding protein, metallothionein, by the glucocorticoid analogue, dexamethasone, gave a specific reduction in Cu-dependent α-syn aggregates. Fe accumulation has long been associated with PD. Intracellularly, Fe is regulated by interactions between the Fe storage protein ferritin and Fe transporters, such as poly(C)-binding protein 1. Analysis of the transcriptional regulation of Fe binding proteins may reveal potential inducers that could modulate Fe homoeostasis in disease. The current review highlights recent studies that suggest that transcriptional inducers may have potential as novel mechanism-based drugs against metal overload in PD. Full article
(This article belongs to the Special Issue Emerging Trends in Metal Biochemistry)
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