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Journal articles on the topic 'Protein metalation'

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Author: Grafiati
Published: 10 March 2023

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1

Foster, Andrew W., Tessa R. Young, Peter T. Chivers, and Nigel J. Robinson. "Protein metalation in biology." Current Opinion in Chemical Biology 66 (February 2022): 102095. http://dx.doi.org/10.1016/j.cbpa.2021.102095.

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2

Wong, Daisy L., Amelia T. Yuan, Natalie C. Korkola, and Martin J. Stillman. "Interplay between Carbonic Anhydrases and Metallothioneins: Structural Control of Metalation." International Journal of Molecular Sciences 21, no. 16 (August 9, 2020): 5697. http://dx.doi.org/10.3390/ijms21165697.

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Carbonic anhydrases (CAs) and metallothioneins (MTs) are both families of zinc metalloproteins central to life, however, they coordinate and interact with their Zn2+ ion cofactors in completely different ways. CAs and MTs are highly sensitive to the cellular environment and play key roles in maintaining cellular homeostasis. In addition, CAs and MTs have multiple isoforms with differentiated regulation. This review discusses current literature regarding these two families of metalloproteins in carcinogenesis, with a dialogue on the association of these two ubiquitous proteins in vitro in the context of metalation. Metalation of CA by Zn-MT and Cd-MT is described. Evidence for protein–protein interactions is introduced from changes in metalation profiles of MT from electrospray ionization mass spectrometry and the metalation rate from stopped-flow kinetics. The implications on cellular control of pH and metal donation is also discussed in the context of diseased states.
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3

Sullivan, Matthew P., Michael Groessl, Samuel M. Meier, Richard L. Kingston, David C. Goldstone, and Christian G. Hartinger. "The metalation of hen egg white lysozyme impacts protein stability as shown by ion mobility mass spectrometry, differential scanning calorimetry, and X-ray crystallography." Chemical Communications 53, no. 30 (2017): 4246–49. http://dx.doi.org/10.1039/c6cc10150j.

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4

Yuan, Amelia T., Natalie C. Korkola, Daisy L. Wong, and Martin J. Stillman. "Metallothionein Cd4S11 cluster formation dominates in the protection of carbonic anhydrase." Metallomics 12, no. 5 (2020): 767–83. http://dx.doi.org/10.1039/d0mt00023j.

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5

Young, Tessa R., and Zhiguang Xiao. "Principles and practice of determining metal–protein affinities." Biochemical Journal 478, no. 5 (March 10, 2021): 1085–116. http://dx.doi.org/10.1042/bcj20200838.

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Metal ions play many critical roles in biology, as structural and catalytic cofactors, and as cell regulatory and signalling elements. The metal–protein affinity, expressed conveniently by the metal dissociation constant, KD, describes the thermodynamic strength of a metal–protein interaction and is a key parameter that can be used, for example, to understand how proteins may acquire metals in a cell and to identify dynamic elements (e.g. cofactor binding, changing metal availabilities) which regulate protein metalation in vivo. Here, we outline the fundamental principles and practical considerations that are key to the reliable quantification of metal–protein affinities. We review a selection of spectroscopic probes which can be used to determine protein affinities for essential biological transition metals (including Mn(II), Fe(II), Co(II), Ni(II), Cu(I), Cu(II) and Zn(II)) and, using selected examples, demonstrate how rational probe selection combined with prudent experimental design can be applied to determine accurate KD values.
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6

Osman, Deenah, Anastasia Cooke, Tessa R. Young, Evelyne Deery, Nigel J. Robinson, and Martin J. Warren. "The requirement for cobalt in vitamin B12: A paradigm for protein metalation." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1868, no. 1 (January 2021): 118896. http://dx.doi.org/10.1016/j.bbamcr.2020.118896.

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7

Bode, Manuela, Michael W. Woellhaf, Maria Bohnert, Martin van der Laan, Frederik Sommer, Martin Jung, Richard Zimmermann, Michael Schroda, and Johannes M. Herrmann. "Redox-regulated dynamic interplay between Cox19 and the copper-binding protein Cox11 in the intermembrane space of mitochondria facilitates biogenesis of cytochrome c oxidase." Molecular Biology of the Cell 26, no. 13 (July 2015): 2385–401. http://dx.doi.org/10.1091/mbc.e14-11-1526.

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Members of the twin Cx9C protein family constitute the largest group of proteins in the intermembrane space (IMS) of mitochondria. Despite their conserved nature and their essential role in the biogenesis of the respiratory chain, the molecular function of twin Cx9C proteins is largely unknown. We performed a SILAC-based quantitative proteomic analysis to identify interaction partners of the conserved twin Cx9C protein Cox19. We found that Cox19 interacts in a dynamic manner with Cox11, a copper transfer protein that facilitates metalation of the Cu(B) center of subunit 1 of cytochrome c oxidase. The interaction with Cox11 is critical for the stable accumulation of Cox19 in mitochondria. Cox19 consists of a helical hairpin structure that forms a hydrophobic surface characterized by two highly conserved tyrosine-leucine dipeptides. These residues are essential for Cox19 function and its specific binding to a cysteine-containing sequence in Cox11. Our observations suggest that an oxidative modification of this cysteine residue of Cox11 stimulates Cox19 binding, pointing to a redox-regulated interplay of Cox19 and Cox11 that is critical for copper transfer in the IMS and thus for biogenesis of cytochrome c oxidase.
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8

Messori, L., and A. Merlino. "Protein metalation by metal-based drugs: X-ray crystallography and mass spectrometry studies." Chem. Commun. 53, no. 85 (2017): 11622–33. http://dx.doi.org/10.1039/c7cc06442j.

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9

Merlino, Antonello, Tiziano Marzo, and Luigi Messori. "Protein Metalation by Anticancer Metallodrugs: A Joint ESI MS and XRD Investigative Strategy." Chemistry - A European Journal 23, no. 29 (February 14, 2017): 6942–47. http://dx.doi.org/10.1002/chem.201605801.

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10

Zoppi, Carlotta, Lara Massai, Damiano Cirri, Chiara Gabbiani, Alessandro Pratesi, and Luigi Messori. "Protein metalation by two structurally related gold(I) carbene complexes: An ESI MS study." Inorganica Chimica Acta 520 (May 2021): 120297. http://dx.doi.org/10.1016/j.ica.2021.120297.

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11

Gabbiani, Chiara, Lara Massai, Federica Scaletti, Elena Michelucci, Laura Maiore, Maria Agostina Cinellu, and Luigi Messori. "Protein metalation by metal-based drugs: reactions of cytotoxic gold compounds with cytochrome c and lysozyme." JBIC Journal of Biological Inorganic Chemistry 17, no. 8 (November 7, 2012): 1293–302. http://dx.doi.org/10.1007/s00775-012-0952-6.

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12

Bilinovich, Stephanie M., Daniel L. Morris, Jeremy W. Prokop, Joel A. Caporoso, Alexandra Taraboletti, Nilubol Duangjumpa, Matthew J. Panzner, Leah P. Shriver, and Thomas C. Leeper. "Silver Binding to Bacterial Glutaredoxins Observed by NMR." Biophysica 1, no. 4 (September 23, 2021): 359–76. http://dx.doi.org/10.3390/biophysica1040027.

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Glutaredoxins (GRXs) are a class of enzymes used in the reduction of protein thiols and the removal of reactive oxygen species. The CPYC active site of GRX is a plausible metal binding site, but was previously theorized not to bind metals due to its cis-proline configuration. We have shown that not only do several transition metals bind to the CPYC active site of the Brucella melitensis GRX but also report a model of a dimeric GRX in the presence of silver. This metal complex has also been characterized using enzymology, mass spectrometry, size exclusion chromatography, and molecular modeling. Metalation of GRX unwinds the end of the helix displaying the CPYC active site to accommodate dimerization in a way that is similar to iron sulfur cluster binding in related homologs and may imply that metal binding is a more common occurrence in this class of oxidoreductases than previously appreciated.
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13

Ndao, Moise, Christopher B. Ponce, and John Spencer Evans. "Oligomer formation, metalation, and the existence of aggregation-prone and mobile sequences within the intracrystalline protein family, Asprich." Faraday Discussions 159 (2012): 449. http://dx.doi.org/10.1039/c2fd20064c.

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14

Hancock, Sara M., Stuart D. Portbury, Adam P. Gunn, Blaine R. Roberts, Ashley I. Bush, and Paul A. Adlard. "Zinc Transporter-3 Knockout Mice Demonstrate Age-Dependent Alterations in the Metalloproteome." International Journal of Molecular Sciences 21, no. 3 (January 28, 2020): 839. http://dx.doi.org/10.3390/ijms21030839.

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Metals are critical cellular elements that are involved in a variety of cellular processes, with recent literature demonstrating that zinc, and the synaptic zinc transporter (ZnT3), are specifically involved in learning and memory and may also be key players in age-related neurodegenerative disorders such as Alzheimer’s disease. Whilst the cellular content and location of metals is critical, recent data has demonstrated that the metalation state of proteins is a determinant of protein function and potential toxicity. As we have previously reported that ZnT3 knockout (KO) mice have deficits in total zinc levels at both 3 and 6 months of age, we were interested in whether there might be changes in the metalloproteomic profile in these animals. To do this, we utilised size exclusion chromatography-inductively coupled plasma mass spectrometry (SEC-ICP-MS) and examined hippocampal homogenates from ZnT3 KO and age-matched wild-type mice at 3, 6 and 18 months of age. Our data suggest that there are alterations in specific metal binding proteins, for zinc, copper and iron all being modulated in the ZnT3 KO mice compared to wild-type (WT). These data suggest that ZnT3 KO mice may have impairments in the levels or localisation of multiple transition metals, and that copper- and iron-dependent cellular pathways may also be impacted in these mice.
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15

Suzuki, Eisuke, Namino Ogawa, Taka-aki Takeda, Yukina Nishito, Yu-ki Tanaka, Takashi Fujiwara, Mayu Matsunaga, et al. "Detailed analyses of the crucial functions of Zn transporter proteins in alkaline phosphatase activation." Journal of Biological Chemistry 295, no. 17 (March 16, 2020): 5669–84. http://dx.doi.org/10.1074/jbc.ra120.012610.

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Numerous zinc ectoenzymes are metalated by zinc and activated in the compartments of the early secretory pathway before reaching their destination. Zn transporter (ZNT) proteins located in these compartments are essential for ectoenzyme activation. We have previously reported that ZNT proteins, specifically ZNT5–ZNT6 heterodimers and ZNT7 homodimers, play critical roles in the activation of zinc ectoenzymes, such as alkaline phosphatases (ALPs), by mobilizing cytosolic zinc into these compartments. However, this process remains incompletely understood. Here, using genetically-engineered chicken DT40 cells, we first determined that Zrt/Irt-like protein (ZIP) transporters that are localized to the compartments of the early secretory pathway play only a minor role in the ALP activation process. These transporters included ZIP7, ZIP9, and ZIP13, performing pivotal functions in maintaining cellular homeostasis by effluxing zinc out of the compartments. Next, using purified ALP proteins, we showed that zinc metalation on ALP produced in DT40 cells lacking ZNT5–ZNT6 heterodimers and ZNT7 homodimers is impaired. Finally, by genetically disrupting both ZNT5 and ZNT7 in human HAP1 cells, we directly demonstrated that the tissue-nonspecific ALP-activating functions of both ZNT complexes are conserved in human cells. Furthermore, using mutant HAP1 cells, we uncovered a previously-unrecognized and unique spatial regulation of ZNT5–ZNT6 heterodimer formation, wherein ZNT5 recruits ZNT6 to the Golgi apparatus to form the heterodimeric complex. These findings fill in major gaps in our understanding of the molecular mechanisms underlying zinc ectoenzyme activation in the compartments of the early secretory pathway.
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16

Marzo, Tiziano, and Diego La Mendola. "Looking Beyond DNA as the Target of Inorganic Chemotherapy Agents: The Key Role of Protein Metalation and Metal Homeostasis." Current Topics in Medicinal Chemistry 21, no. 1 (January 11, 2021): 3–5. http://dx.doi.org/10.2174/156802662101201211094545.

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17

Marzo, Tiziano, and Diego La Mendola. "Looking Beyond DNA as the Target of Inorganic Chemotherapy Agents: The Key Role of Protein Metalation and Metal Homeostasis." Current Topics in Medicinal Chemistry 21, no. 1 (December 11, 2020): 3–5. http://dx.doi.org/10.2174/156802662101201211094545.

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18

Irvine, Gordon W., Kelly E. R. Duncan, Meredith Gullons, and Martin J. Stillman. "Metalation Kinetics of the Human α-Metallothionein 1a Fragment Is Dependent on the Fluxional Structure of the apo-Protein." Chemistry - A European Journal 21, no. 3 (November 17, 2014): 1269–79. http://dx.doi.org/10.1002/chem.201404283.

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19

Bradley, Justin M., Dimitry A. Svistunenko, Michael T. Wilson, Andrew M. Hemmings, Geoffrey R. Moore, and Nick E. Le Brun. "Bacterial iron detoxification at the molecular level." Journal of Biological Chemistry 295, no. 51 (October 12, 2020): 17602–23. http://dx.doi.org/10.1074/jbc.rev120.007746.

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Iron is an essential micronutrient, and, in the case of bacteria, its availability is commonly a growth-limiting factor. However, correct functioning of cells requires that the labile pool of chelatable “free” iron be tightly regulated. Correct metalation of proteins requiring iron as a cofactor demands that such a readily accessible source of iron exist, but overaccumulation results in an oxidative burden that, if unchecked, would lead to cell death. The toxicity of iron stems from its potential to catalyze formation of reactive oxygen species that, in addition to causing damage to biological molecules, can also lead to the formation of reactive nitrogen species. To avoid iron-mediated oxidative stress, bacteria utilize iron-dependent global regulators to sense the iron status of the cell and regulate the expression of proteins involved in the acquisition, storage, and efflux of iron accordingly. Here, we survey the current understanding of the structure and mechanism of the important members of each of these classes of protein. Diversity in the details of iron homeostasis mechanisms reflect the differing nutritional stresses resulting from the wide variety of ecological niches that bacteria inhabit. However, in this review, we seek to highlight the similarities of iron homeostasis between different bacteria, while acknowledging important variations. In this way, we hope to illustrate how bacteria have evolved common approaches to overcome the dual problems of the insolubility and potential toxicity of iron.
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20

Yi, Shiluan, Brian L. Boys, Anne Brickenden, Lars Konermann, and Wing-Yiu Choy. "Effects of Zinc Binding on the Structure and Dynamics of the Intrinsically Disordered Protein Prothymosin α: Evidence for Metalation as an Entropic Switch†." Biochemistry 46, no. 45 (November 2007): 13120–30. http://dx.doi.org/10.1021/bi7014822.

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21

Cavicchioli, Maurício, Aline Zaballa, Queite Paula, Marcela Prieto, Carla Oliveira, Patrizia Civitareale, Maria Ciriolo, and Ana Da Costa Ferreira. "Oxidative Assets Toward Biomolecules and Cytotoxicity of New Oxindolimine-Copper(II) and Zinc(II) Complexes." Inorganics 7, no. 2 (January 26, 2019): 12. http://dx.doi.org/10.3390/inorganics7020012.

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A new oxindolimine ligand derived from isatin (1H-indole-2,3-dione) and 2-aminomethylbenzimidazole was synthesized, leading to two novel complexes after metalation with copper(II) perchlorate or zinc(II) chloride, [Cu(isambz)2](ClO4)2 (complex 1) and [Zn(isambz)Cl2] (complex 2). This new ligand was designed as a more lipophilic compound, in a series of oxindolimine–metal complexes with antitumor properties, having DNA, mitochondria, and some proteins, such as CDK1 kinase and topoisomerase IB, as key targets. The new complexes had their reactivity to human serum albumin (HSA) and DNA, and their cytotoxicity toward tumor cells investigated. The binding to CT-DNA was monitored by circular dichroism (CD) spectroscopy and fluorescence measurements using ethidium bromide in a competitive assay. Consequent DNA cleavage was verified by gel electrophoresis with complex 1, in nmolar concentrations, with formation of linear DNA (form III) after 60 min incubation at 37 °C, in the presence of hydrogen peroxide, which acts as a reducing agent. Formation of reactive oxygen species (ROS) was observed, monitored by spin trapping EPR. Interaction with HSA lead to α-helix structure disturbance, and formation of a stable radical species (HSA–Tyr·) and carbonyl groups in the protein. Despite showing oxidative ability to damage vital biomolecules such as HSA and DNA, these new complexes showed moderate cytotoxicity against hepatocellular carcinoma (HepG2) and neuroblastoma (SHSY5Y) cells, similarly to previous compounds in this series. These results confirm DNA as an important target for these compounds, and additionally indicate that oxidative damage is not the leading mechanism responsible for their cytotoxicity. Additionally, this work emphasizes the importance of ligand characteristics and of speciation in activity of metal complexes.
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22

Franco, Leticia Veloso R., Chen-Hsien Su, Gavin P. McStay, George J. Yu, and Alexander Tzagoloff. "Cox2p of yeast cytochrome oxidase assembles as a stand-alone subunit with the Cox1p and Cox3p modules." Journal of Biological Chemistry 293, no. 43 (September 17, 2018): 16899–911. http://dx.doi.org/10.1074/jbc.ra118.004138.

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Cytochrome oxidase (COX) is a hetero-oligomeric complex of the mitochondrial inner membrane that reduces molecular oxygen to water, a reaction coupled to proton transfer from the mitochondrial matrix to the intermembrane space. In the yeast Saccharomyces cerevisiae, COX is composed of 11–13 different polypeptide subunits. Here, using pulse labeling of mitochondrial gene products in isolated yeast mitochondria, combined with purification of tagged COX subunits and ancillary factors, we studied the Cox2p assembly intermediates. Analysis of radiolabeled Cox2p obtained in pulldown assays by native gel electrophoresis revealed the existence of several assembly intermediates, the largest of which had an estimated mass of 450–550 kDa. None of the other known subunits of COX were present in these Cox2p intermediates. This was also true for the several ancillary factors having still undefined functions in COX assembly. In agreement with earlier evidence, Cox18p and Cox20p, previously shown to be involved in processing and in membrane insertion of the Cox2p precursor, were found to be associated with the two largest Cox2p intermediates. A small fraction of the Cox2p module contained Sco1p and Coa6p, which have been implicated in metalation of the binuclear copper site on this subunit. Our results indicate that following its insertion into the mitochondrial inner membrane, Cox2p assembles as a stand-alone protein with the compositionally more complex Cox1p and Cox3p modules.
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23

Chiaverini, Lorenzo, Alessandro Pratesi, Damiano Cirri, Arianna Nardinocchi, Iogann Tolbatov, Alessandro Marrone, Mariagrazia Di Luca, Tiziano Marzo, and Diego La Mendola. "Anti-Staphylococcal Activity of the Auranofin Analogue Bearing Acetylcysteine in Place of the Thiosugar: An Experimental and Theoretical Investigation." Molecules 27, no. 8 (April 16, 2022): 2578. http://dx.doi.org/10.3390/molecules27082578.

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Auranofin (AF, hereafter) is an orally administered chrysotherapeutic agent approved for the treatment of rheumatoid arthritis that is being repurposed for various indications including bacterial infections. Its likely mode of action involves the impairment of the TrxR system through the binding of the pharmacophoric cation [AuPEt3]+. Accordingly, a reliable strategy to expand the medicinal profile of AF is the replacement of the thiosugar moiety with different ligands. Herein, we aimed to prepare the AF analogue bearing the acetylcysteine ligand (AF-AcCys, hereafter) and characterize its anti-staphylococcal activity. Biological studies revealed that AF-AcCys retains an antibacterial effect superimposable with that of AF against Staphylococcus aureus, whereas it is about 20 times less effective against Staphylococcus epidermidis. Bioinorganic studies confirmed that upon incubation with human serum albumin, AF-AcCys, similarly to AF, induced protein metalation through the [AuPEt3]+ fragment. Additionally, AF-AcCys appeared capable of binding the dodecapeptide Ac-SGGDILQSGCUG-NH2, corresponding to the tryptic C-terminal fragment (488–499) of hTrxR. To shed light on the pharmacological differences between AF and AF-AcCys, we carried out a comparative experimental stability study and a theoretical estimation of bond dissociation energies, unveiling the higher strength of the Au–S bond in AF-AcCys. From the results, it emerged that the lower lipophilicity of AF-AcCys with respect to AF could be a key feature for its different antibacterial activity. The differences and similarities between AF and AF-AcCys are discussed, alongside the opportunities and consequences that chemical structure modifications imply.
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24

Deters, Erin L., Emma L. Rients, Remy Carmichael, Olivia N. Genther-Schroeder, and Stephanie L. Hansen. "349 Dietary Zinc and Ractopamine Elicit Changes in Gene Expression of Zinc Transporters in the Muscle of Finishing Beef Steers." Journal of Animal Science 100, Supplement_3 (September 21, 2022): 166–67. http://dx.doi.org/10.1093/jas/skac247.309.

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Abstract Twenty-four Angus cross steers (467 ± 13 kg) were used to assess the effects of supplemental Zn and ractopamine (RAC; Actogain, Zoetis) on muscle gene expression. Steers were housed in pens (6 steers/pen) with GrowSafe bunks and randomly assigned to treatments (6 steers/treatment) which included 0 (CON), 60 (LO), 120 (MED), or 180 (HI) mg supplemental Zn (Availa-Zn, Zinpro)/kg dry matter. Dietary Zn treatments were initiated on d 0 and RAC supplementation (300 mg/steer/d) began on d 53. Blood and muscle (longissimus thoracis) samples were collected from all steers on d -4, 48, and 67. Plasma Zn concentrations were determined via inductively coupled plasma-mass spectrometry and muscle gene expression was determined via the Fluidigm Biomark HD system. Data were analyzed using ProcMixed of SAS (fixed effect = treatment; experimental unit = steer); treatments were compared using orthogonal linear and quadratic contrast statements. The LO treatment was removed from gene expression analyses due to poor reads. There was a tendency for a quadratic effect on d 48 and 67 plasma Zn (P = 0.10) where plasma was greater in Zn-supplemented animals than CON. Minimal effects of Zn supplementation were observed on muscle gene expression prior to the start of RAC. However, 14 d after the start of RAC, the expression of several genes involved in Zn storage and transport (MT1A, SLC39A7, SLC39A8, SLC39A9, SLC39A10, SLC39A13) linearly decreased with increasing Zn supplementation (P ≤ 0.08). These effects were mainly driven by an increase in gene expression for CON steers, suggesting RAC influences intracellular Zn trafficking or demand. Several of these transporters are located on organelles responsible for Zn-dependent processes like protein synthesis and metalation of enzymes. Therefore, increasing Zn supplementation prior to RAC feeding may support beta-agonist induced muscle growth in beef steers.
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25

Giorgio, Anna, and Antonello Merlino. "Gold metalation of proteins: Structural studies." Coordination Chemistry Reviews 407 (March 2020): 213175. http://dx.doi.org/10.1016/j.ccr.2019.213175.

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26

Perea-García, Ana, Sergi Puig, and Lola Peñarrubia. "The role of post-transcriptional modulators of metalloproteins in response to metal deficiencies." Journal of Experimental Botany 73, no. 6 (November 30, 2021): 1735–50. http://dx.doi.org/10.1093/jxb/erab521.

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Abstract 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.
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27

Holanda, Aldenora Oliveira do Nascimento, Ana Raquel Soares de Oliveira, Kyria Jayanne Clímaco Cruz, Juliana Soares Severo, Jennifer Beatriz Silva Morais, Benedito Borges da Silva, and Dilina do Nascimento Marreiro. "Zinc and metalloproteinases 2 and 9: What is their relation with breast cancer?" Revista da Associação Médica Brasileira 63, no. 1 (January 2017): 78–84. http://dx.doi.org/10.1590/1806-9282.63.01.78.

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Summary Zinc is the catalytic component of proteins that regulate responses to DNA damage, intracellular signaling enzymes, and matrix metalloproteinases, which are important proteins in carcinogenesis. The objective of this review is to bring current information on the participation of zinc and matrix metalloproteinases types 2 and 9 in mechanisms involved in the pathogenesis of breast cancer. We conducted a literature review, in consultation with the PubMed, Lilacs, and Scielo databases. The zinc and cysteine residues are structural elements shared by all members of the family of matrix metalloproteinases, and these proteins appear to be involved in the propagation of various types of neoplasms, including breast cancer. Moreover, transported zinc is likely to be used for the metalation of the catalytic domain of the newly synthesized metalloproteinases before the latter are secreted. Accordingly, increase in zinc concentrations in cellular compartments and the reduction of this trace element in the blood of patients with breast cancer appear to alter the activity of metalloproteinases 2 and 9, contributing to the occurrence of malignancy. Thus, it is necessary to carry out further studies with a view to clarify the role of zinc and metalloproteinases 2 and 9 in the pathogenesis of breast cancer.
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28

Cirri, Damiano, Tiziano Marzo, Iogann Tolbatov, Alessandro Marrone, Francesco Saladini, Ilaria Vicenti, Filippo Dragoni, Adele Boccuto, and Luigi Messori. "In Vitro Anti-SARS-CoV-2 Activity of Selected Metal Compounds and Potential Molecular Basis for Their Actions Based on Computational Study." Biomolecules 11, no. 12 (December 10, 2021): 1858. http://dx.doi.org/10.3390/biom11121858.

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Metal-based drugs represent a rich source of chemical substances of potential interest for the treatment of COVID-19. To this end, we have developed a small but representative panel of nine metal compounds, including both synthesized and commercially available complexes, suitable for medical application and tested them in vitro against the SARS-CoV-2 virus. The screening revealed that three compounds from the panel, i.e., the organogold(III) compound Aubipyc, the ruthenium(III) complex KP1019, and antimony trichloride (SbCl3), are endowed with notable antiviral properties and an acceptable cytotoxicity profile. These initial findings prompted us to perform a computational study to unveil the likely molecular basis of their antiviral actions. Calculations evidenced that the metalation of nucleophile sites in SARS-CoV-2 proteins or nucleobase strands, induced by Aubipyc, SbCl3, and KP1019, is likely to occur. Remarkably, we found that only the deprotonated forms of Cys and Sec residues can react favorably with these metallodrugs. The mechanistic implications of these findings are discussed.
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29

Horn, Nina, and Pernilla Wittung-Stafshede. "ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle." Biomedicines 9, no. 4 (April 6, 2021): 391. http://dx.doi.org/10.3390/biomedicines9040391.

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Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to copper deficiency in nervous tissue, liver, and blood but accumulation in other tissues. Site-specific cellular deficiencies of copper lead to loss of function of copper-dependent enzymes in all tissues, and the range of Menkes disease pathologies observed can now be explained in full by lack of specific copper enzymes. New pathways involving copper activated lysosomal and steroid sulfatases link patient symptoms usually related to other inborn errors of metabolism to Menkes disease. Additionally, new roles for lysyl oxidase in activation of molecules necessary for the innate immune system, and novel adapter molecules that play roles in ERGIC trafficking of brain receptors and other proteins, are emerging. We here summarize the current knowledge of the roles of copper enzyme function in Menkes disease, with a focus on ATP7A-mediated enzyme metalation in the secretory pathway. By establishing mechanistic relationships between copper-dependent cellular processes and Menkes disease symptoms in patients will not only increase understanding of copper biology but will also allow for the identification of an expanding range of copper-dependent enzymes and pathways. This will raise awareness of rare patient symptoms, and thus aid in early diagnosis of Menkes disease patients.
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30

Calabrese, Antonio N., Lauren A. Speechley, and Tara L. Pukala. "Characterisation of Calmodulin Structural Transitions by Ion Mobility Mass Spectrometry." Australian Journal of Chemistry 65, no. 5 (2012): 504. http://dx.doi.org/10.1071/ch12047.

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This study demonstrates the ability of travelling wave ion mobility-mass spectrometry to measure collision cross-sections of ions in the negative mode, using a calibration based approach. Here, negative mode ion mobility-mass spectrometry was utilised to understand structural transitions of calmodulin upon Ca2+ binding and complexation with model peptides melittin and the plasma membrane Ca2+ pump C20W peptide. Coexisting calmodulin conformers were distinguished on the basis of their mass and cross-section, and identified as relatively folded and unfolded populations, with good agreement in collision cross-section to known calmodulin geometries. Titration of calcium tartrate to physiologically relevant Ca2+ levels provided evidence for intermediately metalated species during the transition from apo- to holo-calmodulin, with collision cross-section measurements indicating that higher Ca2+ occupancy is correlated with more compact structures. The binding of two representative peptides which exemplify canonical compact (melittin) and extended (C20W) peptide-calmodulin binding models has also been interrogated by ion mobility mass spectrometry. Peptide binding to calmodulin involves intermediates with metalation states from 1–4 Ca2+, which demonstrate relatively collapsed structures, suggesting neither the existence of holo-calmodulin or a pre-folded calmodulin conformation is a prerequisite for binding target peptides or proteins. The biological importance of the different metal unsaturated calmodulin complexes, if any, is yet to be understood.
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31

Messori, Luigi, and Antonello Merlino. "Ruthenium metalation of proteins: the X-ray structure of the complex formed between NAMI-A and hen egg white lysozyme." Dalton Transactions 43, no. 16 (2014): 6128. http://dx.doi.org/10.1039/c3dt53582g.

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32

Vergara, Alessandro, Irene Russo Krauss, Daniela Montesarchio, Luigi Paduano, and Antonello Merlino. "Investigating the Ruthenium Metalation of Proteins: X-ray Structure and Raman Microspectroscopy of the Complex between RNase A and AziRu." Inorganic Chemistry 52, no. 19 (October 7, 2013): 10714–16. http://dx.doi.org/10.1021/ic401494v.

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33

Puchkova, Ludmila, Polina Babich, Yulia Zatulovskaia, Ekaterina Ilyechova, and Francesca Di Sole. "Copper Metabolism of Newborns Is Adapted to Milk Ceruloplasmin as a Nutritive Source of Copper: Overview of the Current Data." Nutrients 10, no. 11 (October 30, 2018): 1591. http://dx.doi.org/10.3390/nu10111591.

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Copper, which can potentially be a highly toxic agent, is an essential nutrient due to its role as a cofactor for cuproenzymes and its participation in signaling pathways. In mammals, the liver is a central organ that controls copper turnover throughout the body, including copper absorption, distribution, and excretion. In ontogenesis, there are two types of copper metabolism, embryonic and adult, which maintain the balance of copper in each of these periods of life, respectively. In the liver cells, these types of metabolism are characterized by the specific expression patterns and activity levels of the genes encoding ceruloplasmin, which is the main extracellular ferroxidase and copper transporter, and the proteins mediating ceruloplasmin metalation. In newborns, the molecular genetic mechanisms responsible for copper homeostasis and the ontogenetic switch from embryonic to adult copper metabolism are highly adapted to milk ceruloplasmin as a dietary source of copper. In the mammary gland cells, the level of ceruloplasmin gene expression and the alternative splicing of its pre-mRNA govern the amount of ceruloplasmin in the milk, and thus, the amount of copper absorbed by a newborn is controlled. In newborns, the absorption, distribution, and accumulation of copper are adapted to milk ceruloplasmin. If newborns are not breast-fed in the early stages of postnatal development, they do not have this natural control ensuring alimentary copper balance in the body. Although there is still much to be learned about the neonatal consequences of having an imbalance of copper in the mother/newborn system, the time to pay attention to this problem has arrived because the neonatal misbalance of copper may provoke the development of copper-related disorders.
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34

Merlino, Antonello. "Recent Advances in Protein Metalation: Structural Studies." Chemical Communications, 2021. http://dx.doi.org/10.1039/d0cc08053e.

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Protein metalation is the process that determines the formation of adducts upon reaction of metal compounds with proteins. Protein metalation plays a crucial role in different fields, determining mechanism of...
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35

Osman, Deenah, and Nigel J. Robinson. "Protein metalation in a nutshell." FEBS Letters, September 20, 2022. http://dx.doi.org/10.1002/1873-3468.14500.

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36

Hsueh, Shawn C. C., Mark Nijland, Xubiao Peng, Benjamin Hilton, and Steven S. Plotkin. "First Principles Calculation of Protein–Protein Dimer Affinities of ALS-Associated SOD1 Mutants." Frontiers in Molecular Biosciences 9 (March 24, 2022). http://dx.doi.org/10.3389/fmolb.2022.845013.

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Cu,Zn superoxide dismutase (SOD1) is a 32 kDa homodimer that converts toxic oxygen radicals in neurons to less harmful species. The dimerization of SOD1 is essential to the stability of the protein. Monomerization increases the likelihood of SOD1 misfolding into conformations associated with aggregation, cellular toxicity, and neuronal death in familial amyotrophic lateral sclerosis (fALS). The ubiquity of disease-associated mutations throughout the primary sequence of SOD1 suggests an important role of physicochemical processes, including monomerization of SOD1, in the pathology of the disease. Herein, we use a first-principles statistical mechanics method to systematically calculate the free energy of dimer binding for SOD1 using molecular dynamics, which involves sequentially computing conformational, orientational, and separation distance contributions to the binding free energy. We consider the effects of two ALS-associated mutations in SOD1 protein on dimer stability, A4V and D101N, as well as the role of metal binding and disulfide bond formation. We find that the penalty for dimer formation arising from the conformational entropy of disordered loops in SOD1 is significantly larger than that for other protein–protein interactions previously considered. In the case of the disulfide-reduced protein, this leads to a bound complex whose formation is energetically disfavored. Somewhat surprisingly, the loop free energy penalty upon dimerization is still significant for the holoprotein, despite the increased structural order induced by the bound metal cations. This resulted in a surprisingly modest increase in dimer binding free energy of only about 1.5 kcal/mol upon metalation of the protein, suggesting that the most significant stabilizing effects of metalation are on folding stability rather than dimer binding stability. The mutant A4V has an unstable dimer due to weakened monomer-monomer interactions, which are manifested in the calculation by a separation free energy surface with a lower barrier. The mutant D101N has a stable dimer partially due to an unusually rigid β-barrel in the free monomer. D101N also exhibits anticooperativity in loop folding upon dimerization. These computational calculations are, to our knowledge, the most quantitatively accurate calculations of dimer binding stability in SOD1 to date.
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37

Loreto, Domenico, Anna Esposito, Nicola Demitri, Annalisa Guaragna, and Antonello Merlino. "Digging into protein metalation differences triggered by fluorine containing-dirhodium tetracarboxylate analogues." Dalton Transactions, 2022. http://dx.doi.org/10.1039/d2dt00873d.

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Catalytic and biological properties of dirhodium tetracarboxylates ([Rh2(μ-O2CR)4L2], L=axial ligand, R=CH3-, CH3CH2-, etc) largely depend on the nature of the bridging carboxylate equatorial μ-O2CR ligands, which can be easily exchanged...
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38

Buchowiecka, Alicja K. "Protein cysteine S-glycosylation: oxidative hydrolysis of protein S-glycosidic bonds in aqueous alkaline environments." Amino Acids, December 2, 2022. http://dx.doi.org/10.1007/s00726-022-03208-7.

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AbstractSome glycoproteins contain carbohydrates S-linked to cysteine (Cys) residues. However, relatively few S-glycosylated proteins have been detected, due to the lack of an effective research methodology. This work outlines a general concept for the detection of S-glycosylation sites in proteins. The approach was verified by exploratory experiments on a model mixture of β-S-glucosylated polypeptides obtained by the chemical transformation of lysozyme P00698. The model underwent two processes: (1) oxidative hydrolysis of S-glycosidic bonds under alkaline conditions to expose the thiol group of Cys residues; (2) thiol S-alkylation leading to thiol S-adduct formation at the former S-glycosylation sites. Oxidative hydrolysis was conducted in aqueous urea, dimethyl sulfoxide, or trifluoroethanol, with silver nitrate as the reaction promoter, in the presence of triethylamine and/or pyridine. The concurrent formation of stable protein silver thiolates, gluconic acid, and silver nanoclusters was observed. The essential de-metalation of protein silver thiolates using dithiothreitol preceded the S-labeling of Cys residues with 4-vinyl pyridine or a fluorescent reagent. The S-labeled model was sequenced by tandem mass spectrometry to obtain data on the modifications and their distribution over the protein chains. This enabled the efficiency of both S-glycosidic bonds hydrolysis and S-glycosylation site labeling to be evaluated. Suggestions are also given for testing this novel strategy on real proteomic samples.
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39

Merlino, Antonello, Tiziano Marzo, and Luigi Messori. "Frontispiece: Protein Metalation by Anticancer Metallodrugs: A Joint ESI MS and XRD Investigative Strategy." Chemistry - A European Journal 23, no. 29 (May 23, 2017). http://dx.doi.org/10.1002/chem.201782961.

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40

Bulathge, Anjala W., Rhiza Lyne E. Villones, Fabian C. Herbert, Jeremiah J. Gassensmith, and Gabriele Meloni. "Comparative cisplatin reactivity towards human Zn7-Metallothionein-2 and MTF-1 zinc fingers: potential implications in anticancer drug resistance." Metallomics, August 26, 2022. http://dx.doi.org/10.1093/mtomcs/mfac061.

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Abstract Cis-diamminedichloroplatinum(II) (cisplatin) is a widely used metal-based chemotherapeutic drug for the treatment of cancers. However, intrinsic and acquired drug resistance limit the efficacy of cisplatin-based treatments. Increased production of intracellular thiol-rich molecules, in particular metallothioneins (MTs), which form stable coordination complexes with the electrophilic cisplatin, results in cisplatin sequestration leading to pre-target resistance. MT-1/-2 are overexpressed in cancer cells, and their expression is controlled by the Metal Response Element (MRE)-binding Transcription factor-1 (MTF-1), featuring six Cys2His2-type zinc fingers which, upon zinc metalation, recognize specific MRE sequences in the promoter region of MT genes triggering their expression. Cisplatin can efficiently react with protein metal binding sites featuring nucleophilic cysteine and/or histidine residues, including MTs and zinc fingers proteins, but the preferential reactivity towards specific targets with competing binding sites cannot be easily predicted. In this work, by in vitro competition reactions, we investigated the thermodynamic and kinetic preferential reactivity of cisplatin towards human Zn7MT-2, each of the six MTF-1 zinc fingers, and the entire human MTF-1 zinc finger domain. By spectroscopic, spectrometric and electrophoretic mobility shift assays (EMSA), we demonstrated that cisplatin preferentially reacts with Zn7MT-2 to form Cys4-Pt(II) complexes, resulting in zinc release from MT-2. Zinc transfer from MT-2 to the MTF-1 triggers MTF-1 metalation, activation and binding to target MRE sequences, as demonstrated by EMSA with DNA oligonucleotides. The cisplatin-dependent MT-mediated MTF-1 activation leading to apo-MT overexpression potentially establishes one of the molecular mechanisms underlying the development and potentiation of MT-mediated pre-target resistance.
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41

Foster, Andrew W., Sophie E. Clough, Zeynep Aki, Tessa R. Young, Alison R. Clarke, and Nigel J. Robinson. "Metalation calculators for E. coli strain JM109 (DE3): Aerobic, anaerobic and hydrogen peroxide exposed cells cultured in LB media." Metallomics, August 6, 2022. http://dx.doi.org/10.1093/mtomcs/mfac058.

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Abstract Three web-based calculators, and three analogous spreadsheets, have been generated that predict in vivo metal occupancies of proteins based on known metal affinities. The calculations exploit estimates of the availabilities of the labile buffered pools of different metals inside a cell. Here, metal availabilities have been estimated for a strain of E. coli that is commonly used in molecular biology and biochemistry research, for example in the production of recombinant proteins. Metal availabilities have been examined for cells grown in LB medium aerobically, anaerobically and in response to H2O2 by monitoring the abundance of a selected set of metal-responsive transcripts by qPCR. The selected genes are regulated by DNA-binding metal sensors that have been thermodynamically characterised in related bacterial cells enabling gene expression to be read-out as a function of intracellular metal availabilities expressed as free energies for forming metal complexes. The calculators compare these values with the free energies for forming complexes with the protein of interest, derived from metal affinities, to estimate how effectively the protein can compete with exchangeable binding sites in the intracellular milieu. The calculators then inter-compete the different metals, limiting total occupancy of the site to a maximum stoichiometry of 1, to output percentage occupancies with each metal. In addition to making these new and conditional calculators available, an original purpose of this article was to provide a tutorial which discusses constraints of this approach and presents ways in which such calculators might be exploited in basic and applied research, and in next-generation manufacturing.
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42

Foster, Andrew W., Sophie E. Clough, Zeynep Aki, Tessa R. Young, Alison R. Clarke, and Nigel J. Robinson. "Metalation calculators for E. coli strain JM109 (DE3): Aerobic, anaerobic and hydrogen peroxide exposed cells cultured in LB media." Metallomics, August 6, 2022. http://dx.doi.org/10.1093/mtomcs/mfac058.

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Abstract Three web-based calculators, and three analogous spreadsheets, have been generated that predict in vivo metal occupancies of proteins based on known metal affinities. The calculations exploit estimates of the availabilities of the labile buffered pools of different metals inside a cell. Here, metal availabilities have been estimated for a strain of E. coli that is commonly used in molecular biology and biochemistry research, for example in the production of recombinant proteins. Metal availabilities have been examined for cells grown in LB medium aerobically, anaerobically and in response to H2O2 by monitoring the abundance of a selected set of metal-responsive transcripts by qPCR. The selected genes are regulated by DNA-binding metal sensors that have been thermodynamically characterised in related bacterial cells enabling gene expression to be read-out as a function of intracellular metal availabilities expressed as free energies for forming metal complexes. The calculators compare these values with the free energies for forming complexes with the protein of interest, derived from metal affinities, to estimate how effectively the protein can compete with exchangeable binding sites in the intracellular milieu. The calculators then inter-compete the different metals, limiting total occupancy of the site to a maximum stoichiometry of 1, to output percentage occupancies with each metal. In addition to making these new and conditional calculators available, an original purpose of this article was to provide a tutorial which discusses constraints of this approach and presents ways in which such calculators might be exploited in basic and applied research, and in next-generation manufacturing.
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43

Fenlon, Luke A., and James M. Slauch. "Cytoplasmic Copper Detoxification in Salmonella Can Contribute to SodC Metalation but Is Dispensable during Systemic Infection." Journal of Bacteriology 199, no. 24 (September 18, 2017). http://dx.doi.org/10.1128/jb.00437-17.

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ABSTRACT Salmonella enterica serovar Typhimurium is a leading cause of foodborne disease worldwide. Severe infections result from the ability of S. Typhimurium to survive within host immune cells, despite being exposed to various host antimicrobial factors. SodCI, a copper-zinc-cofactored superoxide dismutase, is required to defend against phagocytic superoxide. SodCII, an additional periplasmic superoxide dismutase, although produced during infection, does not function in the host. Previous studies suggested that CueP, a periplasmic copper binding protein, facilitates acquisition of copper by SodCII. CopA and GolT, both inner membrane ATPases that pump copper from the cytoplasm to the periplasm, are a source of copper for CueP. Using in vitro SOD assays, we found that SodCI can also utilize CueP to acquire copper. However, both SodCI and SodCII have a significant fraction of activity independent of CueP and cytoplasmic copper export. We utilized a series of mouse competition assays to address the in vivo role of CueP-mediated SodC activation. A copA golT cueP triple mutant was equally as competitive as the wild type, suggesting that sufficient SodCI is active to defend against phagocytic superoxide independent of CueP and cytoplasmic copper export. We also confirmed that a strain containing a modified SodCII, which is capable of complementing a sodCI deletion, was fully virulent in a copA golT cueP background competed against the wild type. These competitions also address the potential impact of cytoplasmic copper toxicity within the phagosome. Our data suggest that Salmonella does not encounter inhibitory concentrations of copper during systemic infection. IMPORTANCE Salmonella is a leading cause of gastrointestinal disease worldwide. In severe cases, Salmonella can cause life-threatening systemic infections, particularly in very young children, the elderly, or people who are immunocompromised. To cause disease, Salmonella must survive the hostile environment inside host immune cells, a location in which most bacteria are killed. Our work examines how one particular metal, copper, is acquired by Salmonella to activate a protein important for survival within immune cells. At high levels, copper itself can inhibit Salmonella. Using a strain of Salmonella that cannot detoxify intracellular copper, we also addressed the in vivo role of copper as an antimicrobial agent.
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44

Young, Tessa R., Maria Alessandra Martini, Andrew W. Foster, Arthur Glasfeld, Deenah Osman, Richard J. Morton, Evelyne Deery, Martin J. Warren, and Nigel J. Robinson. "Calculating metalation in cells reveals CobW acquires CoII for vitamin B12 biosynthesis while related proteins prefer ZnII." Nature Communications 12, no. 1 (February 19, 2021). http://dx.doi.org/10.1038/s41467-021-21479-8.

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AbstractProtein metal-occupancy (metalation) in vivo has been elusive. To address this challenge, the available free energies of metals have recently been determined from the responses of metal sensors. Here, we use these free energy values to develop a metalation-calculator which accounts for inter-metal competition and changing metal-availabilities inside cells. We use the calculator to understand the function and mechanism of GTPase CobW, a predicted CoII-chaperone for vitamin B12. Upon binding nucleotide (GTP) and MgII, CobW assembles a high-affinity site that can obtain CoII or ZnII from the intracellular milieu. In idealised cells with sensors at the mid-points of their responses, competition within the cytosol enables CoII to outcompete ZnII for binding CobW. Thus, CoII is the cognate metal. However, after growth in different [CoII], CoII-occupancy ranges from 10 to 97% which matches CobW-dependent B12 synthesis. The calculator also reveals that related GTPases with comparable ZnII affinities to CobW, preferentially acquire ZnII due to their relatively weaker CoII affinities. The calculator is made available here for use with other proteins.
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45

Ferraz de Paiva, Raphael Enoque, Eduardo Guimarães Vieira, Daniel Rodrigues da Silva, Camila Anchau Wegermann, and Ana Maria Costa Ferreira. "Anticancer Compounds Based on Isatin-Derivatives: Strategies to Ameliorate Selectivity and Efficiency." Frontiers in Molecular Biosciences 7 (February 4, 2021). http://dx.doi.org/10.3389/fmolb.2020.627272.

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In this review we compare and discuss results of compounds already reported as anticancer agents based on isatin-derivatives, metalated as well as non-metallated. Isatin compounds can be obtained from plants, marine animals, and is also found in human fluids as a metabolite of amino acids. Its derivatives include imines, hydrazones, thiosemicarbazones, among others, already focused on numerous anticancer studies. Some of them have entered in pre-clinical and clinical tests as antiangiogenic compounds or inhibitors of crucial proteins. As free ligands or coordinated to metal ions, such isatin derivatives showed promising antiproliferative properties against different cancer cells, targeting different biomolecules or organelles. Binding to metal ions usually improves its biological properties, indicating a modulation by the metal and by the ligand in a synergistic process. They also reveal diverse mechanisms of action, being able of binding DNA, generating reactive species that cause oxidative damage, and inhibiting selected proteins. Strategies used to improve the efficiency and selectivity of these compounds comprise structural modification of the ligands, metalation with different ions, syntheses of mononuclear and dinuclear species, and use of inserted or anchored compounds in selected drug delivery systems.
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46

Geldon, Stefan, Erika Fernández-Vizarra, and Kostas Tokatlidis. "Redox-Mediated Regulation of Mitochondrial Biogenesis, Dynamics, and Respiratory Chain Assembly in Yeast and Human Cells." Frontiers in Cell and Developmental Biology 9 (September 7, 2021). http://dx.doi.org/10.3389/fcell.2021.720656.

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Mitochondria are double-membrane organelles that contain their own genome, the mitochondrial DNA (mtDNA), and reminiscent of its endosymbiotic origin. Mitochondria are responsible for cellular respiration via the function of the electron oxidative phosphorylation system (OXPHOS), located in the mitochondrial inner membrane and composed of the four electron transport chain (ETC) enzymes (complexes I-IV), and the ATP synthase (complex V). Even though the mtDNA encodes essential OXPHOS components, the large majority of the structural subunits and additional biogenetical factors (more than seventy proteins) are encoded in the nucleus and translated in the cytoplasm. To incorporate these proteins and the rest of the mitochondrial proteome, mitochondria have evolved varied, and sophisticated import machineries that specifically target proteins to the different compartments defined by the two membranes. The intermembrane space (IMS) contains a high number of cysteine-rich proteins, which are mostly imported via the MIA40 oxidative folding system, dependent on the reduction, and oxidation of key Cys residues. Several of these proteins are structural components or assembly factors necessary for the correct maturation and function of the ETC complexes. Interestingly, many of these proteins are involved in the metalation of the active redox centers of complex IV, the terminal oxidase of the mitochondrial ETC. Due to their function in oxygen reduction, mitochondria are the main generators of reactive oxygen species (ROS), on both sides of the inner membrane, i.e., in the matrix and the IMS. ROS generation is important due to their role as signaling molecules, but an excessive production is detrimental due to unwanted oxidation reactions that impact on the function of different types of biomolecules contained in mitochondria. Therefore, the maintenance of the redox balance in the IMS is essential for mitochondrial function. In this review, we will discuss the role that redox regulation plays in the maintenance of IMS homeostasis as well as how mitochondrial ROS generation may be a key regulatory factor for ETC biogenesis, especially for complex IV.
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47

"Residue Modification and Mass Spectrometry for the Investigation of Structural and Metalation Properties of Metallothionein and Cysteine-Rich Proteins." International Journal of Molecular Sciences 18, no. 5 (April 26, 2017): 913. http://dx.doi.org/10.3390/ijms18050913.

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