Journal articles: 'Cu cofactor'

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Murakawa, Takeshi, Kazuo Kurihara, Mitsuo Shoji, Chie Shibazaki, Tomoko Sunami, Taro Tamada, Naomine Yano, et al. "Neutron crystallography of copper amine oxidase reveals keto/enolate interconversion of the quinone cofactor and unusual proton sharing." Proceedings of the National Academy of Sciences 117, no. 20 (May 5, 2020): 10818–24. http://dx.doi.org/10.1073/pnas.1922538117.

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Recent advances in neutron crystallographic studies have provided structural bases for quantum behaviors of protons observed in enzymatic reactions. Thus, we resolved the neutron crystal structure of a bacterial copper (Cu) amine oxidase (CAO), which contains a prosthetic Cu ion and a protein-derived redox cofactor, topa quinone (TPQ). We solved hitherto unknown structures of the active site, including a keto/enolate equilibrium of the cofactor with a nonplanar quinone ring, unusual proton sharing between the cofactor and the catalytic base, and metal-induced deprotonation of a histidine residue that coordinates to the Cu. Our findings show a refined active-site structure that gives detailed information on the protonation state of dissociable groups, such as the quinone cofactor, which are critical for catalytic reactions.

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Kwok, Man Long, Xue Lei Hu, Qi Meng, and King Ming Chan. "Whole-transcriptome sequencing (RNA-seq) analyses of the zebrafish liver cell line, ZFL, after acute exposure to Cu2+ ions." Metallomics 12, no. 5 (2020): 732–51. http://dx.doi.org/10.1039/d0mt00005a.

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Goto, Norika, Hirokazu Hara, Mao Kondo, Naomi Yasuda, Tetsuro Kamiya, Kensuke Okuda, and Tetsuo Adachi. "Hydrogen sulfide increases copper-dependent neurotoxicity via intracellular copper accumulation." Metallomics 12, no. 6 (2020): 868–75. http://dx.doi.org/10.1039/d0mt00015a.

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Morpurgo, L., E. Agostinelli, O. Befani, and B. Mondovì. "Reactions of bovine serum amine oxidase with NN-diethyldithiocarbamate. Selective removal of one copper ion." Biochemical Journal 248, no. 3 (December 15, 1987): 865–70. http://dx.doi.org/10.1042/bj2480865.

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NN-Diethyldithiocarbamate (DDC) was able to bind, at 1.0 mM concentration, only about 50% the Cu(II) ions of bovine plasma amine oxidase. Under reducing conditions, this Cu(II) was removed with inactivation of the enzyme. Up to 90% activity could be recovered by treatment with excess Cu(II). The organic cofactor, sensitive to carbonyl reagents, was reduced in the half-Cu-depleted protein and no longer bound phenylhydrazine. The fully reacted protein, in the presence of 10 mM-DDC, lost 50% Cu(II) upon storage at -20 degrees C, but in this case the residual Cu(II) was in the DDC-bound form and the cofactor was in the oxidized state, as it could still bind phenylhydrazine. In the presence of DDC, the rate of reaction with phenylhydrazine was always low, even at 50% DDC saturation, and all derivatives showed identical modifications of the optical and e.p.r. spectra with respect to the phenylhydrazone of the native protein. It is concluded that the two Cu(II) ions are not equivalent, that removal of a single Cu(II) is sufficient to inhibit the re-oxidation of the organic cofactor, and that both Cu(II) ions are in some way involved in the reaction with phenylhydrazine. After reaction with DDC, the optical and e.p.r. spectra of 63Cu(II)-amine oxidase and of 63Cu(II)-carbonic anhydrase [Morpurgo, Desideri, Rigo, Viglino & Rotilio (1983) Biochim. Biophys. Acta 746, 168-175] are very similar and show distorted equatorial co-ordination to Cu(II) of two sulphur atoms and two magnetically equivalent nitrogen atoms.

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Kwok, Man Long, and King Ming Chan. "Functional characterization of copper transporters zCtr1, zAtox1, zAtp7a and zAtp7b in zebrafish liver cell line ZFL." Metallomics 11, no. 9 (2019): 1532–46. http://dx.doi.org/10.1039/c9mt00159j.

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Tasaki, Eisuke, Kazuya Kobayashi, Kenji Matsuura, and Yoshihito Iuchi. "Long-Lived Termite Queens Exhibit High Cu/Zn-Superoxide Dismutase Activity." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/5127251.

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In most organisms, superoxide dismutases (SODs) are among the most effective antioxidant enzymes that regulate the reactive oxygen species (ROS) generated by oxidative energy metabolism. ROS are considered main proximate causes of aging. However, it remains unclear if SOD activities are associated with organismal longevity. The queens of eusocial insects, such as termites, ants, and honeybees, exhibit extraordinary longevity in comparison with the nonreproductive castes, such as workers. Therefore, the queens are promising candidates to study the underlying mechanisms of aging. Here, we found that queens have higher Cu/Zn-SOD activity than nonreproductive individuals of the termite Reticulitermes speratus. We identified three Cu/Zn-SOD sequences and one Mn-SOD sequence by RNA sequencing in R. speratus. Although the queens showed higher Cu/Zn-SOD activity than the nonreproductive individuals, there were no differences in their expression levels of the Cu/Zn-SOD genes RsSOD1 and RsSOD3A. Copper (Cu2+ and Cu+) is an essential cofactor for Cu/Zn-SOD enzyme activity, and the queens had higher concentrations of copper than the workers. These results suggest that the high Cu/Zn-SOD activity of termite queens is related to their high levels of the cofactor rather than gene expression. This study highlights that Cu/Zn-SOD activity contributes to extraordinary longevity in termites.

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Song, Haiyan, Chunling Ma, Pi Liu, Chun You, Jianping Lin, and Zhiguang Zhu. "A hybrid CO2 electroreduction system mediated by enzyme-cofactor conjugates coupled with Cu nanoparticle-catalyzed cofactor regeneration." Journal of CO2 Utilization 34 (December 2019): 568–75. http://dx.doi.org/10.1016/j.jcou.2019.08.007.

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Whittaker, Mei M., and James W. Whittaker. "Cu(I)-dependent Biogenesis of the Galactose Oxidase Redox Cofactor." Journal of Biological Chemistry 278, no. 24 (April 1, 2003): 22090–101. http://dx.doi.org/10.1074/jbc.m300112200.

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9

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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Chen, Guang, Jia Li, Huimin Han, Ruiying Du, and Xu Wang. "Physiological and Molecular Mechanisms of Plant Responses to Copper Stress." International Journal of Molecular Sciences 23, no. 21 (October 26, 2022): 12950. http://dx.doi.org/10.3390/ijms232112950.

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Copper (Cu) is an essential micronutrient for humans, animals, and plants, and it participates in various morphological, physiological, and biochemical processes. Cu is a cofactor for a variety of enzymes, and it plays an important role in photosynthesis, respiration, the antioxidant system, and signal transduction. Many studies have demonstrated the adverse effects of excess Cu on crop germination, growth, photosynthesis, and antioxidant activity. This review summarizes the biological functions of Cu, the toxicity of excess Cu to plant growth and development, the roles of Cu transport proteins and chaperone proteins, and the transport process of Cu in plants, as well as the mechanisms of detoxification and tolerance of Cu in plants. Future research directions are proposed, which provide guidelines for related research.

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Andrei, Andreea, Yavuz Öztürk, Bahia Khalfaoui-Hassani, Juna Rauch, Dorian Marckmann, Petru-Iulian Trasnea, Fevzi Daldal, and Hans-Georg Koch. "Cu Homeostasis in Bacteria: The Ins and Outs." Membranes 10, no. 9 (September 18, 2020): 242. http://dx.doi.org/10.3390/membranes10090242.

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Copper (Cu) is an essential trace element for all living organisms and used as cofactor in key enzymes of important biological processes, such as aerobic respiration or superoxide dismutation. However, due to its toxicity, cells have developed elaborate mechanisms for Cu homeostasis, which balance Cu supply for cuproprotein biogenesis with the need to remove excess Cu. This review summarizes our current knowledge on bacterial Cu homeostasis with a focus on Gram-negative bacteria and describes the multiple strategies that bacteria use for uptake, storage and export of Cu. We furthermore describe general mechanistic principles that aid the bacterial response to toxic Cu concentrations and illustrate dedicated Cu relay systems that facilitate Cu delivery for cuproenzyme biogenesis. Progress in understanding how bacteria avoid Cu poisoning while maintaining a certain Cu quota for cell proliferation is of particular importance for microbial pathogens because Cu is utilized by the host immune system for attenuating pathogen survival in host cells.

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Fukai, Tohru, Masuko Ushio-Fukai, and Jack H. Kaplan. "Copper transporters and copper chaperones: roles in cardiovascular physiology and disease." American Journal of Physiology-Cell Physiology 315, no. 2 (August 1, 2018): C186—C201. http://dx.doi.org/10.1152/ajpcell.00132.2018.

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Copper (Cu) is an essential micronutrient but excess Cu is potentially toxic. Its important propensity to cycle between two oxidation states accounts for its frequent presence as a cofactor in many physiological processes through Cu-containing enzymes, including mitochondrial energy production (via cytochrome c-oxidase), protection against oxidative stress (via superoxide dismutase), and extracellular matrix stability (via lysyl oxidase). Since free Cu is potentially toxic, the bioavailability of intracellular Cu is tightly controlled by Cu transporters and Cu chaperones. Recent evidence reveals that these Cu transport systems play an essential role in the physiological responses of cardiovascular cells, including cell growth, migration, angiogenesis and wound repair. In response to growth factors, cytokines, and hypoxia, their expression, subcellular localization, and function are tightly regulated. Cu transport systems and their regulators have also been linked to various cardiovascular pathophysiologies such as hypertension, inflammation, atherosclerosis, diabetes, cardiac hypertrophy, and cardiomyopathy. A greater appreciation of the central importance of Cu transporters and Cu chaperones in cell signaling and gene expression in cardiovascular biology offers the possibility of identifying new therapeutic targets for cardiovascular disease.

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Puig, Sergi. "Function and Regulation of the Plant COPT Family of High-Affinity Copper Transport Proteins." Advances in Botany 2014 (July 21, 2014): 1–9. http://dx.doi.org/10.1155/2014/476917.

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Copper (Cu) is an essential micronutrient for all eukaryotes because it participates as a redox active cofactor in multiple biological processes, including mitochondrial respiration, photosynthesis, oxidative stress protection, and iron (Fe) transport. In eukaryotic cells, Cu transport toward the cytoplasm is mediated by the conserved CTR/COPT family of high-affinity Cu transport proteins. This outlook paper reviews the contribution of our research group to the characterization of the function played by the Arabidopsis thaliana COPT1–6 family of proteins in plant Cu homeostasis. Our studies indicate that the different tissue specificity, Cu-regulated expression, and subcellular localization dictate COPT-specialized contribution to plant Cu transport and distribution. By characterizing lack-of-function Arabidopsis mutant lines, we conclude that COPT1 mediates root Cu acquisition, COPT6 facilitates shoot Cu distribution, and COPT5 mobilizes Cu from storage organelles. Furthermore, our work with copt2 mutant and COPT-overexpressing plants has also uncovered Cu connections with Fe homeostasis and the circadian clock, respectively. Future studies on the interaction between COPT transporters and other components of the Cu homeostasis network will improve our knowledge of plant Cu acquisition, distribution, regulation, and utilization by Cu-proteins.

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Ando, Yuko, Shinji Nagata, Schuichi Yanagisawa, and Tadakatsu Yoneyama. "Copper in xylem and phloem saps from rice (Oryza sativa): the effect of moderate copper concentrations in the growth medium on the accumulation of five essential metals and a speciation analysis of copper-containing compounds." Functional Plant Biology 40, no. 1 (2013): 89. http://dx.doi.org/10.1071/fp12158.

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Copper (Cu) is an essential element for cereals, playing important roles as a cofactor of several enzymes. Copper and four other metals (Fe, Mn, Zn and Mo) taken up by roots are efficiently delivered to the shoots via xylem and phloem. Here we investigated the concentrations of Cu, Fe, Mn, Zn and Mo in the xylem and phloem saps as well as in tissues of rice (Oryza sativa L.) seedlings when they were grown under different Cu levels in culture solution. Although the Cu concentrations in the roots and the Mn concentrations in the mature shoot tissues were increased with the increase of the Cu level in the culture solution, the concentrations of Cu and the other four metals in the xylem and phloem saps and the Cu contents in the shoot tissues were only slightly affected by moderate increases in the Cu medium level. The results of our analyses using membrane filtration, size-exclusion chromatography and electrospray ionisation time-of-flight mass spectrometry indicate that Cu in the xylem sap is dominantly complexed by 2′-deoxymugineic acid, whereas Cu in the phloem sap is bound to several compounds, i.e. nicotianamine, histidine and other >3-kDa compounds.

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Nelson, Kyle T., and Joseph R. Prohaska. "Copper deficiency in rodents alters dopamine β-mono-oxygenase activity, mRNA and protein level." British Journal of Nutrition 102, no. 1 (December 15, 2008): 18–28. http://dx.doi.org/10.1017/s0007114508162961.

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Cu is an essential cofactor for at least twelve mammalian enzymes including dopamine β-mono-oxygenase (DBM), which converts dopamine (DA) to noradrenaline (NA). Previous studies reported that certain Cu-deficient (Cu−) rat tissues have lower NA and higher DA than Cu-adequate (Cu+) tissues, suggesting that DBM function was impaired. However, in vitro studies suggested that DBM activity is higher in Cu− tissue. Experiments were conducted on adrenal glands (AG), medulla oblongata/pons (MO), vas deferens (VD) and heart (HT) from a single rat experiment to provide data to help clarify this puzzling contradiction. In vitro DBM activity assays showed Cu− samples had significantly higher activity than Cu+ samples in both AG and MO, but not VD. Activity data were confirmed by Western immunoblots. Quantitative real-time PCR demonstrated higher DBM mRNA in Cu− tissues but unaltered levels of several other cuproenzymes and Cu-binding proteins. Previous pharmacological data implied that high DBM was associated with low NA. HPLC analyses confirmed that NA and DA levels in Cu− MO, VD and HT were significantly lower and higher, respectively, than in Cu+ tissues. However, the NA content of AG was not statistically lower. Furthermore there was no correlation between higher DBM mRNA and lower NA in four Cu−tissues. Adequate dietary Cu is essential to support DBM function in vivo but additional studies are needed to determine the mechanism for increased DBM transcription associated with Cu deficiency.

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Maiti, Biplab K., Teresa Avilés, Marta S. P. Carepo, Isabel Moura, Sofia R. Pauleta, and José J. G. Moura. "Rearrangement of Mo-Cu-S Cluster Reflects the Structural Instability of Orange Protein Cofactor." Zeitschrift für anorganische und allgemeine Chemie 639, no. 8-9 (April 9, 2013): 1361–64. http://dx.doi.org/10.1002/zaac.201300034.

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Wang, Q., M. Burger, T. A. Doane, W. R. Horwath, A. R. Castillo, and F. M. Mitloehner. "Effects of inorganicv. organic copper on denitrification in agricultural soil." Advances in Animal Biosciences 4, s1 (September 2013): 42–49. http://dx.doi.org/10.1017/s2040470013000307.

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Nitrous oxide reductase (N2OR), the enzyme responsible for the reduction of N2O to N2in denitrification, uses copper (Cu) as its cofactor. Its activity is lowered under conditions of Cu deficiency. In general, high organic matter (OM) soil decreases Cu availability. The present study investigated different Cu forms, namely organic (ORG) v. inorganic (INO), and associated concentrations (750, 550, 125, 60 μg Cu/g soil) for their efficacy in affecting denitrification and especially N2OR activity in high OM peat soil in a water saturated anaerobic condition for 24 h. Gas and liquid samples were taken every 8 h and analyzed for NO3−, NO2−, N2O and N2. Inorganic Cu treatments did not affect N transformation rates and N2OR activity among the different treatments (P> 0.05) throughout the incubation compared with the control (CON). The ORG Cu treatments increased NO3−(P< 0.05), NO2−(P< 0.05) and N2O (P< 0.05) transformation rates compared with CON. These changes were ORG Cu dose dependent. N2OR activity increased first in the 750 μg ORG Cu treatment (P< 0.05) during 8 to 16 h followed by the other ORG Cu treatments (P< 0.05) during 16 to 24 h compared with CON. These results highlight the importance of Cu form and concentration on N transformation rate during denitrification. The findings can potentially be applied to systems like soil, wastewater, constructed wetlands, etc., in which reactions of the denitrification pathway are manipulated.

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Petruzzelli, Raffaella, and Roman S. Polishchuk. "Activity and Trafficking of Copper-Transporting ATPases in Tumor Development and Defense against Platinum-Based Drugs." Cells 8, no. 9 (September 13, 2019): 1080. http://dx.doi.org/10.3390/cells8091080.

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Membrane trafficking pathways emanating from the Golgi regulate a wide range of cellular processes. One of these is the maintenance of copper (Cu) homeostasis operated by the Golgi-localized Cu-transporting ATPases ATP7A and ATP7B. At the Golgi, these proteins supply Cu to newly synthesized enzymes which use this metal as a cofactor to catalyze a number of vitally important biochemical reactions. However, in response to elevated Cu, the Golgi exports ATP7A/B to post-Golgi sites where they promote sequestration and efflux of excess Cu to limit its potential toxicity. Growing tumors actively consume Cu and employ ATP7A/B to regulate the availability of this metal for oncogenic enzymes such as LOX and LOX-like proteins, which confer higher invasiveness to malignant cells. Furthermore, ATP7A/B activity and trafficking allow tumor cells to detoxify platinum (Pt)-based drugs (like cisplatin), which are used for the chemotherapy of different solid tumors. Despite these noted activities of ATP7A/B that favor oncogenic processes, the mechanisms that regulate the expression and trafficking of Cu ATPases in malignant cells are far from being completely understood. This review summarizes current data on the role of ATP7A/B in the regulation of Cu and Pt metabolism in malignant cells and outlines questions and challenges that should be addressed to understand how ATP7A and ATP7B trafficking mechanisms might be targeted to counteract tumor development.

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Niccoli Asabella, Artor, Giuseppe Lucio Cascini, Corinna Altini, Domenico Paparella, Antonio Notaristefano, and Giuseppe Rubini. "The Copper Radioisotopes: A Systematic Review with Special Interest to 64Cu." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/786463.

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Copper (Cu) is an important trace element in humans; it plays a role as a cofactor for numerous enzymes and other proteins crucial for respiration, iron transport, metabolism, cell growth, and hemostasis. Natural copper comprises two stable isotopes, 63Cu and 65Cu, and 5 principal radioisotopes for molecular imaging applications (60Cu, 61Cu, 62Cu, and 64Cu) and in vivo targeted radiation therapy (64Cu and 67Cu). The two potential ways to produce Cu radioisotopes concern the use of the cyclotron or the reactor. A noncopper target is used to produce noncarrier-added Cu thanks to a chemical separation from the target material using ion exchange chromatography achieving a high amount of radioactivity with the lowest possible amount of nonradioactive isotopes. In recent years, Cu isotopes have been linked to antibodies, proteins, peptides, and nanoparticles for preclinical and clinical research; pathological conditions that influence Cu metabolism such as Menkes syndrome, Wilson disease, inflammation, tumor growth, metastasis, angiogenesis, and drug resistance have been studied. We aim to discuss all Cu radioisotopes application focusing on 64Cu and in particular its form 64CuCl2 that seems to be the most promising for its half-life, radiation emissions, and stability with chelators, allowing several applications in oncological and nononcological fields.

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Chen, Helen H. W., and Macus Tien Kuo. "Role of Glutathione in the Regulation of Cisplatin Resistance in Cancer Chemotherapy." Metal-Based Drugs 2010 (September 14, 2010): 1–7. http://dx.doi.org/10.1155/2010/430939.

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Three mechanisms have been proposed for the role of glutathione (GSH) in regulating cisplatin (CDDP) sensitivities that affects its ultimate cell-killing ability: (i) GSH may serve as a cofactor in facilitating multidrug resistance protein 2- (MRP2-) mediated CDDP efflux in mammalian cells, since MRP2-transfected cells were shown to confer CDDP resistance; (ii) GSH may serve as a redox-regulating cytoprotector based on the observations that many CDDP-resistant cells overexpress GSH and γ-glutamylcysteine synthesis (γ-GCS), the rate-limiting enzyme for GSH biosynthesis; (iii) GSH may function as a copper (Cu) chelator. Elevated GSH expression depletes the cellular bioavailable Cu pool, resulting in upregulation of the high-affinity Cu transporter (hCtr1) which is also a CDDP transporter. This has been demonstrated that overexpression of GSH by transfection with γ-GCS conferred sensitization to CDDP toxicity. This review describes how these three models were developed and critically reviews their importance to overall CDDP cytotoxicity in cancer cell treatments.

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Guo, Y., L. Nyasae, L. T. Braiterman, and A. L. Hubbard. "NH2-terminal signals in ATP7B Cu-ATPase mediate its Cu-dependent anterograde traffic in polarized hepatic cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 289, no. 5 (November 2005): G904—G916. http://dx.doi.org/10.1152/ajpgi.00262.2005.

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Cu is an essential cofactor of cellular proteins but is toxic in its free state. The hepatic Cu-ATPase ATP7B has two functions in Cu homeostasis: it loads Cu+onto newly synthesized apoceruloplasmin in the secretory pathway, thereby activating the plasma protein; and it participates in the excretion of excess Cu+into the bile. To carry out these two functions, the membrane protein responds to changes in intracellular Cu levels by cycling between the Golgi and apical region. We used polarized hepatic WIF-B cells and high-resolution confocal microscopy to map the itinerary of endogenous and exogenous ATP7B under different Cu conditions. In Cu-depleted cells, ATP7B resided in a post- trans-Golgi network compartment that also contained syntaxin 6, whereas in Cu-loaded cells, the protein relocated to unique vesicles very near to the apical plasma membrane as well as the membrane itself. To determine the role of ATP7B's cytoplasmic NH2terminus in regulating its intracellular movements, we generated seven mutations/deletions in this large [∼650 amino acid (AA)] domain and analyzed the Cu-dependent behavior of the mutant ATP7B proteins in WIF-B cells. Truncation of the ATP7B NH2terminus up to the fifth copper-binding domain (CBD5) yielded an active ATPase that was insensitive to cellular Cu levels and constitutively trafficked to the opposite (basolateral) plasma membrane domain. Fusion of the NH2-terminal 63 AA of ATP7B to the truncated protein restored both its Cu responsiveness and correct intracellular targeting. These results indicate that important targeting information is contained in this relatively short sequence, which is absent from the related CuATPase, ATP7A.

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Schatzman, Sabrina S., Ryan L. Peterson, Mieraf Teka, Bixi He, Diane E. Cabelli, Brendan P. Cormack, and Valeria C. Culotta. "Copper-only superoxide dismutase enzymes and iron starvation stress in Candida fungal pathogens." Journal of Biological Chemistry 295, no. 2 (December 5, 2019): 570–83. http://dx.doi.org/10.1074/jbc.ra119.011084.

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Copper (Cu)-only superoxide dismutases (SOD) represent a newly characterized class of extracellular SODs important for virulence of several fungal pathogens. Previous studies of the Cu-only enzyme SOD5 from the opportunistic fungal pathogen Candida albicans have revealed that the active-site structure and Cu binding of SOD5 strongly deviate from those of Cu/Zn-SODs in its animal hosts, making Cu-only SODs a possible target for future antifungal drug design. C. albicans also expresses a Cu-only SOD4 that is highly similar in sequence to SOD5, but is poorly characterized. Here, we compared the biochemical, biophysical, and cell biological properties of C. albicans SOD4 and SOD5. Analyzing the recombinant proteins, we found that, similar to SOD5, Cu-only SOD4 can react with superoxide at rates approaching diffusion limits. Both SODs were monomeric and they exhibited similar binding affinities for their Cu cofactor. In C. albicans cultures, SOD4 and SOD5 were predominantly cell wall proteins. Despite these similarities, the SOD4 and SOD5 genes strongly differed in transcriptional regulation. SOD5 was predominantly induced during hyphal morphogenesis, together with a fungal burst in reactive oxygen species. Conversely, SOD4 expression was specifically up-regulated by iron (Fe) starvation and controlled by the Fe-responsive transcription factor SEF1. Interestingly, Candida tropicalis and the emerging fungal pathogen Candida auris contain a single SOD5-like SOD rather than a pair, and in both fungi, this SOD was induced by Fe starvation. This unexpected link between Fe homeostasis and extracellular Cu-SODs may help many fungi adapt to Fe-limited conditions of their hosts.

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During, Alexandrine, Meira Fields, Charles G. Lewis, and J. Cecil Smith. "Intestinal β-carotene 15,15′-dioxygenase activity is markedly enhanced in copper-deficient rats fed on high-iron diets and fructose." British Journal of Nutrition 84, no. 1 (July 2000): 117–24. http://dx.doi.org/10.1017/s0007114500001306.

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The purpose of the present work was to examine effects of the Cu–Fe interaction on intestinal β-carotene 15,15′-dioxygenase activity when a wide range of dietary Fe (deficiency to excess) was used in relation to Cu status of rats. The effect of dietary carbohydrates was also examined since they play a role in the Cu–Fe interaction in vivo. Weanling male Sprague-Dawley rats (n 72) were divided into twelve dietary groups, which were fed on either low-, normal-, or high-Fe levels (0·9, 9·0, and 90·0 mmol Fe/kg diet respectively) combined with Cu-adequate or -deficient levels (0·94 and 0·09 mmol Cu/kg diet respectively) and with starch or fructose in the diets. The data showed that both Fe concentration and β-carotene 15,15′-dioxygenase activity in small intestinal mucosa were enhanced with increasing dietary Fe and with Cu deficiency v. Cu adequacy. Dietary fructose did not aggravate the Fe-enhancement, related to Cu deficiency, in the small intestine; however, fructose increased the intestinal dioxygenase activity in rats fed on normal- or high-Fe diets when compared with starch controls. Thus, the highest intestinal dioxygenase activity associated with the lowest hepatic retinol (total) concentration was found in rats fed on the Cu-deficient, high-Fe, fructose-based diet. Finally, a positive linear relationship was found between the dioxygenase activity and Fe concentration in intestinal mucosa. In conclusion, the data indicate that β-carotene 15,15′-dioxygenase activity requires Fe as cofactor in vivoand the enzyme is modulated by the three dietary components: Cu, Fe, and fructose.

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Bertino, Nubia M. F., Leilson C. Grangeiro, João P. N. da Costa, Romualdo M. C. Costa, Rodolfo R. de A. Lacerda, and Victor E. de V. Gomes. "Growth, nutrient accumulation and yield of onion as a function of micronutrient fertilization." Revista Brasileira de Engenharia Agrícola e Ambiental 26, no. 2 (February 2022): 126–34. http://dx.doi.org/10.1590/1807-1929/agriambi.v26n2p126-134.

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ABSTRACT Micronutrients structurally constitute several enzymes and act as a cofactor of essential proteins to maintain cell function, thereby contributing to crop growth and yield. The objective of this study was to evaluate the leaf content, growth, accumulation of micronutrients, classification and yield of onion as a function of fertilization with boron, cooper and zinc in two years of cultivation. The experiments were carried out from June to November in 2018 and 2019, in a soil classified as Ultisol, both at the Rafael Fernandes Experimental Farm, belonging to the Universidade Federal Rural do Semiárido, in the municipality of Mossoró, Rio Grande do Norte, Brazil. The experimental design was in randomized blocks with 15 treatments and four replicates. The treatments consisted of application of doses of B, Cu and Zn, in two experiments. Contents of B, Cu and Zn in the diagnostic leaf, growth, accumulation of B, Cu and Zn in the leaf, bulb and total, classification and commercial, non-commercial and total yields were evaluated. Application of B, Cu and Zn did not influence the number of leaves, relation of bulb shape, leaf, bulb, and total dry mass and yield of onion. Application of B, Cu and Zn, respectively at doses of 1-2-1 kg ha-1 favored a greater accumulation of B, Zn and Cu in the bulb. Higher number of leaves, leaf dry mass, bulb dry mass, total dry mass, class 1 bulbs and non-commercial yield were produced in Experiment 1.

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Lutsenko, Svetlana, Arnab Gupta, Jason L. Burkhead, and Vesna Zuzel. "Cellular multitasking: The dual role of human Cu-ATPases in cofactor delivery and intracellular copper balance." Archives of Biochemistry and Biophysics 476, no. 1 (August 2008): 22–32. http://dx.doi.org/10.1016/j.abb.2008.05.005.

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Xu, Jia, Kaiwu He, Kaiqin Zhang, Chao Yang, Lulin Nie, Ding Dan, Jianjun Liu, Chang-E. Zhang, and Xifei Yang. "Low-Dose Copper Exposure Exacerbates Depression-Like Behavior in ApoE4 Transgenic Mice." Oxidative Medicine and Cellular Longevity 2021 (March 25, 2021): 1–20. http://dx.doi.org/10.1155/2021/6634181.

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Depression is one of the most common neuropsychiatric disorders. Although the pathogenesis of depression is still unknown, environmental risk factors and genetics are implicated. Copper (Cu), a cofactor of multiple enzymes, is involved in regulating depression-related processes. Depressed patients carrying the apolipoprotein ε4 allele display more severe depressive symptoms, indicating that ApoE4 is closely associated with an increased risk of depression. The study explored the effect of low-dose Cu exposure and ApoE4 on depression-like behavior of mice and further investigates the possible mechanisms. The ApoE4 mice and wild-type (WT) mice were treated with 0.13 ppm CuCl2 for 4 months. After the treatment, ApoE4 mice displayed obvious depression-like behavior compared with the WT mice, and Cu exposure further exacerbated the depression-like behavior of ApoE4 mice. There was no significant difference in anxiety behavior and memory behavior. Proteomic analysis revealed that the differentially expressed proteins between Cu-exposed and nonexposed ApoE4 mice were mainly involved in the Ras signaling pathway, protein export, axon guidance, serotonergic synapse, GABAergic synapse, and dopaminergic synapse. Among these differentially expressed proteins, immune response and synaptic function are highly correlated. Representative protein expression changes are quantified by western blot, showing consistent results as determined by proteomic analysis. Hippocampal astrocytes and microglia were increased in Cu-exposed ApoE4 mice, suggesting that neuroglial cells played an important role in the pathogenesis of depression. Taken together, our study demonstrated that Cu exposure exacerbates depression-like behavior of ApoE4 mice and the mechanisms may involve the dysregulation of synaptic function and immune response and overactivation of neuroinflammation.

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Chung, Clive Yik-Sham, Jessica M. Posimo, Sumin Lee, Tiffany Tsang, Julianne M. Davis, Donita C. Brady, and Christopher J. Chang. "Activity-based ratiometric FRET probe reveals oncogene-driven changes in labile copper pools induced by altered glutathione metabolism." Proceedings of the National Academy of Sciences 116, no. 37 (August 26, 2019): 18285–94. http://dx.doi.org/10.1073/pnas.1904610116.

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Copper is essential for life, and beyond its well-established ability to serve as a tightly bound, redox-active active site cofactor for enzyme function, emerging data suggest that cellular copper also exists in labile pools, defined as loosely bound to low-molecular-weight ligands, which can regulate diverse transition metal signaling processes spanning neural communication and olfaction, lipolysis, rest–activity cycles, and kinase pathways critical for oncogenic signaling. To help decipher this growing biology, we report a first-generation ratiometric fluorescence resonance energy transfer (FRET) copper probe, FCP-1, for activity-based sensing of labile Cu(I) pools in live cells. FCP-1 links fluorescein and rhodamine dyes through a Tris[(2-pyridyl)methyl]amine bridge. Bioinspired Cu(I)-induced oxidative cleavage decreases FRET between fluorescein donor and rhodamine acceptor. FCP-1 responds to Cu(I) with high metal selectivity and oxidation-state specificity and facilitates ratiometric measurements that minimize potential interferences arising from variations in sample thickness, dye concentration, and light intensity. FCP-1 enables imaging of dynamic changes in labile Cu(I) pools in live cells in response to copper supplementation/depletion, differential expression of the copper importer CTR1, and redox stress induced by manipulating intracellular glutathione levels and reduced/oxidized glutathione (GSH/GSSG) ratios. FCP-1 imaging reveals a labile Cu(I) deficiency induced by oncogene-driven cellular transformation that promotes fluctuations in glutathione metabolism, where lower GSH/GSSG ratios decrease labile Cu(I) availability without affecting total copper levels. By connecting copper dysregulation and glutathione stress in cancer, this work provides a valuable starting point to study broader cross-talk between metal and redox pathways in health and disease with activity-based probes.

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Puchkova, Ludmila V., Massimo Broggini, Elena V. Polishchuk, Ekaterina Y. Ilyechova, and Roman S. Polishchuk. "Silver Ions as a Tool for Understanding Different Aspects of Copper Metabolism." Nutrients 11, no. 6 (June 17, 2019): 1364. http://dx.doi.org/10.3390/nu11061364.

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In humans, copper is an important micronutrient because it is a cofactor of ubiquitous and brain-specific cuproenzymes, as well as a secondary messenger. Failure of the mechanisms supporting copper balance leads to the development of neurodegenerative, oncological, and other severe disorders, whose treatment requires a detailed understanding of copper metabolism. In the body, bioavailable copper exists in two stable oxidation states, Cu(I) and Cu(II), both of which are highly toxic. The toxicity of copper ions is usually overcome by coordinating them with a wide range of ligands. These include the active cuproenzyme centers, copper-binding protein motifs to ensure the safe delivery of copper to its physiological location, and participants in the Cu(I) ↔ Cu(II) redox cycle, in which cellular copper is stored. The use of modern experimental approaches has allowed the overall picture of copper turnover in the cells and the organism to be clarified. However, many aspects of this process remain poorly understood. Some of them can be found out using abiogenic silver ions (Ag(I)), which are isoelectronic to Cu(I). This review covers the physicochemical principles of the ability of Ag(I) to substitute for copper ions in transport proteins and cuproenzyme active sites, the effectiveness of using Ag(I) to study copper routes in the cells and the body, and the limitations associated with Ag(I) remaining stable in only one oxidation state. The use of Ag(I) to restrict copper transport to tumors and the consequences of large-scale use of silver nanoparticles for human health are also discussed.

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Keith, Karen E., and Miguel A. Valvano. "Characterization of SodC, a Periplasmic Superoxide Dismutase from Burkholderia cenocepacia." Infection and Immunity 75, no. 5 (February 26, 2007): 2451–60. http://dx.doi.org/10.1128/iai.01556-06.

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ABSTRACT Burkholderia cenocepacia is a gram-negative, non-spore-forming bacillus and a member of the Burkholderia cepacia complex. B. cenocepacia can survive intracellularly in phagocytic cells and can produce at least one superoxide dismutase (SOD). The inability of O2 − to cross the cytoplasmic membrane, coupled with the periplasmic location of Cu,ZnSODs, suggests that periplasmic SODs protect bacteria from superoxide that has an exogenous origin (for example, when cells are faced with reactive oxygen intermediates generated by host cells in response to infection). In this study, we identified the sodC gene encoding a Cu,ZnSOD in B. cenocepacia and demonstrated that a sodC null mutant was not sensitive to a H2O2, 3-morpholinosydnonimine, or paraquat challenge but was killed by exogenous superoxide generated by the xanthine/xanthine oxidase method. The sodC mutant also exhibited a growth defect in liquid medium compared to the parental strain, which could be complemented in trans. The mutant was killed more rapidly than the parental strain was killed in murine macrophage-like cell line RAW 264.7, but killing was eliminated when macrophages were treated with an NADPH oxidase inhibitor. We also confirmed that SodC is periplasmic and identified the metal cofactor. B. cenocepacia SodC was resistant to inhibition by H2O2 and was unusually resistant to KCN for a Cu,ZnSOD. Together, these observations establish that B. cenocepacia produces a periplasmic Cu,ZnSOD that protects this bacterium from exogenously generated O2 − and contributes to intracellular survival of this bacterium in macrophages.

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Fereiro, Jerry A., Xi Yu, Israel Pecht, Mordechai Sheves, Juan Carlos Cuevas, and David Cahen. "Tunneling explains efficient electron transport via protein junctions." Proceedings of the National Academy of Sciences 115, no. 20 (April 30, 2018): E4577—E4583. http://dx.doi.org/10.1073/pnas.1719867115.

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Metalloproteins, proteins containing a transition metal ion cofactor, are electron transfer agents that perform key functions in cells. Inspired by this fact, electron transport across these proteins has been widely studied in solid-state settings, triggering the interest in examining potential use of proteins as building blocks in bioelectronic devices. Here, we report results of low-temperature (10 K) electron transport measurements via monolayer junctions based on the blue copper protein azurin (Az), which strongly suggest quantum tunneling of electrons as the dominant charge transport mechanism. Specifically, we show that, weakening the protein–electrode coupling by introducing a spacer, one can switch the electron transport from off-resonant to resonant tunneling. This is a consequence of reducing the electrode’s perturbation of the Cu(II)-localized electronic state, a pattern that has not been observed before in protein-based junctions. Moreover, we identify vibronic features of the Cu(II) coordination sphere in transport characteristics that show directly the active role of the metal ion in resonance tunneling. Our results illustrate how quantum mechanical effects may dominate electron transport via protein-based junctions.

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Ghosh, Dibbendu, Soumen Sinhababu, Bernard D. Santarsiero, and Neal P. Mankad. "A W/Cu Synthetic Model for the Mo/Cu Cofactor of Aerobic CODH Indicates That Biochemical CO Oxidation Requires a Frustrated Lewis Acid/Base Pair." Journal of the American Chemical Society 142, no. 29 (June 29, 2020): 12635–42. http://dx.doi.org/10.1021/jacs.0c03343.

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Ipsen, Johan Ø., Magnus Hallas-Møller, Søren Brander, Leila Lo Leggio, and Katja S. Johansen. "Lytic polysaccharide monooxygenases and other histidine-brace copper proteins: structure, oxygen activation and biotechnological applications." Biochemical Society Transactions 49, no. 1 (January 15, 2021): 531–40. http://dx.doi.org/10.1042/bst20201031.

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Lytic polysaccharide monooxygenases (LPMOs) are mononuclear copper enzymes that catalyse the oxidative cleavage of glycosidic bonds. They are characterised by two histidine residues that coordinate copper in a configuration termed the Cu-histidine brace. Although first identified in bacteria and fungi, LPMOs have since been found in all biological kingdoms. LPMOs are now included in commercial enzyme cocktails used in industrial biorefineries. This has led to increased process yield due to the synergistic action of LPMOs with glycoside hydrolases. However, the introduction of LPMOs makes control of the enzymatic step in industrial stirred-tank reactors more challenging, and the operational stability of the enzymes is reduced. It is clear that much is still to be learned about the interaction between LPMOs and their complex natural and industrial environments, and fundamental scientific studies are required towards this end. Several atomic-resolution structures have been solved providing detailed information on the Cu-coordination sphere and the interaction with the polysaccharide substrate. However, the molecular mechanisms of LPMOs are still the subject of intense investigation; the key question being how the proteinaceous environment controls the copper cofactor towards the activation of the O-O bond in O2 and cleavage of the glycosidic bonds in polysaccharides. The need for biochemical characterisation of each putative LPMO is discussed based on recent reports showing that not all proteins with a Cu-histidine brace are enzymes.

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Novoa-Aponte, Lorena, Cheng Xu, Fernando C. Soncini, and José M. Argüello. "The Two-Component System CopRS Maintains Subfemtomolar Levels of Free Copper in the Periplasm of Pseudomonas aeruginosa Using a Phosphatase-Based Mechanism." mSphere 5, no. 6 (December 23, 2020): e01193-20. http://dx.doi.org/10.1128/msphere.01193-20.

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ABSTRACTTwo-component systems control periplasmic Cu+ homeostasis in Gram-negative bacteria. In characterized systems such as Escherichia coli CusRS, upon Cu+ binding to the periplasmic sensing region of CusS, a cytoplasmic phosphotransfer domain of the sensor phosphorylates the response regulator CusR. This drives the expression of efflux transporters, chaperones, and redox enzymes to ameliorate metal toxic effects. Here, we show that the Pseudomonas aeruginosa two-component sensor histidine kinase CopS exhibits a Cu-dependent phosphatase activity that maintains CopR in a nonphosphorylated state when the periplasmic Cu levels are below the activation threshold of CopS. Upon Cu+ binding to the sensor, the phosphatase activity is blocked and the phosphorylated CopR activates transcription of the CopRS regulon. Supporting the model, mutagenesis experiments revealed that the ΔcopS strain exhibits maximal expression of the CopRS regulon, lower intracellular Cu+ levels, and increased Cu tolerance compared to wild-type cells. The invariant phosphoacceptor residue His235 of CopS was not required for the phosphatase activity itself but was necessary for its Cu dependency. To sense the metal, the periplasmic domain of CopS binds two Cu+ ions at its dimeric interface. Homology modeling of CopS based on CusS structure (four Ag+ binding sites) clearly supports the different binding stoichiometries in the two systems. Interestingly, CopS binds Cu+/2+ with 3 × 10−14 M affinity, pointing to the absence of free (hydrated) Cu+/2+ in the periplasm.IMPORTANCE Copper is a micronutrient required as cofactor in redox enzymes. When free, copper is toxic, mismetallating proteins and generating damaging free radicals. Consequently, copper overload is a strategy that eukaryotic cells use to combat pathogens. Bacteria have developed copper-sensing transcription factors to control copper homeostasis. The cell envelope is the first compartment that has to cope with copper stress. Dedicated two-component systems control the periplasmic response to metal overload. This paper shows that the sensor kinase of the copper-sensing two-component system present in Pseudomonadales exhibits a signal-dependent phosphatase activity controlling the activation of its cognate response regulator, distinct from previously described periplasmic Cu sensors. Importantly, the data show that the system is activated by copper levels compatible with the absence of free copper in the cell periplasm. These observations emphasize the diversity of molecular mechanisms that have evolved in bacteria to manage the copper cellular distribution.

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Ghosh, Somdatta, Jordi Cirera, Michael A. Vance, Tetsuya Ono, Kiyoshi Fujisawa, and Edward I. Solomon. "Spectroscopic and Electronic Structure Studies of Phenolate Cu(II) Complexes: Phenolate Ring Orientation and Activation Related to Cofactor Biogenesis." Journal of the American Chemical Society 130, no. 48 (December 3, 2008): 16262–73. http://dx.doi.org/10.1021/ja8044986.

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Horn, Darryl, Hassan Al-Ali, and Antoni Barrientos. "Cmc1p Is a Conserved Mitochondrial Twin CX9C Protein Involved in Cytochrome c Oxidase Biogenesis." Molecular and Cellular Biology 28, no. 13 (April 28, 2008): 4354–64. http://dx.doi.org/10.1128/mcb.01920-07.

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ABSTRACT Copper is an essential cofactor of two mitochondrial enzymes: cytochrome c oxidase (COX) and Cu-Zn superoxide dismutase (Sod1p). Copper incorporation into these enzymes is facilitated by metallochaperone proteins which probably use copper from a mitochondrial matrix-localized pool. Here we describe a novel conserved mitochondrial metallochaperone-like protein, Cmc1p, whose function affects both COX and Sod1p. In Saccharomyces cerevisiae, Cmc1p localizes to the mitochondrial inner membrane facing the intermembrane space. Cmc1p is essential for full expression of COX and respiration, contains a twin CX9C domain conserved in other COX assembly copper chaperones, and has the ability to bind copper(I). Additionally, mutant cmc1 cells display increased mitochondrial Sod1p activity, while CMC1 overexpression results in decreased Sod1p activity. Our results suggest that Cmc1p could play a direct or indirect role in copper trafficking and distribution to COX and Sod1p.

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Appel, Mason J., Katlyn K. Meier, Julien Lafrance-Vanasse, Hyeongtaek Lim, Chi-Lin Tsai, Britt Hedman, Keith O. Hodgson, John A. Tainer, Edward I. Solomon, and Carolyn R. Bertozzi. "Formylglycine-generating enzyme binds substrate directly at a mononuclear Cu(I) center to initiate O2activation." Proceedings of the National Academy of Sciences 116, no. 12 (March 1, 2019): 5370–75. http://dx.doi.org/10.1073/pnas.1818274116.

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The formylglycine-generating enzyme (FGE) is required for the posttranslational activation of type I sulfatases by oxidation of an active-site cysteine to Cα-formylglycine. FGE has emerged as an enabling biotechnology tool due to the robust utility of the aldehyde product as a bioconjugation handle in recombinant proteins. Here, we show that Cu(I)–FGE is functional in O2activation and reveal a high-resolution X-ray crystal structure of FGE in complex with its catalytic copper cofactor. We establish that the copper atom is coordinated by two active-site cysteine residues in a nearly linear geometry, supporting and extending prior biochemical and structural data. The active cuprous FGE complex was interrogated directly by X-ray absorption spectroscopy. These data unambiguously establish the configuration of the resting enzyme metal center and, importantly, reveal the formation of a three-coordinate tris(thiolate) trigonal planar complex upon substrate binding as furthermore supported by density functional theory (DFT) calculations. Critically, inner-sphere substrate coordination turns on O2activation at the copper center. These collective results provide a detailed mechanistic framework for understanding why nature chose this structurally unique monocopper active site to catalyze oxidase chemistry for sulfatase activation.

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Crooks, Elliot J., Brandon A. Irizarry, Martine Ziliox, Toru Kawakami, Tiffany Victor, Feng Xu, Hironobu Hojo, et al. "Copper stabilizes antiparallel β-sheet fibrils of the amyloid β40 (Aβ40)-Iowa variant." Journal of Biological Chemistry 295, no. 27 (May 6, 2020): 8914–27. http://dx.doi.org/10.1074/jbc.ra119.011955.

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Cerebral amyloid angiopathy (CAA) is a vascular disorder that primarily involves deposition of the 40-residue–long β-amyloid peptide (Aβ40) in and along small blood vessels of the brain. CAA is often associated with Alzheimer's disease (AD), which is characterized by amyloid plaques in the brain parenchyma enriched in the Aβ42 peptide. Several recent studies have suggested a structural origin that underlies the differences between the vascular amyloid deposits in CAA and the parenchymal plaques in AD. We previously have found that amyloid fibrils in vascular amyloid contain antiparallel β-sheet, whereas previous studies by other researchers have reported parallel β-sheet in fibrils from parenchymal amyloid. Using X-ray fluorescence microscopy, here we found that copper strongly co-localizes with vascular amyloid in human sporadic CAA and familial Iowa-type CAA brains compared with control brain blood vessels lacking amyloid deposits. We show that binding of Cu(II) ions to antiparallel fibrils can block the conversion of these fibrils to the more stable parallel, in-register conformation and enhances their ability to serve as templates for seeded growth. These results provide an explanation for how thermodynamically less stable antiparallel fibrils may form amyloid in or on cerebral vessels by using Cu(II) as a structural cofactor.

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Gadupudi, Gopi S., and King-Thom Chung. "Comparative genotoxicity of 3-hydroxyanthranilic acid and anthranilic acid in the presence of a metal cofactor Cu (II) in vitro." Mutation Research/Genetic Toxicology and Environmental Mutagenesis 726, no. 2 (December 2011): 200–208. http://dx.doi.org/10.1016/j.mrgentox.2011.09.012.

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Claros, Miguel, Alicia Casitas, and Julio Lloret-Fillol. "Visible-Light Reductive Cyclization of Nonactivated Alkyl Chlorides." Synlett 30, no. 13 (July 17, 2019): 1496–507. http://dx.doi.org/10.1055/s-0037-1611878.

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Nonactivated alkyl chlorides are readily available and bench-stable feedstocks; however, they exhibit an inherent chemical inertness, in part, due to their large negative reduction potentials, which have precluded their widespread use as radical precursors in visible-light photocatalysis. Herein, we highlight some recent strategies for activating challenging organic halides under light irradiation, with special emphasis in C(sp3)–halide bonds. In this line, a brief summary of the reactivity of Vitamin B12, F430 cofactor and derivatives is required to comprehend the chemistry behind our developed Cu/M (M = Co, Ni) dual catalytic system. Catalyst design has been key for developing a mild and general photoredox methodology for the intramolecular reductive cyclization of nonactivated alkyl chlorides with tethered alkenes. The cleavage of strong C(sp3)–Cl bonds is mediated by a highly nucleophilic low-valent cobalt or nickel intermediate generated by visible-light photoredox reduction employing a copper photosensitizer.

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Ang, Abel, Juliet M. Pullar, Margaret J. Currie, and Margreet C. M. Vissers. "Vitamin C and immune cell function in inflammation and cancer." Biochemical Society Transactions 46, no. 5 (October 9, 2018): 1147–59. http://dx.doi.org/10.1042/bst20180169.

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Vitamin C (ascorbate) is maintained at high levels in most immune cells and can affect many aspects of the immune response. Intracellular levels generally respond to variations in plasma ascorbate availability, and a combination of inadequate intake and increased turnover during severe stress can result in low plasma ascorbate status. Intracellular ascorbate supports essential functions and, in particular, acts as an enzyme cofactor for Fe- or Cu-containing oxygenases. Newly discovered enzymes in this family regulate cell metabolism and epigenetics, and dysregulation of their activity can affect cell phenotype, growth and survival pathways, and stem cell phenotype. This brief overview details some of the recent advances in our understanding of how ascorbate availability can affect the hydroxylases controlling the hypoxic response and the DNA and histone demethylases. These processes play important roles in the regulation of the immune system, altering cell survival pathways, metabolism and functions.

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Zahn, James A., David J. Bergmann, Jeffery M. Boyd, Ryan C. Kunz, and Alan A. DiSpirito. "Membrane-Associated Quinoprotein Formaldehyde Dehydrogenase from Methylococcus capsulatus Bath." Journal of Bacteriology 183, no. 23 (December 1, 2001): 6832–40. http://dx.doi.org/10.1128/jb.183.23.6832-6840.2001.

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ABSTRACT A membrane-associated, dye-linked formaldehyde dehydrogenase (DL-FalDH) was isolated from the obligate methylotrophMethylococcus capsulatus Bath. The enzyme was the major formaldehyde-oxidizing enzyme in cells cultured in high (above 1 μmol of Cu per mg of cell protein) copper medium and expressing the membrane-associated methane monooxygenase. Soluble NAD(P)+-linked formaldehyde oxidation was the major activity in cells cultured in low-copper medium and expressing the soluble methane monooxygenase (Tate and Dalton, Microbiology 145:159–167, 1999; Vorholt et al., J. Bacteriol. 180:5351–5356, 1998). The membrane-associated enzyme is a homotetramer with a subunit molecular mass of 49,500 Da. UV-visible absorption, electron paramagnetic resonance, and electrospray mass spectrometry suggest the redox cofactor of the DL-FalDH is pyrroloquinoline quinone (PQQ), with a PQQ-to-subunit stochiometry of approximately 1:1. The enzyme was specific for formaldehyde, oxidizing formaldehyde to formate, and utilized the cytochrome b 559/569 complex as the physiological electron acceptor.

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Huang, Ju, Michel Nguyen, Yan Liu, Anne Robert, and Bernard Meunier. "The TDMQ Regulators of Copper Homeostasis Do Not Disturb the Activities of Cu,Zn-SOD, Tyrosinase, or the CoIII Cofactor Vitamin B12." European Journal of Inorganic Chemistry 2019, no. 10 (February 27, 2019): 1384–88. http://dx.doi.org/10.1002/ejic.201801332.

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Murakawa, Takeshi, Hideyuki Hayashi, Tomoko Sunami, Kazuo Kurihara, Taro Tamada, Ryota Kuroki, Mamoru Suzuki, Katsuyuki Tanizawa, and Toshihide Okajima. "High-resolution crystal structure of copper amine oxidase fromArthrobacter globiformis: assignment of bound diatomic molecules as O2." Acta Crystallographica Section D Biological Crystallography 69, no. 12 (November 19, 2013): 2483–94. http://dx.doi.org/10.1107/s0907444913023196.

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The crystal structure of a copper amine oxidase fromArthrobacter globiformiswas determined at 1.08 Å resolution with the use of low-molecular-weight polyethylene glycol (LMW PEG; average molecular weight ∼200) as a cryoprotectant. The final crystallographicRfactor andRfreewere 13.0 and 15.0%, respectively. Several molecules of LMW PEG were found to occupy cavities in the protein interior, including the active site, which resulted in a marked reduction in the overallBfactor and consequently led to a subatomic resolution structure for a relatively large protein with a monomer molecular weight of ∼70 000. About 40% of the presumed H atoms were observed as clear electron densities in theFo−Fcdifference map. Multiple minor conformers were also identified for many residues. Anisotropic displacement fluctuations were evaluated in the active site, which contains a post-translationally derived quinone cofactor and a Cu atom. Furthermore, diatomic molecules, most likely to be molecular oxygen, are bound to the protein, one of which is located in a region that had previously been proposed as an entry route for the dioxygen substrate from the central cavity of the dimer interface to the active site.

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Chillappagari, Shashi, Marcus Miethke, Hein Trip, Oscar P. Kuipers, and Mohamed A. Marahiel. "Copper Acquisition Is Mediated by YcnJ and Regulated by YcnK and CsoR in Bacillus subtilis." Journal of Bacteriology 191, no. 7 (January 23, 2009): 2362–70. http://dx.doi.org/10.1128/jb.01616-08.

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ABSTRACT Copper is an essential cofactor for many enzymes, and at over a threshold level, it is toxic for all organisms. To understand the mechanisms underlying copper homeostasis of the gram-positive bacterium Bacillus subtilis, we have performed microarray studies under copper-limiting conditions. These studies revealed that the ycnJ gene encodes a protein that plays an important role in copper metabolism, as it shows a significant, eightfold upregulation under copper-limiting conditions and its disruption causes a growth-defective phenotype under copper deprivation as well as a reduced intracellular content of copper. Native gel shift experiments with the periplasmic N-terminal domain of the YcnJ membrane protein (135 residues) disclosed its strong affinity to Cu(II) ions in vitro. Inspection of the upstream sequence of ycnJ revealed that the ycnK gene encodes a putative transcriptional regulator, whose deletion caused an elevated expression of ycnJ, especially under conditions of copper excess. Further studies demonstrated that the recently identified copper efflux regulator CsoR also is involved in the regulation of ycnJ expression, leading to a new model for copper homeostasis in B. subtilis.

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Visani, Giuseppe, Anita Manti, Laura Valentini, Barbara Canonico, Federica Loscocco, Alessandro Isidori, Elisa Gabucci, et al. "Environmental Nanoparticles Are Significantly over-Expressed in Acute Myeloid Leukemia: a Novel Pathogenetic Cofactor?" Blood 126, no. 23 (December 3, 2015): 4965. http://dx.doi.org/10.1182/blood.v126.23.4965.4965.

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Abstract Background: Continuing growth in the incidence of leukemia suggests a possible environmental etiology correlated to the increase of environmental pollution. Recently, environmental particulate pollution (EPP) has been declared by IARC a Class I carcinogenic agent; it looks reasonable to presume that not only chemicals like benzene and its derivatives, but also other components like EPP could be worth of study. No specific researches have up to now focused the role of EPP on acute myeloid leukemia; we thus have identified a suitable instrumentation and protocol to show the presence and composition of particulate matter in blood samples of patients affected by acute myeloid leukemia patients and in healthy controls. Methods: 38 peripheral blood samples (19 acute myeloid leukemia, 19 healthy controls) were analyzed by means of an Environmental Scanning Electron Microscopy (ESEM) coupled with an Energy Dispersive Spectroscopy (EDS) a sensor capable of identifying the composition of micro- and nano-particles of exogenous nature in pathological tissues (applied for the first time in the current study on blood samples). The results were statistically treated with unpaired two-tailed Student's t-test, MANOVA and Principal Component Analysis. Results: A consistent quantity of micron-, submicron- and nano-sized foreign bodies (from 20 micron down to 100nm) was documented in 18/19 AML cases, whereas they were absent or rare in the controls. The particles appeared as singlet and aggregates (ranging from 5 to 20micron), either in close contact with blood elements or interacting with plasma. Some reacted with blood proteins thus forming composite clusters. A total of 141 aggregates (median 8, range 0-18) in AML, compared to a total of 12 aggregates in controls (median 1, range 0-3) were counted. The aggregate analysis showed variable sizes and number of particles, with a total of 5394 particles in leukemia cases compared to a total of 207 in controls. The total numbers of aggregates and particles were statistically different between cases and controls (MANOVA, P<0.001 e P=0.009 respectively). Aggregates were then analyzed with EDS, identifying their elemental composition. The particles mostly contained highly reactive metals, and appeared not biocompatible and not biodegradable. In particular, micro- and nano-sized particulates were segregated in organic-inorganic clusters, with statistically higher frequency of a subgroup of elements in AML samples (Si, P=0.03; Al, P=0.03; Fe, P=0.002; Ti, P=0.04, Cu, P=0.02, respectively). The analyses of the chemical spectra in some cases allowed to recognize and identify the source of the contamination. Conclusion: In conclusion, we demonstrated the exposure of a subset of AML patients to environmental contaminants, with invasive character in the human body, not biocompatible and biopersistent. AML, as well as myelodysplastic syndromes, are derived from precursor cells critical in innate immunity, that submicronic particles could have triggered. New etiopathogenic hypotheses involving an interaction among sub-micron and nanosized particles with blood components are under evaluation. Disclosures No relevant conflicts of interest to declare.

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Bettger, William J. "Zinc and selenium, site-specific versus general antioxidation." Canadian Journal of Physiology and Pharmacology 71, no. 9 (September 1, 1993): 721–24. http://dx.doi.org/10.1139/y93-108.

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The essential nutrients zinc (Zn) and selenium (Se) provide an antioxidant function to animal cells by very different mechanisms. Se is an integral part of Se-dependent glutathione peroxidases, a group of water-soluble enzymes that catalyze the destruction of water-soluble and, in some cases, membrane-bound hydroperoxides. In dietary Se deficiency, Se-dependent glutathione peroxidase activities are decreased; at Se intakes above that which is required for optimal growth, there is a slight to moderate increase in Se-dependent glutathione peroxidase activities. Because of the enzymatic nature of the major role of Se as an antioxidant, Se can be categorized as having a general antioxidant function, controlling peroxide levels in cells by degrading hydroperoxides. On the other hand, Zn functions as an antioxidant only at specific sites, and is not a required cofactor for an antioxidant enzyme. Although Zn plays a structural role in the enzyme Cu,Zn superoxide dismutase, the activity of this enzyme is not decreased in Zn deficiency and its activity is usually depressed at high Zn intakes. Zn may function as a site-specific antioxidant by two mechanisms. Firstly, it competes with Fe and Cu for binding to cell membranes and some proteins, displacing these redox-active metals and making them more available for binding to ferritin and metallothionein, respectively. Secondly, Zn binds the sulfhydryl groups in proteins, protecting them from oxidation. Zn status does not directly control tissue peroxide levels but can protect specific molecules against oxidative and peroxidative damage.Key words: zinc, selenium, antioxidant, free radicals.

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Spears, Jerry W. "139 Ruminal microbiota mineral requirements to optimize performance on different diets." Journal of Animal Science 98, Supplement_3 (November 2, 2020): 139–40. http://dx.doi.org/10.1093/jas/skaa054.243.

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Abstract This presentation will discuss mineral requirements of ruminal microorganisms, and the effect of trace mineral source on ruminal fermentation. Sulfur and phosphorus are required in relatively large amounts by ruminal microorganisms, and dietary deficiencies of these minerals have been related to impaired ruminal fermentation. A number of trace minerals are required in low concentrations by ruminal microorganisms. With the except of cobalt (Co) minimal trace mineral requirements of the host ruminant appear to be considerably greater than that needed for rumen microbial requirements. It is well known that certain bacteria can synthesize vitamin B12 from inorganic Co. Some bacteria require vitamin B12 as a growth factor, and adequate dietary Co is needed to allow sufficient ruminal B12 synthesis to meet their requirement. Vitamin B12 is needed as a cofactor for ruminal microorganisms to convert succinate to propionate. Dietary Co deficiency results in decreased ruminal propionate in ruminants fed high concentrate diets, and decreased fiber digestion in ruminants fed high fiber diets. Attempts have been made to use high concentrations of certain trace minerals to favorably manipulate ruminal fermentation. For example, attempts have been made to increase rumen protein bypass by feeding high dietary zinc (Zn). However, studies have indicated that high concentrations of copper (Cu), Zn, and iron reduce cellulose digestion in vitro. Recent studies have indicated lower fiber digestibility in cattle supplemented with sulfate sources of Cu, Zn, and manganese compared with those fed similar concentrations from hydroxy or certain organic sources. Additional research is needed to elucidate the mechanism(s) whereby trace mineral sources affect fiber digestibility differently.

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48

Cao, Shanshan, Miaomiao Wu, Shihui Xu, Xiuwen Yan, and Xiaohua Mao. "Identification of a Putative Flavin Adenine Dinucleotide-Binding Monooxygenase as a Regulator for Myxococcus xanthus Development." Journal of Bacteriology 197, no. 7 (January 20, 2015): 1185–96. http://dx.doi.org/10.1128/jb.02555-14.

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ABSTRACTGene clusters coding for the chaperone/usher (CU) pathway are widely distributed in many important environmental and pathogenic microbes; however, information about the regulatory machineries controlling CU gene expression during multicellular morphogenesis is missing. TheMyxococcus xanthusMcu system, encoded by themcuABCDgene cluster, represents a prototype of the archaic CU family that functions in spore coat formation. Using genome-wide transposon mutagenesis, we identified MXAN2872 to be a potential regulator of themcuABCoperon and demonstrated the necessity of MXAN2872 formcuABCexpression and fruiting body morphogenesis in early development.In silico, biochemical, and genetic analyses suggest that MXAN2872 encodes a Baeyer-Villiger monooxygenase (BVMO) of flavoproteins, and the potential cofactor-binding site as well as the BVMO fingerprint sequence is important for the regulatory role of the MXAN2872 protein. The expression profile ofmcuAin strains with an MXAN2872 deletion and point mutation agrees well with the timing of cell aggregation of these mutants. Furthermore, McuA could not be detected either in afruA-null mutant, where starvation-induced aggregation was completely blocked, or in the glycerol-induced spores, where sporulation was uncoupled from cell aggregation. In sum, the present work uncovers a positive role for MXAN2872, a metabolic enzyme-encoding gene, in controllingM. xanthusdevelopment. MXAN2872 functions by affecting the onset of cell aggregation, thereby leading to a secondary effect on the timing ofmcuABCexpression of this model organism.IMPORTANCEIdentification of the players that driveMyxococcus xanthusfruiting body formation is necessary for studying the mechanism of multicellular morphogenesis in this model organism. This study identifies MXAN2872, a gene encoding a putative flavin adenine dinucleotide-binding monooxygenase, to be a new interesting regulator regulating the timing of developmental aggregation. In addition, MXAN2872 seems to affect the expression of the chaperone/usher gene clustermcuin a manner that is aggregation dependent. Thus, in organisms characterized by a developmental cycle, expression of the chaperone/usher pathway can be controlled by morphological checkpoints, demonstrating another layer of complexity in the regulation of this conserved protein secretion pathway.

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49

Ilyechova, Ekaterina, Elisa Bonaldi, Iurii Orlov, Ekaterina Skomorokhova, Ludmila Puchkova, and Massimo Broggini. "CRISP-R/Cas9 Mediated Deletion of Copper Transport Genes CTR1 and DMT1 in NSCLC Cell Line H1299. Biological and Pharmacological Consequences." Cells 8, no. 4 (April 6, 2019): 322. http://dx.doi.org/10.3390/cells8040322.

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Copper, the highly toxic micronutrient, plays two essential roles: it is a catalytic and structural cofactor for Cu-dependent enzymes, and it acts as a secondary messenger. In the cells, copper is imported by CTR1 (high-affinity copper transporter 1), a transmembrane high-affinity copper importer, and DMT1 (divalent metal transporter). In cytosol, enzyme-specific chaperones receive copper from CTR1 C-terminus and deliver it to their apoenzymes. DMT1 cannot be a donor of catalytic copper because it does not have a cytosol domain which is required for copper transfer to the Cu-chaperons that assist the formation of cuproenzymes. Here, we assume that DMT1 can mediate copper way required for a regulatory copper pool. To verify this hypothesis, we used CRISPR/Cas9 to generate H1299 cell line with CTR1 or DMT1 single knockout (KO) and CTR1/DMT1 double knockout (DKO). To confirm KOs of the genes qRT-PCR were used. Two independent clones for each gene were selected for further studies. In CTR1 KO cells, expression of the DMT1 gene was significantly increased and vice versa. In subcellular compartments of the derived cells, copper concentration dropped, however, in nuclei basal level of copper did not change dramatically. CTR1 KO cells, but not DMT1 KO, demonstrated reduced sensitivity to cisplatin and silver ions, the agents that enter the cell through CTR1. Using single CTR1 and DMT1 KO, we were able to show that both, CTR1 and DMT1, provided the formation of vital intracellular cuproenzymes (SOD1, COX), but not secretory ceruloplasmin. The loss of CTR1 resulted in a decrease in the level of COMMD1, XIAP, and NF-κB. Differently, the DMT1 deficiency induced increase of the COMMD1, HIF1α, and XIAP levels. The possibility of using CTR1 KO and DMT1 KO cells to study homeodynamics of catalytic and signaling copper selectively is discussed.

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Masuri, Sebastiano, Petr Vaňhara, Maria Grazia Cabiddu, Lukáš Moráň, Josef Havel, Enzo Cadoni, and Tiziana Pivetta. "Copper(II) Phenanthroline-Based Complexes as Potential AntiCancer Drugs: A Walkthrough on the Mechanisms of Action." Molecules 27, no. 1 (December 22, 2021): 49. http://dx.doi.org/10.3390/molecules27010049.

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Copper is an endogenous metal ion that has been studied to prepare a new antitumoral agent with less side-effects. Copper is involved as a cofactor in several enzymes, in ROS production, in the promotion of tumor progression, metastasis, and angiogenesis, and has been found at high levels in serum and tissues of several types of human cancers. Under these circumstances, two strategies are commonly followed in the development of novel anticancer Copper-based drugs: the sequestration of free Copper ions and the synthesis of Copper complexes that trigger cell death. The latter strategy has been followed in the last 40 years and many reviews have covered the anticancer properties of a broad spectrum of Copper complexes, showing that the activity of these compounds is often multi factored. In this work, we would like to focus on the anticancer properties of mixed Cu(II) complexes bearing substituted or unsubstituted 1,10-phenanthroline based ligands and different classes of inorganic and organic auxiliary ligands. For each metal complex, information regarding the tested cell lines and the mechanistic studies will be reported and discussed. The exerted action mechanisms were presented according to the auxiliary ligand/s, the metallic centers, and the increasing complexity of the compound structures.

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Journal articles on the topic 'Cu cofactor'

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