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Maturation of the respiratory complex II flavoprotein.
Sharma P, Maklashina E, Cecchini G, Iverson TM
(2019) Curr Opin Struct Biol 59: 38-46
MeSH Terms: Animals, Cell Respiration, Electron Transport Chain Complex Proteins, Electron Transport Complex II, Flavin-Adenine Dinucleotide, Flavoproteins, Humans, Protein Binding, Protein Subunits, Structure-Activity Relationship
Show Abstract · Added April 1, 2019
Respiratory complexes are complicated multi-subunit cofactor-containing machines that allow cells to harvest energy from the environment. Maturation of these complexes requires protein folding, cofactor insertion, and assembly of multiple subunits into a final, functional complex. Because the intermediate states in complex maturation are transitory, these processes are poorly understood. This review gives an overview of the process of maturation in respiratory complex II with a focus on recent structural studies on intermediates formed during covalent flavinylation of the catalytic subunit, SDHA. Covalent flavinylation has an evolutionary significance because variants of complex II enzymes with the covalent ligand removed by mutagenesis cannot oxidize succinate, but can still perform the reverse reaction and reduce fumarate. Since succinate oxidation is a key step of aerobic respiration, the covalent bond of complex II appears to be important for aerobic life.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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10 MeSH Terms
Yeast require redox switching in DNA primase.
O'Brien E, Salay LE, Epum EA, Friedman KL, Chazin WJ, Barton JK
(2018) Proc Natl Acad Sci U S A 115: 13186-13191
MeSH Terms: Crystallography, X-Ray, DNA Primase, Electron Transport, Iron-Sulfur Proteins, Models, Molecular, Mutation, Oxidation-Reduction, Protein Conformation, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Show Abstract · Added March 26, 2019
Eukaryotic DNA primases contain a [4Fe4S] cluster in the C-terminal domain of the p58 subunit (p58C) that affects substrate affinity but is not required for catalysis. We show that, in yeast primase, the cluster serves as a DNA-mediated redox switch governing DNA binding, just as in human primase. Despite a different structural arrangement of tyrosines to facilitate electron transfer between the DNA substrate and [4Fe4S] cluster, in yeast, mutation of tyrosines Y395 and Y397 alters the same electron transfer chemistry and redox switch. Mutation of conserved tyrosine 395 diminishes the extent of p58C participation in normal redox-switching reactions, whereas mutation of conserved tyrosine 397 causes oxidative cluster degradation to the [3Fe4S] species during p58C redox signaling. Switching between oxidized and reduced states in the presence of the Y397 mutations thus puts primase [4Fe4S] cluster integrity and function at risk. Consistent with these observations, we find that yeast tolerate mutations to Y395 in p58C, but the single-residue mutation Y397L in p58C is lethal. Our data thus show that a constellation of tyrosines for protein-DNA electron transfer mediates the redox switch in eukaryotic primases and is required for primase function in vivo.
Copyright © 2018 the Author(s). Published by PNAS.
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MeSH Terms
The unassembled flavoprotein subunits of human and bacterial complex II have impaired catalytic activity and generate only minor amounts of ROS.
Maklashina E, Rajagukguk S, Iverson TM, Cecchini G
(2018) J Biol Chem 293: 7754-7765
MeSH Terms: Bacterial Proteins, Catalysis, Crystallography, X-Ray, Electron Transport Complex II, Escherichia coli, Flavoproteins, Humans, Models, Molecular, Oxidation-Reduction, Protein Conformation, Protein Subunits, Reactive Oxygen Species
Show Abstract · Added April 1, 2019
Complex II (SdhABCD) is a membrane-bound component of mitochondrial and bacterial electron transport chains, as well as of the TCA cycle. In this capacity, it catalyzes the reversible oxidation of succinate. SdhABCD contains the SDHA protein harboring a covalently bound FAD redox center and the iron-sulfur protein SDHB, containing three distinct iron-sulfur centers. When assembly of this complex is compromised, the flavoprotein SDHA may accumulate in the mitochondrial matrix or bacterial cytoplasm. Whether the unassembled SDHA has any catalytic activity, for example in succinate oxidation, fumarate reduction, reactive oxygen species (ROS) generation, or other off-pathway reactions, is not known. Therefore, here we investigated whether unassembled SdhA flavoprotein, its homolog fumarate reductase (FrdA), and the human SDHA protein have succinate oxidase or fumarate reductase activity and can produce ROS. Using recombinant expression in , we found that the free flavoproteins from these divergent biological sources have inherently low catalytic activity and generate little ROS. These results suggest that the iron-sulfur protein SDHB in complex II is necessary for robust catalytic activity. Our findings are consistent with those reported for single-subunit flavoprotein homologs that are not associated with iron-sulfur or heme partner proteins.
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Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA.
Wauchope OR, Mitchener MM, Beavers WN, Galligan JJ, Camarillo JM, Sanders WD, Kingsley PJ, Shim HN, Blackwell T, Luong T, deCaestecker M, Fessel JP, Marnett LJ
(2018) Nucleic Acids Res 46: 3458-3467
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Type II, DNA Adducts, DNA, Mitochondrial, Electron Transport, Endothelial Cells, Gene Expression Regulation, Humans, Hypertension, Pulmonary, Lipid Peroxidation, Mice, Mice, Transgenic, Mitochondria, Mutagenesis, Oxidants, Oxidative Stress, Purine Nucleosides, Reactive Oxygen Species, Superoxides
Show Abstract · Added March 14, 2018
Reactive oxygen species (ROS) are formed in mitochondria during electron transport and energy generation. Elevated levels of ROS lead to increased amounts of mitochondrial DNA (mtDNA) damage. We report that levels of M1dG, a major endogenous peroxidation-derived DNA adduct, are 50-100-fold higher in mtDNA than in nuclear DNA in several different human cell lines. Treatment of cells with agents that either increase or decrease mitochondrial superoxide levels leads to increased or decreased levels of M1dG in mtDNA, respectively. Sequence analysis of adducted mtDNA suggests that M1dG residues are randomly distributed throughout the mitochondrial genome. Basal levels of M1dG in mtDNA from pulmonary microvascular endothelial cells (PMVECs) from transgenic bone morphogenetic protein receptor 2 mutant mice (BMPR2R899X) (four adducts per 106 dG) are twice as high as adduct levels in wild-type cells. A similar increase was observed in mtDNA from heterozygous null (BMPR2+/-) compared to wild-type PMVECs. Pulmonary arterial hypertension is observed in the presence of BMPR2 signaling disruptions, which are also associated with mitochondrial dysfunction and oxidant injury to endothelial tissue. Persistence of M1dG adducts in mtDNA could have implications for mutagenesis and mitochondrial gene expression, thereby contributing to the role of mitochondrial dysfunction in diseases.
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3 Members
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19 MeSH Terms
Introduction to Metals in Biology 2018: Copper homeostasis and utilization in redox enzymes.
Guengerich FP
(2018) J Biol Chem 293: 4603-4605
MeSH Terms: Animals, Copper, Electron Transport Complex IV, Humans, Superoxide Dismutase
Show Abstract · Added March 14, 2018
This 11th Thematic Metals in Biology Thematic Series deals with copper, a transition metal with a prominent role in biochemistry. Copper is a very versatile element, and both deficiencies and excesses can be problematic. The five Minireviews in this series deal with several aspects of copper homeostasis in microorganisms and mammals and the role of this metal in two enzymes, copper-only superoxide dismutase and cytochrome oxidase.
© 2018 Guengerich.
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5 MeSH Terms
Crystal structure of an assembly intermediate of respiratory Complex II.
Sharma P, Maklashina E, Cecchini G, Iverson TM
(2018) Nat Commun 9: 274
MeSH Terms: Crystallography, X-Ray, Electron Transport Complex II, Escherichia coli, Escherichia coli Proteins, Flavin-Adenine Dinucleotide, Oxidoreductases
Show Abstract · Added April 1, 2019
Flavin is covalently attached to the protein scaffold in ~10% of flavoenzymes. However, the mechanism of covalent modification is unclear, due in part to challenges in stabilizing assembly intermediates. Here, we capture the structure of an assembly intermediate of the Escherichia coli Complex II (quinol:fumarate reductase (FrdABCD)). The structure contains the E. coli FrdA subunit bound to covalent FAD and crosslinked with its assembly factor, SdhE. The structure contains two global conformational changes as compared to prior structures of the mature protein: the rotation of a domain within the FrdA subunit, and the destabilization of two large loops of the FrdA subunit, which may create a tunnel to the active site. We infer a mechanism for covalent flavinylation. As supported by spectroscopic and kinetic analyses, we suggest that SdhE shifts the conformational equilibrium of the FrdA active site to disfavor succinate/fumarate interconversion and enhance covalent flavinylation.
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Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis.
Feichtinger RG, Neureiter D, Skaria T, Wessler S, Cover TL, Mayr JA, Zimmermann FA, Posselt G, Sperl W, Kofler B
(2017) Oxid Med Cell Longev 2017: 1320241
MeSH Terms: Electron Transport Complex I, Female, Gastritis, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Helicobacter Infections, Helicobacter pylori, Humans, Male, Neoplasm Proteins, Oxidative Phosphorylation, Stomach Neoplasms
Show Abstract · Added March 21, 2018
Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas ("intestinal" and "diffuse"), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.
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12 MeSH Terms
Response to Comments on "The [4Fe4S] cluster of human DNA primase functions as a redox switch using DNA charge transport".
O'Brien E, Holt ME, Thompson MK, Salay LE, Ehlinger AC, Chazin WJ, Barton JK
(2017) Science 357:
MeSH Terms: Biological Transport, DNA, DNA Primase, Electron Transport, Humans, Oxidation-Reduction
Show Abstract · Added March 24, 2018
Baranovskiy and Pellegrini argue that, based on structural data, the path for charge transfer through the [4Fe4S] domain of primase is not feasible. Our manuscript presents electrochemical data directly showing charge transport through DNA to the [4Fe4S] cluster of a primase p58C construct and a reversible switch in the DNA-bound signal with oxidation/reduction, which is inhibited by mutation of three tyrosine residues. Although the dispositions of tyrosines differ in different constructs, all are within range for microsecond electron transfer.
Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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6 MeSH Terms
Virulence factors enhance Citrobacter rodentium expansion through aerobic respiration.
Lopez CA, Miller BM, Rivera-Chávez F, Velazquez EM, Byndloss MX, Chávez-Arroyo A, Lokken KL, Tsolis RM, Winter SE, Bäumler AJ
(2016) Science 353: 1249-53
MeSH Terms: Aerobiosis, Amyloid Precursor Protein Secretases, Animals, Citrobacter rodentium, Colitis, Colon, Cytochromes, Dibenzazepines, Electron Transport Chain Complex Proteins, Enterobacteriaceae Infections, Gene Deletion, Hyperplasia, Intestinal Mucosa, Ki-67 Antigen, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Nitrates, Oxidoreductases, Receptors, Notch, Virulence Factors
Show Abstract · Added March 30, 2020
Citrobacter rodentium uses a type III secretion system (T3SS) to induce colonic crypt hyperplasia in mice, thereby gaining an edge during its competition with the gut microbiota through an unknown mechanism. Here, we show that by triggering colonic crypt hyperplasia, the C. rodentium T3SS induced an excessive expansion of undifferentiated Ki67-positive epithelial cells, which increased oxygenation of the mucosal surface and drove an aerobic C. rodentium expansion in the colon. Treatment of mice with the γ-secretase inhibitor dibenzazepine to diminish Notch-driven colonic crypt hyperplasia curtailed the fitness advantage conferred by aerobic respiration during C. rodentium infection. We conclude that C. rodentium uses its T3SS to induce histopathological lesions that generate an intestinal microenvironment in which growth of the pathogen is fueled by aerobic respiration.
Copyright © 2016, American Association for the Advancement of Science.
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CtaM Is Required for Menaquinol Oxidase aa3 Function in Staphylococcus aureus.
Hammer ND, Schurig-Briccio LA, Gerdes SY, Gennis RB, Skaar EP
(2016) mBio 7:
MeSH Terms: Aerobiosis, Electron Transport Chain Complex Proteins, Electron Transport Complex IV, Heme, Oxidation-Reduction, Staphylococcus aureus
Show Abstract · Added April 8, 2017
UNLABELLED - Staphylococcus aureus is the leading cause of skin and soft tissue infections, bacteremia, osteomyelitis, and endocarditis in the developed world. The ability of S. aureus to cause substantial disease in distinct host environments is supported by a flexible metabolism that allows this pathogen to overcome challenges unique to each host organ. One feature of staphylococcal metabolic flexibility is a branched aerobic respiratory chain composed of multiple terminal oxidases. Whereas previous biochemical and spectroscopic studies reported the presence of three different respiratory oxygen reductases (o type, bd type, and aa3 type), the genome contains genes encoding only two respiratory oxygen reductases, cydAB and qoxABCD Previous investigation showed that cydAB and qoxABCD are required to colonize specific host organs, the murine heart and liver, respectively. This work seeks to clarify the relationship between the genetic studies showing the unique roles of the cydAB and qoxABCD in virulence and the respiratory reductases reported in the literature. We establish that QoxABCD is an aa3-type menaquinol oxidase but that this enzyme is promiscuous in that it can assemble as a bo3-type menaquinol oxidase. However, the bo3 form of QoxABCD restricts the carbon sources that can support the growth of S. aureus In addition, QoxABCD function is supported by a previously uncharacterized protein, which we have named CtaM, that is conserved in aerobically respiring Firmicutes In total, these studies establish the heme A biosynthesis pathway in S. aureus, determine that QoxABCD is a type aa3 menaquinol oxidase, and reveal CtaM as a new protein required for type aa3 menaquinol oxidase function in multiple bacterial genera.
IMPORTANCE - Staphylococcus aureus relies upon the function of two terminal oxidases, CydAB and QoxABCD, to aerobically respire and colonize distinct host tissues. Previous biochemical studies support the conclusion that a third terminal oxidase is also present. We establish the components of the S. aureus electron transport chain by determining the heme cofactors that interact with QoxABCD. This insight explains previous observations by revealing that QoxABCD can utilize different heme cofactors and confirms that the electron transport chain of S. aureus is comprised of two terminal menaquinol oxidases. In addition, a newly identified protein, CtaM, is found to be required for the function of QoxABCD. These results provide a more complete assessment of the molecular mechanisms that support staphylococcal respiration.
Copyright © 2016 Hammer et al.
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6 MeSH Terms