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Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling.
Sierra JC, Piazuelo MB, Luis PB, Barry DP, Allaman MM, Asim M, Sebrell TA, Finley JL, Rose KL, Hill S, Holshouser SL, Casero RA, Cleveland JL, Woster PM, Schey KL, Bimczok D, Schneider C, Gobert AP, Wilson KT
(2020) Oncogene 39: 4465-4474
MeSH Terms: Adenocarcinoma, Animals, Cell Transformation, Neoplastic, DNA Damage, Gastritis, Helicobacter Infections, Helicobacter pylori, Mice, Mice, Inbred C57BL, Mice, Knockout, Organoids, Oxidoreductases Acting on CH-NH Group Donors, Proteome, RNA, Messenger, Signal Transduction, Spermidine, Spermine, Stomach Neoplasms, beta Catenin
Show Abstract · Added May 1, 2020
Helicobacter pylori infection is the main risk factor for the development of gastric cancer, the third leading cause of cancer death worldwide. H. pylori colonizes the human gastric mucosa and persists for decades. The inflammatory response is ineffective in clearing the infection, leading to disease progression that may result in gastric adenocarcinoma. We have shown that polyamines are regulators of the host response to H. pylori, and that spermine oxidase (SMOX), which metabolizes the polyamine spermine into spermidine plus HO, is associated with increased human gastric cancer risk. We now used a molecular approach to directly address the role of SMOX, and demonstrate that Smox-deficient mice exhibit significant reductions of gastric spermidine levels and H. pylori-induced inflammation. Proteomic analysis revealed that cancer was the most significantly altered functional pathway in Smox gastric organoids. Moreover, there was also less DNA damage and β-catenin activation in H. pylori-infected Smox mice or gastric organoids, compared to infected wild-type animals or gastroids. The link between SMOX and β-catenin activation was confirmed in human gastric organoids that were treated with a novel SMOX inhibitor. These findings indicate that SMOX promotes H. pylori-induced carcinogenesis by causing inflammation, DNA damage, and activation of β-catenin signaling.
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19 MeSH Terms
Distinct Immunomodulatory Effects of Spermine Oxidase in Colitis Induced by Epithelial Injury or Infection.
Gobert AP, Al-Greene NT, Singh K, Coburn LA, Sierra JC, Verriere TG, Luis PB, Schneider C, Asim M, Allaman MM, Barry DP, Cleveland JL, Destefano Shields CE, Casero RA, Washington MK, Piazuelo MB, Wilson KT
(2018) Front Immunol 9: 1242
MeSH Terms: Animals, Citrobacter rodentium, Colitis, Cytokines, Dextran Sulfate, Disease Models, Animal, Gene Deletion, Immunity, Mucosal, Immunomodulation, Intestinal Mucosa, Male, Mice, Mice, Knockout, Oxidoreductases Acting on CH-NH Group Donors, Spermidine, Spermine
Show Abstract · Added June 23, 2018
Polyamines have been implicated in numerous biological processes, including inflammation and carcinogenesis. Homeostatic regulation leads to interconversion of the polyamines putrescine and the downstream metabolites spermidine and spermine. The enzyme spermine oxidase (SMOX), which back-converts spermine to spermidine, contributes to regulation of polyamine levels, but can also have other effects. We have implicated SMOX in gastric inflammation and carcinogenesis due to infection by the pathogen . In addition, we reported that SMOX can be upregulated in humans with inflammatory bowel disease. Herein, we utilized -deficient mice to examine the role of SMOX in two murine colitis models, infection and dextran sulfate sodium (DSS)-induced epithelial injury. In -infected wild-type (WT) mice, there were marked increases in colon weight/length and histologic injury, with mucosal hyperplasia and inflammatory cell infiltration; these changes were ameliorated in mice. In contrast, with DSS, mice exhibited substantial mortality, and increased body weight loss, colon weight/length, and histologic damage. In -infected WT mice, there were increased colonic levels of the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10, and the cytokines IL-6, TNF-α, CSF3, IFN-γ, and IL-17; each were downregulated in mice. In DSS colitis, increased levels of IL-6, CSF3, and IL-17 were further increased in mice. In both models, putrescine and spermidine were increased in WT mice; in mice, the main effect was decreased spermidine and spermidine/spermine ratio. With , polyamine levels correlated with histologic injury, while with DSS, spermidine was inversely correlated with injury. Our studies indicate that SMOX has immunomodulatory effects in experimental colitis polyamine flux. Thus, SMOX contributes to the immunopathogenesis of infection, but is protective in DSS colitis, indicating the divergent effects of spermidine.
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16 MeSH Terms
HemX Modulates Glutamyl-tRNA Reductase Abundance To Regulate Heme Biosynthesis.
Choby JE, Grunenwald CM, Celis AI, Gerdes SY, DuBois JL, Skaar EP
(2018) mBio 9:
MeSH Terms: Aldehyde Oxidoreductases, Bacterial Proteins, Gene Deletion, Gene Expression, Gene Expression Regulation, Bacterial, Heme, Methyltransferases, Staphylococcus aureus
Show Abstract · Added March 15, 2018
is responsible for a significant amount of devastating disease. Its ability to colonize the host and cause infection is supported by a variety of proteins that are dependent on the cofactor heme. Heme is a porphyrin used broadly across kingdoms and is synthesized from common cellular precursors and iron. While heme is critical to bacterial physiology, it is also toxic in high concentrations, requiring that organisms encode regulatory processes to control heme homeostasis. In this work, we describe a posttranscriptional regulatory strategy in heme biosynthesis. The first committed enzyme in the heme biosynthetic pathway, glutamyl-tRNA reductase (GtrR), is regulated by heme abundance and the integral membrane protein HemX. GtrR abundance increases dramatically in response to heme deficiency, suggesting a mechanism by which responds to the need to increase heme synthesis. Additionally, HemX is required to maintain low levels of GtrR in heme-proficient cells, and inactivation of leads to increased heme synthesis. Excess heme synthesis in a Δ mutant activates the staphylococcal heme stress response, suggesting that regulation of heme synthesis is critical to reduce self-imposed heme toxicity. Analysis of diverse organisms indicates that HemX is widely conserved among heme-synthesizing bacteria, suggesting that HemX is a common factor involved in the regulation of GtrR abundance. Together, this work demonstrates that regulates heme synthesis by modulating GtrR abundance in response to heme deficiency and through the activity of the broadly conserved HemX. is a leading cause of skin and soft tissue infections, endocarditis, bacteremia, and osteomyelitis, making it a critical health care concern. Development of new antimicrobials against requires knowledge of the physiology that supports this organism's pathogenesis. One component of staphylococcal physiology that contributes to growth and virulence is heme. Heme is a widely utilized cofactor that enables diverse chemical reactions across many enzyme families. relies on many critical heme-dependent proteins and is sensitive to excess heme toxicity, suggesting must maintain proper intracellular heme homeostasis. Because provides heme for heme-dependent enzymes via synthesis from common precursors, we hypothesized that regulation of heme synthesis is one mechanism to maintain heme homeostasis. In this study, we identify that posttranscriptionally regulates heme synthesis by restraining abundance of the first heme biosynthetic enzyme, GtrR, via heme and the broadly conserved membrane protein HemX.
Copyright © 2018 Choby et al.
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8 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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MeSH Terms
New crystal forms of the integral membrane Escherichia coli quinol:fumarate reductase suggest that ligands control domain movement.
Starbird CA, Tomasiak TM, Singh PK, Yankovskaya V, Maklashina E, Eisenbach M, Cecchini G, Iverson TM
(2018) J Struct Biol 202: 100-104
MeSH Terms: Binding Sites, Catalytic Domain, Crystallography, Crystallography, X-Ray, Escherichia coli Proteins, Ligands, Membrane Proteins, Models, Molecular, Oxidoreductases, Protein Domains, Rotation
Show Abstract · Added April 1, 2019
Quinol:fumarate reductase (QFR) is an integral membrane protein and a member of the respiratory Complex II superfamily. Although the structure of Escherichia coli QFR was first reported almost twenty years ago, many open questions of catalysis remain. Here we report two new crystal forms of QFR, one grown from the lipidic cubic phase and one grown from dodecyl maltoside micelles. QFR crystals grown from the lipid cubic phase processed as P1, merged to 7.5 Å resolution, and exhibited crystal packing similar to previous crystal forms. Crystals grown from dodecyl maltoside micelles processed as P2, merged to 3.35 Å resolution, and displayed a unique crystal packing. This latter crystal form provides the first view of the E. coli QFR active site without a dicarboxylate ligand. Instead, an unidentified anion binds at a shifted position. In one of the molecules in the asymmetric unit, this is accompanied by rotation of the capping domain of the catalytic subunit. In the other molecule, this is associated with loss of interpretable electron density for this same capping domain. Analysis of the structure suggests that the ligand adjusts the position of the capping domain.
Copyright © 2017 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Proteolytic processing of lysyl oxidase-like-2 in the extracellular matrix is required for crosslinking of basement membrane collagen IV.
López-Jiménez AJ, Basak T, Vanacore RM
(2017) J Biol Chem 292: 16970-16982
MeSH Terms: Amino Acid Oxidoreductases, Basement Membrane, Collagen Type IV, Extracellular Matrix, HEK293 Cells, Humans, Mutagenesis, Site-Directed, Protein Domains, Protein Processing, Post-Translational, Proteolysis
Show Abstract · Added November 3, 2017
Lysyl oxidase-like-2 (LOXL2) is an enzyme secreted into the extracellular matrix that crosslinks collagens by mediating oxidative deamination of lysine residues. Our previous work demonstrated that this enzyme crosslinks the 7S domain, a structural domain that stabilizes collagen IV scaffolds in the basement membrane. Despite its relevant role in extracellular matrix biosynthesis, little is known about the structural requirements of LOXL2 that enable collagen IV crosslinking. In this study, we demonstrate that LOXL2 is processed extracellularly by serine proteases, generating a 65-kDa form lacking the first two scavenger receptor cysteine-rich domains. Site-specific mutagenesis to prevent proteolytic processing generated a full-length enzyme that is active toward a soluble substrate, but fails to crosslink insoluble collagen IV within the extracellular matrix. In contrast, the processed form of LOXL2 binds to collagen IV and crosslinks the 7S domain. Together, our data demonstrate that proteolytic processing is an important event that allows LOXL2-mediated crosslinking of basement membrane collagen IV.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
1 Communities
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10 MeSH Terms
Nonsteroidal Anti-inflammatory Drug Interaction with Prostacyclin Synthase Protects from Miscarriage.
Velez Edwards DR, Edwards TL, Bray MJ, Torstenson E, Jones S, Shrubsole MJ, Muff HJ, Hartmann KE
(2017) Sci Rep 7: 9874
MeSH Terms: Abortion, Spontaneous, Adult, Alleles, Anti-Inflammatory Agents, Non-Steroidal, Cytochrome P-450 Enzyme System, Disease Susceptibility, Female, Genotype, Humans, Intramolecular Oxidoreductases, Odds Ratio, Polymorphism, Single Nucleotide, Pregnancy, Risk Factors
Show Abstract · Added February 21, 2019
This study evaluates the relationship between single nucleotide polymorphisms (SNPs) in nonsteroidal anti-inflammatory drug (NSAID) metabolism and related pathways and spontaneous abortion (SAB, gestation < 20 weeks) risk. Women were enrolled in Right from the Start (2004-2010) prospective cohort. Periconceptional NSAIDs reported through the sixth week of pregnancy were obtained from study interviews. We evaluated 201 SNPs in 600 European American women. Interaction analyses between NSAID use and SNPs were conducted using logistic regression, adjusted for confounders. We also evaluated prostaglandin E2 urinary metabolite (PGE-M) in an independent population for association with SNPs using linear regression. NSAID use was reported by 63% of cases and 62% controls. The most significant interaction was at prostacyclin synthase (PGIS) rs5602 (OR = 0.34, 95% CI 0.19-0.60, p = 2.45 × 10) and was significant after a Bonferroni correction. NSAID users were protected from SAB (OR = 0.78, 95% CI 0.56-1.10), while non-NSAID users were at increased risk (OR = 2.11, 95% CI 1.35-3.29) in rs5602 stratified analyses. rs5602 also associated with increased PGE-M levels (Beta = 0.09, 95% CI -0.002-0.19, p = 0.033). We identified an association between a PGIS variant and SAB risk that is modified by NSAIDs use during pregnancy and directly associated with increased levels of PGE metabolites. This suggests the potential use of genetic information to guide pharmaceutical intervention to prevent adverse pregnancy outcomes.
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14 MeSH Terms
Building collagen IV smart scaffolds on the outside of cells.
Brown KL, Cummings CF, Vanacore RM, Hudson BG
(2017) Protein Sci 26: 2151-2161
MeSH Terms: Amino Acid Motifs, Amino Acid Oxidoreductases, Animals, Antigens, Neoplasm, Basement Membrane, Collagen Type IV, Eukaryotic Cells, Extracellular Matrix, Gene Expression Regulation, Humans, Peroxidases, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Structure, Secondary, Protein Subunits, Receptors, Interleukin-1
Show Abstract · Added November 2, 2017
Collagen IV scaffolds assemble through an intricate pathway that begins intracellularly and is completed extracellularly. Multiple intracellular enzymes act in concert to assemble collagen IV protomers, the building blocks of collagen IV scaffolds. After being secreted from cells, protomers are activated to initiate oligomerization, forming insoluble networks that are structurally reinforced with covalent crosslinks. Within these networks, embedded binding sites along the length of the protomer lead to the "decoration" of collagen IV triple helix with numerous functional molecules. We refer to these networks as "smart" scaffolds, which as a component of the basement membrane enable the development and function of multicellular tissues in all animal phyla. In this review, we present key molecular mechanisms that drive the assembly of collagen IV smart scaffolds.
© 2017 The Protein Society.
1 Communities
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16 MeSH Terms
Structural and biochemical analyses reveal insights into covalent flavinylation of the Complex II homolog quinol:fumarate reductase.
Starbird CA, Maklashina E, Sharma P, Qualls-Histed S, Cecchini G, Iverson TM
(2017) J Biol Chem 292: 12921-12933
MeSH Terms: Amino Acid Substitution, Biocatalysis, Crystallography, X-Ray, Enzyme Stability, Escherichia coli, Escherichia coli Proteins, Flavin-Adenine Dinucleotide, Gene Deletion, Glutamic Acid, Hot Temperature, Models, Molecular, Molecular Docking Simulation, Mutagenesis, Site-Directed, Mutation, Oxidoreductases, Protein Conformation, Protein Denaturation, Protein Interaction Domains and Motifs, Protein Multimerization, Protein Processing, Post-Translational, Protein Subunits, Recombinant Proteins, Structural Homology, Protein, Succinate Dehydrogenase
Show Abstract · Added April 1, 2019
The Complex II homolog quinol:fumarate reductase (QFR, FrdABCD) catalyzes the interconversion of fumarate and succinate at a covalently attached FAD within the FrdA subunit. The SdhE assembly factor enhances covalent flavinylation of Complex II homologs, but the mechanisms underlying the covalent attachment of FAD remain to be fully elucidated. Here, we explored the mechanisms of covalent flavinylation of the QFR FrdA subunit. Using a Δ strain, we show that the requirement for the assembly factor depends on the cellular redox environment. We next identified residues important for the covalent attachment and selected the FrdA residue, which contributes to proton shuttling during fumarate reduction, for detailed biophysical and structural characterization. We found that QFR complexes containing FrdA have a structure similar to that of the WT flavoprotein, but lack detectable substrate binding and turnover. In the context of the isolated FrdA subunit, the anticipated assembly intermediate during covalent flavinylation, FrdA variants had stability similar to that of WT FrdA, contained noncovalent FAD, and displayed a reduced capacity to interact with SdhE. However, small-angle X-ray scattering (SAXS) analysis of WT FrdA cross-linked to SdhE suggested that the FrdA residue is unlikely to contribute directly to the FrdA-SdhE protein-protein interface. We also found that no auxiliary factor is absolutely required for flavinylation, indicating that the covalent flavinylation is autocatalytic. We propose that multiple factors, including the SdhE assembly factor and bound dicarboxylates, stimulate covalent flavinylation by preorganizing the active site to stabilize the quinone-methide intermediate.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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MeSH Terms
Trapping redox partnerships in oxidant-sensitive proteins with a small, thiol-reactive cross-linker.
Allan KM, Loberg MA, Chepngeno J, Hurtig JE, Tripathi S, Kang MG, Allotey JK, Widdershins AH, Pilat JM, Sizek HJ, Murphy WJ, Naticchia MR, David JB, Morano KA, West JD
(2016) Free Radic Biol Med 101: 356-366
MeSH Terms: Cross-Linking Reagents, Disulfides, Glutathione Peroxidase, Methionine Sulfoxide Reductases, Oxidants, Oxidation-Reduction, Oxidative Stress, Oxidoreductases Acting on Sulfur Group Donors, Peroxiredoxins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sulfhydryl Compounds, Sulfones, Thioredoxins, tert-Butylhydroperoxide
Show Abstract · Added April 24, 2017
A broad range of redox-regulated proteins undergo reversible disulfide bond formation on oxidation-prone cysteine residues. Heightened reactivity of the thiol groups in these cysteines also increases susceptibility to modification by organic electrophiles, a property that can be exploited in the study of redox networks. Here, we explored whether divinyl sulfone (DVSF), a thiol-reactive bifunctional electrophile, cross-links oxidant-sensitive proteins to their putative redox partners in cells. To test this idea, previously identified oxidant targets involved in oxidant defense (namely, peroxiredoxins, methionine sulfoxide reductases, sulfiredoxin, and glutathione peroxidases), metabolism, and proteostasis were monitored for cross-link formation following treatment of Saccharomyces cerevisiae with DVSF. Several proteins screened, including multiple oxidant defense proteins, underwent intermolecular and/or intramolecular cross-linking in response to DVSF. Specific redox-active cysteines within a subset of DVSF targets were found to influence cross-linking; in addition, DVSF-mediated cross-linking of its targets was impaired in cells first exposed to oxidants. Since cross-linking appeared to involve redox-active cysteines in these proteins, we examined whether potential redox partners became cross-linked to them upon DVSF treatment. Specifically, we found that several substrates of thioredoxins were cross-linked to the cytosolic thioredoxin Trx2 in cells treated with DVSF. However, other DVSF targets, like the peroxiredoxin Ahp1, principally formed intra-protein cross-links upon DVSF treatment. Moreover, additional protein targets, including several known to undergo S-glutathionylation, were conjugated via DVSF to glutathione. Our results indicate that DVSF is of potential use as a chemical tool for irreversibly trapping and discovering thiol-based redox partnerships within cells.
Copyright © 2016 Elsevier Inc. All rights reserved.
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15 MeSH Terms