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The Structure of the Bifunctional Everninomicin Biosynthetic Enzyme EvdMO1 Suggests Independent Activity of the Fused Methyltransferase-Oxidase Domains.
Starbird CA, Perry NA, Chen Q, Berndt S, Yamakawa I, Loukachevitch LV, Limbrick EM, Bachmann BO, Iverson TM, McCulloch KM
(2018) Biochemistry 57: 6827-6837
MeSH Terms: Amino Acid Sequence, Aminoglycosides, Bacterial Proteins, Biosynthetic Pathways, Catalytic Domain, Conserved Sequence, Crystallography, X-Ray, Gene Fusion, Genes, Bacterial, Methyltransferases, Micromonospora, Models, Molecular, Oxygenases, Protein Interaction Domains and Motifs, Sequence Homology, Amino Acid
Show Abstract · Added April 1, 2019
Members of the orthosomycin family of natural products are decorated polysaccharides with potent antibiotic activity and complex biosynthetic pathways. The defining feature of the orthosomycins is an orthoester linkage between carbohydrate moieties that is necessary for antibiotic activity and is likely formed by a family of conserved oxygenases. Everninomicins are octasaccharide orthosomycins produced by Micromonospora carbonacea that have two orthoester linkages and a methylenedioxy bridge, three features whose formation logically requires oxidative chemistry. Correspondingly, the evd gene cluster encoding everninomicin D encodes two monofunctional nonheme iron, α-ketoglutarate-dependent oxygenases and one bifunctional enzyme with an N-terminal methyltransferase domain and a C-terminal oxygenase domain. To investigate whether the activities of these domains are linked in the bifunctional enzyme EvdMO1, we determined the structure of the N-terminal methyltransferase domain to 1.1 Å and that of the full-length protein to 3.35 Å resolution. Both domains of EvdMO1 adopt the canonical folds of their respective superfamilies and are connected by a short linker. Each domain's active site is oriented such that it faces away from the other domain, and there is no evidence of a channel connecting the two. Our results support EvdMO1 working as a bifunctional enzyme with independent catalytic activities.
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15 MeSH Terms
Immunity drives regulation in cancer through NF-κB.
Collignon E, Canale A, Al Wardi C, Bizet M, Calonne E, Dedeurwaerder S, Garaud S, Naveaux C, Barham W, Wilson A, Bouchat S, Hubert P, Van Lint C, Yull F, Sotiriou C, Willard-Gallo K, Noel A, Fuks F
(2018) Sci Adv 4: eaap7309
MeSH Terms: Adaptive Immunity, Biomarkers, DNA Methylation, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Immunity, Immunity, Innate, Mixed Function Oxygenases, NF-kappa B, Neoplasms, Neoplasms, Basal Cell, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins
Show Abstract · Added March 31, 2020
Ten-eleven translocation enzymes (TET1, TET2, and TET3), which induce DNA demethylation and gene regulation by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), are often down-regulated in cancer. We uncover, in basal-like breast cancer (BLBC), genome-wide 5hmC changes related to regulation. We further demonstrate that repression is associated with high expression of immune markers and high infiltration by immune cells. We identify in BLBC tissues an anticorrelation between expression and the major immunoregulator family nuclear factor κB (NF-κB). In vitro and in mice, is down-regulated in breast cancer cells upon NF-κB activation through binding of p65 to its consensus sequence in the promoter. We lastly show that these findings extend to other cancer types, including melanoma, lung, and thyroid cancers. Together, our data suggest a novel mode of regulation for in cancer and highlight a new paradigm in which the immune system can influence cancer cell epigenetics.
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MeSH Terms
Fur regulation of Staphylococcus aureus heme oxygenases is required for heme homeostasis.
Lojek LJ, Farrand AJ, Weiss A, Skaar EP
(2018) Int J Med Microbiol 308: 582-589
MeSH Terms: Aerobiosis, Bacterial Proteins, Gene Expression Regulation, Bacterial, Heme, Heme Oxygenase (Decyclizing), Homeostasis, Iron, Mixed Function Oxygenases, Oxygenases, Repressor Proteins, Staphylococcus aureus
Show Abstract · Added March 15, 2018
Heme is a cofactor that is essential for cellular respiration and for the function of many enzymes. If heme levels become too low within the cell, S. aureus switches from producing energy via respiration to producing energy by fermentation. S. aureus encodes two heme oxygenases, IsdI and IsdG, which cleave the porphyrin heme ring releasing iron for use as a nutrient source. Both isdI and isdG are only expressed under low iron conditions and are regulated by the canonical Ferric Uptake Regulator (Fur). Here we demonstrate that unregulated expression of isdI and isdG within S. aureus leads to reduced growth under low iron conditions. Additionally, the constitutive expression of these enzymes leads to decreased heme abundance in S. aureus, an increase in the fermentation product lactate, and increased resistance to gentamicin. This work demonstrates that S. aureus has developed tuning mechanisms, such as Fur regulation, to ensure that the cell has sufficient quantities of heme for efficient ATP production through aerobic respiration.
Copyright © 2018 Elsevier GmbH. All rights reserved.
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11 MeSH Terms
Hypoxia-inducible factor prolyl-4-hydroxylation in FOXD1 lineage cells is essential for normal kidney development.
Kobayashi H, Liu J, Urrutia AA, Burmakin M, Ishii K, Rajan M, Davidoff O, Saifudeen Z, Haase VH
(2017) Kidney Int 92: 1370-1383
MeSH Terms: Anemia, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Clinical Trials, Phase III as Topic, Disease Models, Animal, Enzyme Inhibitors, Forkhead Transcription Factors, Humans, Hydroxylation, Hypoxia-Inducible Factor-Proline Dioxygenases, Kidney, Kidney Diseases, Mice, Molecular Targeted Therapy, Mutation, Organ Size, Procollagen-Proline Dioxygenase, Renal Insufficiency, Stromal Cells
Show Abstract · Added November 21, 2017
Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.
Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
Oxygen sensors as therapeutic targets in kidney disease.
Haase VH
(2017) Nephrol Ther 13 Suppl 1: S29-S34
MeSH Terms: Erythropoietin, Homeostasis, Humans, Hypoxia, Hypoxia-Inducible Factor-Proline Dioxygenases, Kidney, Oxygen, Prolyl-Hydroxylase Inhibitors, Renal Insufficiency, Chronic
Show Abstract · Added June 7, 2017
Hypoxia is a common clinical problem that has profound effects on renal homeostasis. Prolyl-4-hydroxylases PHD1, 2 and 3 function as oxygen sensors and control the activity of hypoxia-inducible factor (HIF), an oxygen-sensitive transcription factor that regulates a multitude of hypoxia responses, which help cells and tissues to adapt to low oxygen environments. This review provides an overview of the molecular mechanisms that govern these hypoxia responses and discusses clinical experience with compounds that inhibit prolyl-4-hydroxylases to harness HIF responses for therapy in nephrology.
Copyright © 2017 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.
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9 MeSH Terms
Therapeutic targeting of the HIF oxygen-sensing pathway: Lessons learned from clinical studies.
Haase VH
(2017) Exp Cell Res 356: 160-165
MeSH Terms: Anemia, Animals, Erythropoiesis, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Oxygen
Show Abstract · Added May 10, 2017
The oxygen-sensitive hypoxia-inducible factor (HIF) pathway plays a central role in the control of erythropoiesis and iron metabolism. The discovery of prolyl hydroxylase domain (PHD) proteins as key regulators of HIF activity has led to the development of inhibitory compounds that are now in phase 3 clinical development for the treatment of renal anemia, a condition that is commonly found in patients with advanced chronic kidney disease. This review provides a concise overview of clinical effects associated with pharmacologic PHD inhibition and was written in memory of Professor Lorenz Poellinger.
Copyright © 2017 Elsevier Inc. All rights reserved.
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8 MeSH Terms
HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism.
Haase VH
(2017) Hemodial Int 21 Suppl 1: S110-S124
MeSH Terms: Anemia, Barbiturates, Clinical Trials as Topic, Erythropoiesis, Erythropoietin, Glycine, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Iron, Isoquinolines, Picolinic Acids, Prolyl-Hydroxylase Inhibitors, Renal Dialysis
Show Abstract · Added April 28, 2017
A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.
© 2017 International Society for Hemodialysis.
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13 MeSH Terms
Prolyl-4-hydroxylase 2 and 3 coregulate murine erythropoietin in brain pericytes.
Urrutia AA, Afzal A, Nelson J, Davidoff O, Gross KW, Haase VH
(2016) Blood 128: 2550-2560
MeSH Terms: Animals, Brain, Erythropoietin, Gene Expression Regulation, Hypoxia, Brain, Hypoxia-Inducible Factor-Proline Dioxygenases, Mice, Mice, Transgenic, Pericytes, Procollagen-Proline Dioxygenase, Transcription Factors, Transcription, Genetic
Show Abstract · Added September 30, 2016
A classic response to systemic hypoxia is the increased production of red blood cells due to hypoxia-inducible factor (HIF)-mediated induction of erythropoietin (EPO). EPO is a glycoprotein hormone that is essential for normal erythropoiesis and is predominantly synthesized by peritubular renal interstitial fibroblast-like cells, which express cellular markers characteristic of neuronal cells and pericytes. To investigate whether the ability to synthesize EPO is a general functional feature of pericytes, we used conditional gene targeting to examine the von Hippel-Lindau/prolyl-4-hydroxylase domain (PHD)/HIF axis in cell-expressing neural glial antigen 2, a known molecular marker of pericytes in multiple organs. We found that pericytes in the brain synthesized EPO in mice with genetic HIF activation and were capable of responding to systemic hypoxia with the induction of Epo. Using high-resolution multiplex in situ hybridization, we determined that brain pericytes represent an important cellular source of Epo in the hypoxic brain (up to 70% of all Epo-expressing cells). We furthermore determined that Epo transcription in brain pericytes was HIF-2 dependent and cocontrolled by PHD2 and PHD3, oxygen- and 2-oxoglutarate-dependent prolyl-4-hydroxylases that regulate HIF activity. In summary, our studies provide experimental evidence that pericytes in the brain have the ability to function as oxygen sensors and respond to hypoxia with EPO synthesis. Our findings furthermore suggest that the ability to synthesize EPO may represent a functional feature of pericytes in the brain and kidney.
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12 MeSH Terms
Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease.
Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH
(2016) Kidney Int 90: 1115-1122
MeSH Terms: Aged, Anemia, Double-Blind Method, Female, Glycine, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Male, Middle Aged, Outcome Assessment, Health Care, Picolinic Acids, Renal Insufficiency, Chronic
Show Abstract · Added September 22, 2016
Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD. The primary endpoint was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained either a mean hemoglobin level of 11.0 g/dl or more or a mean increase in hemoglobin of 1.2 g/dl or more over the predose average. Significantly, the primary endpoint was met in 54.9% of patients on vadadustat and 10.3% of patients on placebo. Significant increases in both reticulocytes and total iron-binding capacity and significant decreases in both serum hepcidin and ferritin levels were observed in patients on vadadustat compared with placebo. The overall incidence of adverse events was comparable between the 2 groups. Serious adverse events occurred in 23.9% and 15.3% of the vadadustat- and placebo-treated patients, respectively. Three deaths occurred in the vadadustat arm. Thus, this phase 2b study demonstrated that vadadustat raised and maintained hemoglobin levels in a predictable and controlled manner while enhancing iron mobilization in patients with nondialysis-dependent CKD.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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12 MeSH Terms
Association of FMO3 Variants and Trimethylamine N-Oxide Concentration, Disease Progression, and Mortality in CKD Patients.
Robinson-Cohen C, Newitt R, Shen DD, Rettie AE, Kestenbaum BR, Himmelfarb J, Yeung CK
(2016) PLoS One 11: e0161074
MeSH Terms: Biomarkers, Disease Progression, Female, Humans, Male, Methylamines, Middle Aged, Oxygenases, Polymorphism, Single Nucleotide, Prognosis, Prospective Studies, Renal Insufficiency, Chronic, Survival Rate
Show Abstract · Added September 19, 2017
Elevated levels of circulating pro-atherogenic uremic solutes, particularly trimethylamine N-oxide (TMAO), have been implicated in cardiovascular disease development in patients with chronic kidney disease (CKD). TMAO is generated from trimethylamine (TMA) via metabolism by hepatic flavin-containing monooxygenase isoform 3 (FMO3). We determined the functional effects of three common FMO3 variants at amino acids 158, 308, and 257 on TMAO concentrations in a prospective cohort study and evaluated associations of polymorphisms with CKD progression and mortality. Each additional minor allele at amino acid 158 was associated with a 0.38 μg/mL higher circulating TMAO (p = 0.01) and with faster rates of annualized relative eGFR decline. Participants with 0, 1 and 2 variant alleles averaged an eGFR loss of 8%, 12%, and 14% per year, respectively (p-for trend = 0.05). Compared to participants with the homozygous reference allele, heterozygous and homozygous variant participants had a 2.0-fold (95% CI: 0.85, 4.6) and 2.2-fold (95% CI: 0.89, 5.48) higher risk of mortality, respectively (p-for-trend = 0.04). No associations with clinical outcomes were observed for allelic variants at amino acids 257 or 308. Understanding the contribution of genetic variation of FMO3 to disease progression and all-cause mortality can guide recommendations for diet modification or pharmacotherapy in CKD patients at increased risk of adverse outcomes.
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13 MeSH Terms