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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
High Throughput Screening for Colorectal Cancer Specific Compounds.
Xie J, Wang C, Gore JC
(2016) Comb Chem High Throughput Screen 19: 180-8
MeSH Terms: Antineoplastic Agents, Apoptosis, Cardiac Glycosides, Cardiotonic Agents, Cell Line, Tumor, Cell Proliferation, Colorectal Neoplasms, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Glioma, High-Throughput Screening Assays, Humans, Hypolipidemic Agents, Structure-Activity Relationship
Show Abstract · Added February 6, 2016
The development of new anti-cancer therapeutic agents is necessary to improve antitumor efficacy and reduce toxicities. Here we report using a systematic anticancer drug screening approach we developed previously, to concurrently screen colon and glioma cancer cell lines for 2000 compounds with known bioactivity and 1920 compounds with unknown activity. The hits specific to each tumor cell line were then selected, and further tested with the same cells transfected with EGFP (Enhanced Green Fluorescent Protein) alone. By comparing the percentage of signal reduction from the same cells transfected with the sensor-conjugated reporter system; hits preferably causing apoptosis were identified. Among the known lead compounds, many cardiac glycosides used as cardiotonic drugs were found to effectively and specifically kill colon cancer cells, while statins (hypolipidemic agents) used as cholesterol lowering drugs were relatively more effective in killing glioma cells.
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14 MeSH Terms
Oxidative cyclizations in orthosomycin biosynthesis expand the known chemistry of an oxygenase superfamily.
McCulloch KM, McCranie EK, Smith JA, Sarwar M, Mathieu JL, Gitschlag BL, Du Y, Bachmann BO, Iverson TM
(2015) Proc Natl Acad Sci U S A 112: 11547-52
MeSH Terms: Aminoglycosides, Anti-Bacterial Agents, Catalytic Domain, Crystallography, X-Ray, Cyclization, Hydrogen, Hygromycin B, Metals, Micromonospora, Multigene Family, Oligosaccharides, Open Reading Frames, Oxidation-Reduction, Oxygen, Oxygenases, Phylogeny, Protein Binding, Protein Structure, Secondary, Reproducibility of Results, Streptomyces
Show Abstract · Added April 1, 2019
Orthosomycins are oligosaccharide antibiotics that include avilamycin, everninomicin, and hygromycin B and are hallmarked by a rigidifying interglycosidic spirocyclic ortho-δ-lactone (orthoester) linkage between at least one pair of carbohydrates. A subset of orthosomycins additionally contain a carbohydrate capped by a methylenedioxy bridge. The orthoester linkage is necessary for antibiotic activity but rarely observed in natural products. Orthoester linkage and methylenedioxy bridge biosynthesis require similar oxidative cyclizations adjacent to a sugar ring. We have identified a conserved group of nonheme iron, α-ketoglutarate-dependent oxygenases likely responsible for this chemistry. High-resolution crystal structures of the EvdO1 and EvdO2 oxygenases of everninomicin biosynthesis, the AviO1 oxygenase of avilamycin biosynthesis, and HygX of hygromycin B biosynthesis show how these enzymes accommodate large substrates, a challenge that requires a variation in metal coordination in HygX. Excitingly, the ternary complex of HygX with cosubstrate α-ketoglutarate and putative product hygromycin B identified an orientation of one glycosidic linkage of hygromycin B consistent with metal-catalyzed hydrogen atom abstraction from substrate. These structural results are complemented by gene disruption of the oxygenases evdO1 and evdMO1 from the everninomicin biosynthetic cluster, which demonstrate that functional oxygenase activity is critical for antibiotic production. Our data therefore support a role for these enzymes in the production of key features of the orthosomycin antibiotics.
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MeSH Terms
Nikkomycin Z is an effective inhibitor of the chytrid fungus linked to global amphibian declines.
Holden WM, Fites JS, Reinert LK, Rollins-Smith LA
(2014) Fungal Biol 118: 48-60
MeSH Terms: Aminoglycosides, Amphibians, Animals, Antifungal Agents, Cell Wall, Chytridiomycota
Show Abstract · Added May 20, 2014
Fungal infections in humans, wildlife, and plants are a growing concern because of their devastating effects on human and ecosystem health. In recent years, populations of many amphibian species have declined, and some have become extinct due to chytridiomycosis caused by the fungal pathogen Batrachochytrium dendrobatidis. For some endangered amphibian species, captive colonies are the best intermediate solution towards eventual reintroduction, and effective antifungal treatments are needed to cure chytridiomycosis and limit the spread of this pathogen in such survival assurance colonies. Currently, the best accepted treatment for infected amphibians is itraconazole, but its toxic side effects reduce its usefulness for many species. Safer antifungal treatments are needed for disease control. Here, we show that nikkomycin Z, a chitin synthase inhibitor, dramatically alters the cell wall stability of B. dendrobatidis cells and completely inhibits growth of B. dendrobatidis at 250 μM. Low doses of nikkomycin Z enhanced the effectiveness of natural antimicrobial skin peptide mixtures tested in vitro. These studies suggest that nikkomycin Z would be an effective treatment to significantly reduce the fungal burden in frogs infected by B. dendrobatidis.
Copyright © 2013 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.
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6 MeSH Terms
The invasive chytrid fungus of amphibians paralyzes lymphocyte responses.
Fites JS, Ramsey JP, Holden WM, Collier SP, Sutherland DM, Reinert LK, Gayek AS, Dermody TS, Aune TM, Oswald-Richter K, Rollins-Smith LA
(2013) Science 342: 366-9
MeSH Terms: Aminoglycosides, Amphibians, Animals, Apoptosis, Cell Proliferation, Chytridiomycota, Host-Pathogen Interactions, Lymphocytes, Mycoses, Spores, Fungal, Xenopus laevis
Show Abstract · Added March 7, 2014
The chytrid fungus, Batrachochytrium dendrobatidis, causes chytridiomycosis and is a major contributor to global amphibian declines. Although amphibians have robust immune defenses, clearance of this pathogen is impaired. Because inhibition of host immunity is a common survival strategy of pathogenic fungi, we hypothesized that B. dendrobatidis evades clearance by inhibiting immune functions. We found that B. dendrobatidis cells and supernatants impaired lymphocyte proliferation and induced apoptosis; however, fungal recognition and phagocytosis by macrophages and neutrophils was not impaired. Fungal inhibitory factors were resistant to heat, acid, and protease. Their production was absent in zoospores and reduced by nikkomycin Z, suggesting that they may be components of the cell wall. Evasion of host immunity may explain why this pathogen has devastated amphibian populations worldwide.
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11 MeSH Terms
The GABRG2 nonsense mutation, Q40X, associated with Dravet syndrome activated NMD and generated a truncated subunit that was partially rescued by aminoglycoside-induced stop codon read-through.
Huang X, Tian M, Hernandez CC, Hu N, Macdonald RL
(2012) Neurobiol Dis 48: 115-23
MeSH Terms: Aminoglycosides, Codon, Nonsense, Codon, Terminator, Epilepsies, Myoclonic, HEK293 Cells, Humans, Nonsense Mediated mRNA Decay, Protein Subunits, Receptors, GABA-A
Show Abstract · Added January 24, 2015
The GABRG2 nonsense mutation, Q40X, is associated with the severe epilepsy syndrome, Dravet syndrome, and is predicted to generate a premature translation-termination codon (PTC) in the GABA(A) receptor γ2 subunit mRNA in a position that codes for the first amino acid of the mutant subunit. We determined the effects of the mutation on γ2 subunit mRNA and protein synthesis and degradation, as well as on α1β2γ2 GABA(A) receptor assembly, trafficking and surface expression in HEK cells. Using bacterial artificial chromosome (BAC) constructs, we found that γ2(Q40X) subunit mRNA was degraded by nonsense mediated mRNA decay (NMD). Undegraded mutant mRNA was translated to a truncated peptide, likely the signal peptide, which was cleaved further. We also found that mutant γ2(Q40X) subunits did not assemble into functional receptors, thus decreasing GABA-evoked current amplitudes. The GABRG2(Q40X) mutation is one of several epilepsy-associated nonsense mutations that have the potential to be rescued by reading through the PTC, thus restoring full-length protein translation. As a first approach, we investigated the use of the aminoglycoside, gentamicin, to rescue translation of intact mutant subunits by inducing mRNA read-through. In the presence of gentamicin, synthesis of full length γ2 subunits was partially restored, and surface biotinylation and whole cell recording experiments suggested that rescued γ2 subunits could corporate into functional, surface GABA(A) receptors, indicating a possible direction for future therapy.
Copyright © 2012 Elsevier Inc. All rights reserved.
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9 MeSH Terms
Acute kidney injury after placement of an antibiotic-impregnated cement spacer during revision total knee arthroplasty.
Menge TJ, Koethe JR, Jenkins CA, Wright PW, Shinar AA, Miller GG, Holt GE
(2012) J Arthroplasty 27: 1221-7.e1-2
MeSH Terms: Acute Kidney Injury, Aged, Aminoglycosides, Anti-Bacterial Agents, Arthroplasty, Replacement, Knee, Bone Cements, Cohort Studies, Creatinine, Female, Humans, Incidence, Kidney, Knee Prosthesis, Male, Middle Aged, Prosthesis-Related Infections, Reoperation, Retrospective Studies, Tobramycin
Show Abstract · Added May 27, 2014
We performed a retrospective cohort study of 84 patients to determine the incidence and predictors of acute kidney injury after antibiotic-impregnated cement spacer (ACS) placement for infected total knee arthroplasties. Acute kidney injury was defined as a more than 50% rise in serum creatinine from a preoperative baseline to a level greater than 1.4 mg/dL within 90 days postoperatively. Total incidence was 17% (n = 14; 95% confidence interval [CI], 10%-26%), and acute kidney injury was significantly associated with ACS tobramycin dose as both a dichotomous variable (>4.8 g; odds ratio, 5.87; 95% CI, 1.43-24.19; P = .01) and linear variable (odds ratio, 1.24 for every 1-g increase; 95% CI, 1.00-1.52; P = .049). Routine monitoring of serum creatinine and measurement of serum aminoglycoside levels in response to a threshold creatinine rise may be warranted after the placement of an aminoglycoside-containing ACS.
Copyright © 2012 Elsevier Inc. All rights reserved.
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19 MeSH Terms
Adopting real-time surveillance dashboards as a component of an enterprisewide medication safety strategy.
Waitman LR, Phillips IE, McCoy AB, Danciu I, Halpenny RM, Nelsen CL, Johnson DC, Starmer JM, Peterson JF
(2011) Jt Comm J Qual Patient Saf 37: 326-32
MeSH Terms: Aminoglycosides, Anticoagulants, Communication, Decision Support Systems, Clinical, Humans, Medical Records Systems, Computerized, Medication Errors, Pharmacy Service, Hospital, Safety Management
Show Abstract · Added May 19, 2014
BACKGROUND - High-alert medications are frequently responsible for adverse drug events and present significant hazards to inpatients, despite technical improvements in the way they are ordered, dispensed, and administered.
METHODS - A real-time surveillance application was designed and implemented to enable pharmacy review of high-alert medication orders to complement existing computerized provider order entry and integrated clinical decision support systems in a tertiary care hospital. The surveillance tool integrated real-time data from multiple clinical systems and applied logical criteria to highlight potentially high-risk scenarios. Use of the surveillance system for adult inpatients was analyzed for warfarin, heparin and enoxaparin, and aminoglycoside antibiotics.
RESULTS - Among 28,929 hospitalizations during the study period, patients eligible to appear on a dashboard included 2224 exposed to warfarin, 8383 to heparin or enoxaparin, and 893 to aminoglycosides. Clinical pharmacists reviewed the warfarin and aminoglycoside dashboards during 100% of the days in the study period-and the heparinlenoxaparin dashboard during 71% of the days. Displayed alert conditions ranged from common events, such as 55% of patients receiving aminoglycosides were missing a baseline creatinine, to rare events, such as 0.1% of patients exposed to heparin were given a bolus greater than 10,000 units. On the basis of interpharmacist communication and electronic medical record notes recorded within the dashboards, interventions to prevent further patient harm were frequent.
CONCLUSIONS - Even in an environment with sophisticated computerized provider order entry and clinical decision support systems, real-time pharmacy surveillance of high-alert medications provides an important platform for intercepting medication errors and optimizing therapy.
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9 MeSH Terms
Assignment and stereocontrol of hibarimicin atropoisomers.
Romaine IM, Hempel JE, Shanmugam G, Hori H, Igarashi Y, Polavarapu PL, Sulikowski GA
(2011) Org Lett 13: 4538-41
MeSH Terms: Glycosides, Molecular Conformation, Naphthacenes, Stereoisomerism
Show Abstract · Added September 16, 2013
A stereochemical feature of the hibarimicins is a central biaryl (HMP-Y6) or aryl-quinone (hibarimicinone) incorporated as a single atropodiastereomer. Herein, a chiral resolution and deracemization process to access optically enriched biaryls aR-3 and aS-3 is described. From these atropoenantiomers the BCD-EFG ring system of HMP-Y6 is constructed [(+)-aR-7]. Comparison of CD spectra of aR-7 to HMP-Y6 leads to the assignment of HMP-Y6 and hibarimicin B atropoisomers as aR and aS, respectively.
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4 MeSH Terms
Transcripts from a novel BMPR2 termination mutation escape nonsense mediated decay by downstream translation re-initiation: implications for treating pulmonary hypertension.
Hamid R, Hedges LK, Austin E, Phillips JA, Loyd JE, Cogan JD
(2010) Clin Genet 77: 280-6
MeSH Terms: Aminoglycosides, Bone Morphogenetic Protein Receptors, Type II, Codon, Nonsense, Female, Humans, Hypertension, Pulmonary, Lymphocytes, Male, Mutation, Pedigree
Show Abstract · Added March 5, 2014
Bone morphogenetic protein receptor type 2 (BMPR2) gene mutations are a major risk factor for heritable pulmonary arterial hypertension (HPAH), an autosomal dominant fatal disease. We have previously shown that BMPR2 transcripts that contain premature termination codon (PTC) mutations are rapidly and nearly completely degraded through nonsense mediated decay (NMD). Here we report a unique PTC mutation (W13X) that did not behave in the predicted manner. We found that patient-derived cultured lymphocytes (CLs) contained readily detectable levels of the PTC-containing transcript. Further analysis suggested that this transcript escaped NMD by translational re-initiation at a downstream Kozak sequence, resulting in the omission of 173 amino acids. Treatment of CLs containing the PTC with an aminoglycoside decreased the truncated protein levels, with a reciprocal increase in full-length BMPR2 protein and, importantly, BMPR-II signaling. This is the first demonstration of aminoglycoside-mediated 'repair' of a BMPR2 mutation at the protein level in patient-derived cells and has obvious implications for treatment of HPAH where no disease-specific treatment options are available. Our data also suggest the need for a more thorough characterization of mutations prior to labeling them as haploinsufficient or dominant negative based simply on sequencing data.
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10 MeSH Terms