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1.
Appl Microbiol Biotechnol ; 102(1): 297-304, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29098413

ABSTRACT

Aurovertins are the structurally diverse polyketides that distribute widely in different fungal species. They feature a 2,6-dioxabicyclo[3.2.1]-octane ring in structure and exhibit the potential antitumor activity against breast cancer as F1-ATPase ß subunit inhibitor. In this study, we constructed the biosynthetic pathway of aurovertin in an Aspergillus nidulans host and obtained seven aurovertin-type compounds. Surprisingly, three new aurovertin geometric isomers were characterized. By introducing an inducible promoter xylP(p) in the pathway gene acyltransferase aurG, we can control the product ratios among different aurovertin compounds by adding glucose and/or inducer xylose. The yields of aurovertins could be increased up to about 20 times by adding a constitutive promoter gpdA(p) to transcription factor AurF, which indicates AurF's positive role in the biosynthesis of aurovertin. Taken together, our results provided not only an efficient way to generate bioactive fungal natural products but also realized the rational controlling their yields with designed promoters.


Subject(s)
Aspergillus nidulans/metabolism , Aurovertins/metabolism , Biosynthetic Pathways/genetics , Acyltransferases/genetics , Aspergillus nidulans/drug effects , Aspergillus nidulans/enzymology , Aspergillus nidulans/genetics , Aurovertins/analysis , Aurovertins/chemistry , Aurovertins/isolation & purification , Binding Sites , Biological Products/metabolism , Biosynthetic Pathways/physiology , Glucose/pharmacology , Kinetics , Promoter Regions, Genetic , Xylose/pharmacology
2.
Org Lett ; 18(6): 1366-9, 2016 Mar 18.
Article in English | MEDLINE | ID: mdl-26954888

ABSTRACT

Citreoviridin (1) belongs to a class of F1-ATPase ß-subunit inhibitors that are synthesized by highly reducing polyketide synthases. These potent mycotoxins share an α-pyrone polyene structure, and they include aurovertin, verrucosidin, and asteltoxin. The identification of the citreoviridin biosynthetic gene cluster in Aspergillus terreus var. aureus and its reconstitution using heterologous expression in Aspergillus nidulans are reported. Two intermediates were isolated that allowed the proposal of the biosynthetic pathway of citreoviridin.


Subject(s)
Aspergillus nidulans/chemistry , Aurovertins/chemistry , Mycotoxins/chemistry , Polyketide Synthases/metabolism , Pyrones/chemistry , Aspergillus nidulans/genetics , Aurovertins/isolation & purification , Aurovertins/pharmacology , Biosynthetic Pathways , Molecular Structure , Multigene Family , Mycotoxins/isolation & purification , Mycotoxins/pharmacology , Polyketides/metabolism , Pyrones/isolation & purification , Pyrones/pharmacology
3.
Chem Biodivers ; 13(2): 253-9, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26880440

ABSTRACT

A comparative metabolomic study of a marine derived fungus (Aspergillus terreus) grown under various culture conditions is presented. The fungus was grown in eleven different culture conditions using solid agar, broth cultures, or grain based media (OSMAC). Multivariate analysis of LC/MS data from the organic extracts revealed drastic differences in the metabolic profiles and guided our subsequent isolation efforts. The compound 7-desmethylcitreoviridin was isolated and identified, and is fully described for the first time. In addition, 16 known fungal metabolites were also isolated and identified. All compounds were elucidated by detailed spectroscopic analysis and tested for antibacterial activities against five human pathogens and tested for cytotoxicity. This study demonstrates that LC/MS based multivariate analysis provides a simple yet powerful tool to analyze the metabolome of a single fungal strain grown under various conditions. This approach allows environmentally-induced changes in metabolite expression to be rapidly visualized, and uses these differences to guide the discovery of new bioactive molecules.


Subject(s)
Anti-Bacterial Agents/chemistry , Aspergillus/chemistry , Biological Products/chemistry , Bioprospecting , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Aspergillus/growth & development , Aurovertins/chemistry , Aurovertins/isolation & purification , Aurovertins/pharmacology , Bacteria/drug effects , Bacterial Infections/drug therapy , Biological Products/isolation & purification , Biological Products/pharmacology , Chromatography, Liquid , Humans , Mass Spectrometry , Mycotoxins/chemistry , Mycotoxins/isolation & purification , Mycotoxins/pharmacology
4.
PLoS One ; 10(4): e0121987, 2015.
Article in English | MEDLINE | ID: mdl-25853891

ABSTRACT

A set of isolates very similar to or potentially conspecific with an unidentified Penicillium isolate NRRL 735, was assembled using a BLAST search of ITS similarity among described (GenBank) and undescribed Penicillium isolates in our laboratories. DNA was amplified from six loci of the assembled isolates and sequenced. Two species in section Cinnamopurpurea are self-compatible sexual species, but the asexual species had polymorphic loci suggestive of sexual reproduction and variation in conidium size suggestive of ploidy level differences typical of heterothallism. Accordingly we use genealogical concordance analysis, a technique valid only in heterothallic organisms, for putatively asexual species. Seven new species were revealed in the analysis and are described here. Extrolite analysis showed that two of the new species, P. colei and P. monsserratidens produce the mycotoxin citreoviridin that has demonstrated pharmacological activity against human lung tumors. These isolates could provide leads in pharmaceutical research.


Subject(s)
Aurovertins/pharmacology , DNA, Fungal/isolation & purification , Mycotoxins/pharmacology , Penicillium/genetics , Aurovertins/isolation & purification , Cell Line, Tumor , DNA, Fungal/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mycotoxins/isolation & purification , Penicillium/chemistry , Penicillium/isolation & purification , Phylogeny , Sequence Analysis, DNA , Species Specificity
5.
Article in English | MEDLINE | ID: mdl-25190053

ABSTRACT

The mycotoxin citreoviridin has been associated with the 'yellow rice' disease, which caused cardiac beriberi in Japan. In Brazil, the consumption of contaminated rice was suspected to be involved in a recent beriberi outbreak. In this work, citreoviridin was produced by Penicillium citreonigrum, cultivated in 500 ml yeast extract sucrose (YES) liquid medium for 8 days at 25ºC, and the toxin extracted with chloroform from the liquid medium and the mycelium. A total of 15.3 g of crude extract was obtained from 48 culture flasks, with an estimated citreoviridin contend of 5.54 g, 74.3% being present in the mycelia. Semi-preparative HPLC of the crude extract yielded 27.1% citreoviridin. The HPLC-purified citreoviridin fraction was fully characterised by UV/VIS, FT-IR, (1)H- and (13)C-NMR, LC-MS/MS and LC-MSD TOF, and purity confirmed by gravimetric analysis. Isocitreoviridin was also produced by P. citreonigrum, accounting for about 10% of the citreoviridin present in the crude extract, most transformed into citreoviridin after 10 months under freezing conditions protected from light. Citreoviridin was shown to be stable under the same conditions, although it can suffer isomerisation after a longer storage period. Isomerisation is a potential source of variability in toxicological studies and purity of the material should be checked before study initiation.


Subject(s)
Aurovertins/isolation & purification , Culture Media/chemistry , Penicillium/metabolism , Sucrose/chemistry , Chromatography, High Pressure Liquid , Food Analysis , Food Contamination/analysis , Food Microbiology , Magnetic Resonance Spectroscopy , Oryza/microbiology , Tandem Mass Spectrometry
6.
Org Lett ; 15(5): 1020-3, 2013 Mar 01.
Article in English | MEDLINE | ID: mdl-23405967

ABSTRACT

Novel polyketides, citreoviripyrone A (1) and B (2), known citreomontanin (3), and (-)-citreoviridin (4) were isolated from the mycelium of the endophytic fungus. The endophytic fungus, which belongs to the genus Penicillium, was separated from surface-sterilized healthy leaves of Catharanthus roseus. The structures of 1 and 2 were determined on the basis of NMR data, and 1 was characterized as an α-pyrone polyketide featuring bicyclo[4.2.0]octadiene. The biomimetic synthesis of 1 and 2 from 3 elucidated a plausible biosynthetic pathway. Both Zn(II)-type and NAD(+)-dependent histone deacetylase inhibitors significantly enhanced the production of 1 and 3.


Subject(s)
Catharanthus/microbiology , Penicillium/chemistry , Polyketides/chemical synthesis , Aurovertins/chemistry , Aurovertins/isolation & purification , Histone Deacetylase Inhibitors/pharmacology , Mesna/pharmacology , Molecular Structure , NAD/pharmacology , Nuclear Magnetic Resonance, Biomolecular , Plant Leaves/microbiology , Polyketides/chemistry , Pyrones/chemistry , Pyrones/isolation & purification
7.
J Nat Prod ; 71(2): 278-80, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18211004

ABSTRACT

Analysis of fermentation broth of the entomopathogenic fungus Metarhizium anisopliae has led to isolation of aurovertin D ( 1) and three new aurovertin-type metabolites, aurovertin F ( 2), aurovertin G ( 3), and aurovertin H ( 4). Their structures were determined on the basis of spectroscopic analyses and chemical conversions.


Subject(s)
Aurovertins/isolation & purification , Metarhizium/chemistry , Aurovertins/chemistry , Aurovertins/pharmacology , Japan , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Stereoisomerism
8.
J Antibiot (Tokyo) ; 58(6): 412-5, 2005 Jun.
Article in English | MEDLINE | ID: mdl-16156519

ABSTRACT

A new polyene pyrone, aurovertin E (2), was isolated along with aurovertin B (1) from the culture mycelia of the basidiomycete Albatrellus confluens. Their structures were elucidated on the basis of spectroscopic studies including 2D NMR experiments. This is the first example of the occurrence of aurovertins in basidiomycetes.


Subject(s)
Aurovertins/metabolism , Aurovertins/isolation & purification , Aurovertins/pharmacology , Basidiomycota/metabolism , Chemical Phenomena , Chemistry, Physical , Culture Media , Enzyme Inhibitors/pharmacology , Fermentation , Magnetic Resonance Spectroscopy , Proton-Translocating ATPases/antagonists & inhibitors , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet
9.
J Bioenerg Biomembr ; 15(2): 81-91, 1983 Apr.
Article in English | MEDLINE | ID: mdl-18251098

ABSTRACT

The purity of aurovertins A, B, and D, which inhibit the mitochondrial ATPase and show fluorescence enhancement when bound, has been determined by high-resolution proton nuclear magnetic resonance. This technique demonstrated that solvent molecules, especially water, are tightly bound to crystalline aurovertins B and D. The molar absorption coefficient for aurovertins A, B, and D at the longest wavelength maximum (367.5-369 nm) has been determined to be 38,500 liter x mol(-1) x cm(-1). This correct molar absorption coefficient should enable correct binding stoichiometries for aurovertin to ATPases to be determined.


Subject(s)
Aurovertins/metabolism , Mitochondrial Proton-Translocating ATPases/metabolism , Ascomycota/metabolism , Aurovertins/isolation & purification , Aurovertins/pharmacology , Binding Sites , Fluorescence , Kinetics , Magnetic Resonance Spectroscopy , Mitochondrial Proton-Translocating ATPases/antagonists & inhibitors , Solvents , Spectrophotometry, Ultraviolet
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