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1.
Int J Mol Sci ; 24(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36674833

RESUMO

Hispidin is a polyketide found in plants and fungi. In bioluminescent fungi, hispidin serves as a precursor of luciferin and is produced by hispidin synthases. Previous studies revealed that hispidin synthases differ in orthologous polyketide synthases from non-bioluminescent fungi by the absence of two domains with predicted ketoreductase and dehydratase activities. Here, we investigated the hypothesis that the loss of these domains in evolution led to the production of hispidin and the emergence of bioluminescence. We cloned three orthologous polyketide synthases from non-bioluminescent fungi, as well as their truncated variants, and assessed their ability to produce hispidin in a bioluminescence assay in yeast. Interestingly, expression of the full-length enzyme hsPKS resulted in dim luminescence, indicating that small amounts of hispidin are likely being produced as side products of the main reaction. Deletion of the ketoreductase and dehydratase domains resulted in no luminescence. Thus, domain truncation by itself does not appear to be a sufficient step for the emergence of efficient hispidin synthases from orthologous polyketide synthases. At the same time, the production of small amounts of hispidin or related compounds by full-length enzymes suggests that ancestral fungal species were well-positioned for the evolution of bioluminescence.


Assuntos
Policetídeo Sintases , Pironas , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Óxido Nítrico Sintase/metabolismo , Fungos/genética , Fungos/metabolismo , Hidroliases/metabolismo
2.
Mar Drugs ; 20(12)2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36547925

RESUMO

Three new dibenzo-α-pyrone derivatives, alternolides A-C (1-3), and seven known congeners (4-10) were isolated from the marine-derived fungus of Alternaria alternata LW37 assisted by the one strain-many compounds (OSMAC) strategy. The structures of 1-3 were established by extensive spectroscopic analyses, and their absolute configurations were determined by modified Snatzke's method and electronic circular dichroism (ECD) calculations. Compounds 6 and 7 showed good 1,1-diphenyl-2-picrylhydrazyl (DPPH) antioxidant scavenging activities with IC50 values of 83.94 ± 4.14 and 23.60 ± 1.23 µM, respectively. Additionally, 2, 3 and 7 exhibited inhibitory effects against α-glucosidase with IC50 values of 725.85 ± 4.75, 451.25 ± 6.95 and 6.27 ± 0.68 µM, respectively. The enzyme kinetics study indicated 2 and 3 were mixed-type inhibitors of α-glucosidase with Ki values of 347.0 and 108.5 µM, respectively. Furthermore, the interactions of 2, 3 and 7 with α-glucosidase were investigated by molecular docking.


Assuntos
Pironas , alfa-Glucosidases , alfa-Glucosidases/metabolismo , Pironas/farmacologia , Simulação de Acoplamento Molecular , Alternaria/química , Antioxidantes/química , Estrutura Molecular , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química
3.
Molecules ; 27(24)2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36558129

RESUMO

A straightforward approach for the construction of the new class of conjugated pyrans based on enamination of 2-methyl-4-pyrones with DMF-DMA was developed. 2-(2-(Dimethylamino)vinyl)-4-pyrones are highly reactive substrates that undergo 1,6-conjugate addition/elimination or 1,3-dipolar cycloaddition/elimination followed by substitution of the dimethylamino group without ring opening. This strategy includes selective transformations leading to conjugated and isoxazolyl-substituted 4-pyrone structures. The photophysical properties of the prepared 4-pyrones were determined in view of further design of novel merocyanine fluorophores. A solvatochromism was found for enamino-substituted 4-pyrones accompanied by a strong increase in fluorescence intensity in alcohols. The prepared conjugated structures demonstrated valuable photophysical properties, such as a large Stokes shift (up to 204 nm) and a good quantum yield (up to 28%).


Assuntos
Piranos , Pironas , Piranos/química , Pironas/química
4.
Molecules ; 27(23)2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36500237

RESUMO

Molecular docking, molecular dynamics (MD) simulations and the linear interaction energy (LIE) method were used here to predict binding modes and free energy for a set of 1,2,3-triazole-based KA analogs as potent inhibitors of Tyrosinase (TYR), a key metalloenzyme of the melanogenesis process. Initially, molecular docking calculations satisfactorily predicted the binding mode of evaluated KA analogs, where the KA part overlays the crystal conformation of the KA inhibitor into the catalytic site of TYR. The MD simulations were followed by the LIE method, which reproduced the experimental binding free energies for KA analogs with an r2 equal to 0.97, suggesting the robustness of our theoretical model. Moreover, the van der Waals contributions performed by some residues such as Phe197, Pro201, Arg209, Met215 and Val218 are responsible for the binding recognition of 1,2,3-triazole-based KA analogs in TYR catalytic site. Finally, our calculations provide suitable validation of the combination of molecular docking, MD, and LIE approaches as a powerful tool in the structure-based drug design of new and potent TYR inhibitors.


Assuntos
Simulação de Dinâmica Molecular , Triazóis , Simulação de Acoplamento Molecular , Triazóis/farmacologia , Pironas/farmacologia , Pironas/química , Monofenol Mono-Oxigenase , Ligação Proteica
5.
Eur J Med Chem ; 244: 114866, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36368255

RESUMO

Lipids-lowering is considered as the most effective approach to decrease the risk of Atherosclerotic cardiovascular disease (ASCVD), of which atherosclerosis is the most common cause. Natural products containing a unique type of α-pyrone was reported to suppress atherosclerosis in which α-pyrone might be considered as an important pharmacore. In this study, an efficient one-pot intramolecular C-H activation strategy was applied to the synthesis of potentially bioactive α-pyrone derivatives. As the result, three different scaffolds were quickly and conveniently generated, including thiophenes, pyrrole and indole derivatives. Among of them, eight α-pyrone derivatives showed potential effects to promote the uptake of LDL in HepG2 cells. Active unique α-pyrones compounds exhibiting potent in vitro and in vivo lipids-lowering effects, and a novel mechanism associated with the regulation of LXR-IDOL-LDLR axis, the new pathway targeted pharmacologically to control plasma cholesterol levels, were disclosed firstly in this study.


Assuntos
Aterosclerose , Receptores de LDL , Humanos , Receptores de LDL/metabolismo , Receptores Nucleares Órfãos/metabolismo , Receptores X do Fígado/metabolismo , Pironas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Fígado/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Lipídeos
6.
J Nat Prod ; 85(11): 2603-2609, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36327116

RESUMO

The secondary metabolite pseudopyronine B, isolated from Pseudomonas mosselii P33, was biotransformed by human P450 enzymes, heterologously expressed in the fission yeast Schizosaccharomyces pombe. Small-scale studies confirmed that both CYP4F2 and CYP4F3A were capable of oxidizing the substrate, with the former achieving a higher yield. In larger-scale studies using CYP4F2, three new oxidation products were obtained, the structures of which were elucidated by UV-vis, 1D and 2D NMR, and HR-MS spectroscopy. These corresponded to hydroxylated, carboxylated, and ester derivatives (1-3) of pseudopyronine B, all of which had been oxidized exclusively at the ω-position of the C-6 alkyl chain. In silico homology modeling experiments highlighted key interactions between oxygen atoms of the pyrone ring and two serine residues and a histidine residue of CYP4F2, which hold the substrate in a suitable orientation for oxidation at the terminus of the C-6 alkyl chain. Additional modeling studies with all three pseudopyronines revealed that the seven-carbon alkyl chain of pseudopyronine B was the perfect length for oxidation, with the terminal carbon lying close to the heme iron. The antibacterial activity of the substrates and three oxidation products was also assessed, revealing that oxidation at the ω-position removes all antimicrobial activity. This study both increases the range of known substrates for human CYF4F2 and CYP4F3A enzymes and demonstrates their utility in producing additional natural product derivatives.


Assuntos
Antibacterianos , Sistema Enzimático do Citocromo P-450 , Pironas , Humanos , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Biotransformação , Sistema Enzimático do Citocromo P-450/metabolismo , Família 4 do Citocromo P450/metabolismo , Hidroxilação , Oxirredução , Pironas/química , Pironas/metabolismo , Pironas/farmacologia , Schizosaccharomyces/enzimologia
7.
ACS Chem Biol ; 17(11): 3169-3177, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36255735

RESUMO

Thermorubin is a tetracyclic naphthoisocoumarin natural product that demands investigation due to its novel mechanism of bacterial protein synthesis inhibition and its unusual structural features. In this work, we describe the identification of the biosynthetic cluster responsible for thermorubin from the sequenced Laceyella sacchari producer species and its confirmation via heterologous production in Escherichia coli. Based on an in-depth annotation of the cluster, we propose a biosynthetic pathway that accounts for the formation of the unique, nonterminal pyrone. Additionally, the expression and use of salicylate synthase TheO enabled testing of the stability properties of this extremophile-derived enzyme. TheO displayed rapid kinetics and a remarkably robust secondary structure, converting chorismate to salicylate with a KM of 109 ± 12 µM, kcat of 9.17 ± 0.36 min-1, and catalytic efficiency (kcat/KM) of 84 ± 9 nM-1 min-1, and retained significant activity up to 50 °C. These studies serve as the basis for continued biosynthetic investigations and bioinspired synthetic approaches.


Assuntos
Pironas , Salicilatos , Pironas/metabolismo , Salicilatos/metabolismo , Fenóis/metabolismo , Escherichia coli/metabolismo
8.
Mar Drugs ; 20(10)2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36286413

RESUMO

Six new pairs of γ-pyrone polypropionate enantiomers with an unusual peroxyl bridge at the side chain, namely (±)-ocellatuperoxides A-F (1-6), were isolated and characterized from the South China Sea photosynthetic mollusk Placobranchus ocellatus. Extensive spectroscopic analysis, single crystal X-ray diffraction analysis, ECD- (electronic circular dichroism) comparison, and TDDFT (time-dependent density functional theory) ECD computation were used to determine the structures and absolute configurations of new compounds. In a cell viability assay, several compounds showed considerable anti-tumoral effects on human non-small cell lung cancer cells A549 with Gefitinib (7.4 µM) and Erlotinib (2.1 µM) as positive controls. Further RNA-sequencing analysis and gene expression evaluation indicated that the anti-tumoral activity of the most effective compound 3 was associated with the regulation of several important genes, such as FGFR1 and HDAC5.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Humanos , Pironas/química , Estrutura Molecular , Peróxidos , Cloridrato de Erlotinib , Gefitinibe , Moluscos/química , Dicroísmo Circular , RNA
9.
Toxins (Basel) ; 14(10)2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36287930

RESUMO

Ustilaginoidins are a class of bis-naphtho-γ-pyrone mycotoxins produced by the pathogen Villosiclava virens of rice false smut, which has recently become one of the most devastating diseases in rice-growing regions worldwide. In this research, the nanobody phage display library was established after an alpaca was immunized with the hemiustilaginoidin F-hapten coupled with bovine serum albumin (BSA). Heterologous antigen selection and combing trypsin with competition alternant elution methods were performed for nanobody screening. Two nanobodies, namely, Nb-B15 and Nb-C21, were selected for the establishment of indirect competitive enzyme-linked immunosorbent assays (ic-ELISAs). For Nb-B15 and Nb-C21, their IC50 values were 11.86 µg/mL and 11.22 µg/mL, and the detection ranges were at 3.41-19.98 µg/mL and 1.17-32.13 µg/mL, respectively. Two nanobodies had a broad spectrum to quantify the contents of total ustilaginoidins in rice samples according to cross-reactivity. The recognition mechanisms of Nb-B15 and Nb-C21 against ustilaginoidin A were elucidated by molecular modeling and docking. The key amino acid sites for the binding of Nb-B15 or Nb-C21 to ustilaginoidin A were mainly located in the FR1 and CDR1 regions. As Nb-B15 was superior to Nb-C21 in the aspects of protein expression, ELISA titer, and tolerance to organic solvents, it was selected for application in the detection of actual contaminated rice samples. The total ustilaginoidin contents of rice samples were analyzed by Nb-B15-based ic-ELISA and HPLC-DAD, between which the results were found to be consistent. The developed immunoassay based on the nanobody from the alpaca can be employed as a rapid and effective method for detection of total utilaginoidins in contaminated rice samples.


Assuntos
Camelídeos Americanos , Micotoxinas , Oryza , Anticorpos de Domínio Único , Animais , Oryza/química , Pironas , Soroalbumina Bovina , Tripsina , Micotoxinas/análise , Imunoensaio , Ensaio de Imunoadsorção Enzimática/métodos , Solventes , Haptenos , Aminoácidos , Antígenos Heterófilos
10.
Molecules ; 27(19)2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36234916

RESUMO

New resveratrol-thiophene and resveratrol-maltol hybrids were synthesized as cholinesterase inhibitors and antioxidants. As with photostability experiments, biological tests also found remarkable differences in the properties and behavior of thiophene and maltol hybrids. While resveratrol-thiophene hybrids have excellent inhibitory and antioxidant properties (similar to the activity of reference drug galantamine), maltols have been proven to be weaker inhibitors and antioxidants. The molecular docking of selected active ligands gave insight into the structures of docked enzymes. It enabled the identification of interactions between the ligand and the active site of both cholinesterases. The maltols that proved to be active cholinesterase inhibitors were able to coordinate Fe3+ ion, forming complexes of 1:1 composition. Their formation constants, determined by spectrophotometry, are very similar, lgK = 11.6-12.6, suggesting that Fe3+ binds to the common hydroxy-pyranone moiety and is hardly affected by the other aromatic part of the ligand. Accordingly, the characteristic bands in their individual absorption spectra are uniformly red-shifted relative to those of the free ligands. The crystal structures of two new resveratrol-maltol hybrids were recorded, giving additional information on the molecules' intermolecular hydrogen bonds and packing. In this way, several functionalities of these new resveratrol hybrids were examined as a necessary approach to finding more effective drugs for complicated neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Oligoelementos , Doença de Alzheimer/metabolismo , Antioxidantes/química , Antioxidantes/farmacologia , Quelantes/química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Colinesterases/metabolismo , Galantamina , Humanos , Ligantes , Simulação de Acoplamento Molecular , Pironas , Resveratrol , Relação Estrutura-Atividade , Tiofenos
11.
Planta ; 256(5): 99, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36222913

RESUMO

MAIN CONCLUSION: Using virus-induced gene silencing, we demonstrated that the enzymes GES, ISY, and MLPL are responsible for nepetalactone biosynthesis in Nepeta cataria. Nepetalactone is the main iridoid that is found in the Nepeta genus and is well-known for its psychoactive effect on house cats. Moreover, there is a burgeoning interest into the effect of nepetalactone on insects. Although the enzymes for nepetalactone biosynthesis have been biochemically assayed in vitro, validation of the role that these enzymes have in planta has not been demonstrated. Virus-induced gene silencing (VIGS) is a silencing method that relies on transient transformation and is an approach that has been particularly successful when applied to a variety of non-model plants. Here, we use a recently designed visual-marker dependent VIGS system to demonstrate that the nepetalactone biosynthetic enzymes GES, ISY, and MLPL impact nepetalactone biosynthesis in Nepeta cataria.


Assuntos
Nepeta , Monoterpenos Ciclopentânicos , Iridoides , Nepeta/química , Nepeta/genética , Pironas/química , Pironas/farmacologia
12.
Fitoterapia ; 163: 105324, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36216139

RESUMO

Cytospones E-J (1-6), six unreported α-pyrone derivatives, together with six known ones (7-12) were isolated from the solid culture of the endophytic fungus Cytospora rhizophorae A761, an endophytic fungus from Gynochthodes officinalis. The structures of the unreported compounds were unambiguously elucidated through spectroscopic analyses (1D, 2D NMR and HRESIMS), and their absolute configurations were assigned by single-crystal X-ray diffraction (Cu Kα) analyses. Furthermore, cytospones E-J were evaluated for anti-inflammatory and α-glucosidase inhibitory activities.


Assuntos
Ascomicetos , Estrutura Molecular , Ascomicetos/química , Cristalografia por Raios X , Pironas
13.
Chem Biodivers ; 19(11): e202200682, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36208125

RESUMO

A novel styrylpyrone derivative, named phelliribsin B (1), as well as four biogenetically related known compounds, phellifuropyranone A (2), inoscavin C (3), inoscavin A (4), and inoscavin D (5) were separated and purified from the medicinal fungus Phellinus ribis. The structure of phelliribsin B was determined by spectroscopic analysis, and the absolute configuration was assigned by experimental and calculated ECD data. Additionally, the plausible biosynthetic pathway of 1 was also proposed. Compound 1 showed moderately cytotoxic activity against HepG2 and SKOV-3 tumor cell lines with IC50 values of 32.71 and 57.89 µM, respectively. Based on the results of cytotoxicity against HepG2 tumor cells, the structure-activity relationship of compounds 1-4 with similar skeletons was discussed. The styrylpyrone derivatives with similar skeletons have moderately cytotoxic activity and have the potential to play an important role in the anti-tumor treatment.


Assuntos
Phellinus , Pironas , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Fungos/química , Estrutura Molecular , Phellinus/química , Relação Estrutura-Atividade , Pironas/química , Pironas/farmacologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-36078255

RESUMO

Soybean plants are highly susceptible to Fusarium species, which significantly reduce soybean production and quality. Several Fusarium species have been reported to synthesize mycotoxins, such as trichothecene, which have been related to major human diseases. In November 2021, soybean pods in Nantong municipality, China, showed black necrotic lesions during the harvest stage. The disease incidence reached 69%. The pathogen was identified as Fusarium sulawense via morphological analysis and sequencing of ITS, EF1-α and RPB2 genes. A PCR assay with primers targeting the trichothecene biosynthesis genes suggested that the three isolates could synthesize trichothecenes. The effectiveness of fungicide carbendazim and natural metabolites dipicolinic acid and kojic acid was screened for the management of F. sulawense on postharvest soybean pods. The highest efficacy was obtained when combining 3.8 mg/mL carbendazim and 0.84 mg/mL dipicolinic acid (curative efficacy: 49.1% lesion length inhibition; preventive efficacy: 82.7% lesion length inhibition), or 1.9 mg/mL carbendazim and 0.71 mg/mL kojic acid (preventive efficacy: 84.9% lesion length inhibition). Collectively, this report will lead to a better understanding of the safety hazards found in soybean products in China and reveals the application of dipicolinic and kojic acids to reduce the use of carbendazim.


Assuntos
Fusarium , Benzimidazóis , Carbamatos , Fusarium/genética , Humanos , Ácidos Picolínicos , Pironas , Soja , Triticum
15.
Molecules ; 27(18)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36144705

RESUMO

Marine sponges continue to attract remarkable attention as one of the richest pools of bioactive metabolites in the marine environment. The genus Smenospongia (order Dictyoceratida, family Thorectidae) sponges can produce diverse classes of metabolites with unique and unusual chemical skeletons, including terpenoids (sesqui-, di-, and sesterterpenoids), indole alkaloids, aplysinopsins, bisspiroimidazolidinones, chromenes, γ-pyrones, phenyl alkenes, naphthoquinones, and polyketides that possessed diversified bioactivities. This review provided an overview of the reported metabolites from Smenospongia sponges, including their biosynthesis, synthesis, and bioactivities in the period from 1980 to June 2022. The structural characteristics and diverse bioactivities of these metabolites could attract a great deal of attention from natural-product chemists and pharmaceuticals seeking to develop these metabolites into medicine for the treatment and prevention of certain health concerns.


Assuntos
Produtos Biológicos , Naftoquinonas , Policetídeos , Poríferos , Alcenos/metabolismo , Animais , Benzopiranos/metabolismo , Produtos Biológicos/química , Alcaloides Indólicos/química , Naftoquinonas/metabolismo , Preparações Farmacêuticas/metabolismo , Policetídeos/metabolismo , Poríferos/química , Pironas/metabolismo , Terpenos/metabolismo , Terpenos/farmacologia
16.
Mar Drugs ; 20(9)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36135742

RESUMO

There has been a tremendous increase in the rate of new terpenoids from marine-derived fungi being discovered, while new monoterpenes were rarely isolated from marine-derived fungi in the past two decades. Three new monoterpenes, diaporterpenes A-C (1-3), and one new α-pyrones, diaporpyrone A (6), along with nine known polyketides 4, 5, and 7-13 were isolated from the ascidian-derived fungus Diaporthe sp. SYSU-MS4722. Their planar structures were elucidated based on extensive spectroscopic analyses (1D and 2D NMR and HR-ESIMS). The absolute configurations of 1 and 3 were identified by an X-ray crystallographic diffraction experiment using Cu-Ka radiation, and those of compound 2 were assigned by calculating NMR chemical shifts and ECD spectra. It afforded an example of natural epimers with different physical properties, especially crystallization, due to the difference in intermolecular hydrogen bonding. Compounds 9, 10, and 13 showed moderate total antioxidant capacity (0.82 of 9; 0.70 of 10; 0.48 of 13) with Trolox (total antioxidant capacity: 1.0) as a positive control, and compounds 5 and 7 showed anti-inflammatory activity with IC50 values of 35.4 and 40.8 µM, respectively (positive control indomethacin: IC50 = 35.8 µM).


Assuntos
Policetídeos , Urocordados , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Fungos/química , Indometacina , Estrutura Molecular , Monoterpenos , Policetídeos/química , Pironas/química
17.
Int J Mol Sci ; 23(18)2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36142671

RESUMO

ATP citrate lyase (ACLY) is a key enzyme in glucolipid metabolism and its aberrantly high expression is closely associated with various cancers, hyperlipemia and atherosclerotic cardiovascular diseases. Prospects of ACLY inhibitors as treatments of these diseases are excellent. To date, flavonoids have not been extensively reported as ACLY inhibitors. In our study, 138 flavonoids were screened and 21 of them were subjected to concentration-response curves. A remarkable structure-activity relationship (SAR) trend was found: ortho-dihydroxyphenyl and a conjugated system maintained by a pyrone ring were critical for inhibitory activity. Among these flavonoids, herbacetin had a typical structure and showed a non-aggregated state in solution and a high inhibition potency (IC50 = 0.50 ± 0.08 µM), and therefore was selected as a representative for the ligand-protein interaction study. In thermal shift assays, herbacetin improved the thermal stability of ACLY, suggesting a direct interaction with ACLY. Kinetic studies determined that herbacetin was a noncompetitive inhibitor of ACLY, as illustrated by molecular docking and dynamics simulation. Together, this work demonstrated flavonoids as novel and potent ACLY inhibitors with a remarkable SAR trend, which may help design high-potency ACLY inhibitors. In-depth studies of herbacetin deepened our understanding of the interactions between flavonoids and ACLY.


Assuntos
ATP Citrato (pro-S)-Liase , Pironas , ATP Citrato (pro-S)-Liase/metabolismo , Flavonoides/farmacologia , Cinética , Ligantes , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
18.
mBio ; 13(5): e0180022, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36000736

RESUMO

Fungal secondary metabolites with antibiotic activities can promote fungal adaptation to diverse environments. Besides the global regulator, individual biosynthetic gene clusters (BGCs) usually contain a pathway-specific transcription factor for the tight regulation of fungal secondary metabolism. Here, we report the chemical biology mediated by a supercluster containing three BGCs in the entomopathogenic fungus Metarhizium robertsii. These clusters are jointly controlled by an embedded transcription factor that orchestrates the collective production of four classes of chemicals: ustilaginoidin, indigotide, pseurotin, and hydroxyl-ovalicin. The ustilaginoidin BGC is implicated as a late-acquired cluster in Metarhizium to produce both the bis-naphtho-γ-pyrones and the monomeric naphtho-γ-pyrone glycosides (i.e., indigotides). We found that the biosynthesis of indigotides additionally requires the functions of paired methylglucosylation genes located outside the supercluster. The pseurotin/ovalicin BGCs are blended and mesosyntenically conserved to the intertwined pseurotin/fumagillin BGCs of Aspergillus fumigatus. However, the former have lost a few genes, including a polyketide synthase gene responsible for the production of a pentaene chain used for assembly with ovalicin to form fumagillin, as observed in A. fumigatus. The collective production of chemical cocktails by this supercluster was dispensable for fungal virulence against insects and could enable the fungus to combat different bacteria better than the metabolite(s) produced by an individual BGC could. Thus, our results unveil a novel strategy employed by fungi to manage chemical ecology against diverse bacteria. IMPORTANCE Fungal chemical ecology is largely mediated by the metabolite(s) produced by individual biosynthetic gene clusters (BGCs) with antibiotic activities. We report a supercluster containing three BGCs that are jointly controlled by an embedded master regulator in the insect pathogen Metarhizium robertsii. Four classes of chemicals, namely, ustilaginoidin, indigotide, pseurotin, and hydroxyl-ovalicin, are collectively produced by these three BGCs along with the contributions of tailoring enzyme genes located outside the supercluster. The production of these metabolites is not required for the fungal infection of insect hosts, but it benefits the fungus to combat diverse bacteria. The findings reveal and advocate a "the-more-the-better" strategy employed by fungi to manage effective adaptations to diverse environments.


Assuntos
Metarhizium , Policetídeo Sintases , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Pironas/metabolismo , Metarhizium/genética , Metarhizium/metabolismo , Metabolismo Secundário/genética , Família Multigênica , Bactérias/genética , Fatores de Transcrição/metabolismo , Antibacterianos/metabolismo , Glicosídeos
19.
Angew Chem Int Ed Engl ; 61(42): e202212016, 2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-36005743

RESUMO

2-Pyrones with a chiral branched allylic silyl ether substituent underwent intramolecular Diels-Alder reactions with remarkably high π-facial- and endo-selectivities. The resulting diastereomerically and enantiomerically pure cycloadducts were transformed into the natural products (+)-lycopladine A and (-)-lycoposerramine R.


Assuntos
Produtos Biológicos , Pironas , Alcaloides , Éteres , Piridinas , Piridonas , Sesquiterpenos , Estereoisomerismo
20.
Toxins (Basel) ; 14(8)2022 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-36006179

RESUMO

Natural compounds have always represented an important source for new drugs. Although fungi represent one such viable source, to date, no fungal metabolite has been marketed as an anticancer drug. Based on our work with phytotoxins as potential chemical scaffolds and our recent findings involving three phytopathogenic fungi, i.e., Cochliobolus australiensis, Kalmusia variispora and Hymenoscyphus fraxineus, herein, we evaluate the in vitro anti-cancer activity of the metabolites of these fungi by MTT assays on three cancer cell models harboring various resistance levels to chemotherapeutic drugs. Radicinin, a phytotoxic dihydropyranopyran-4,5-dione produced by Cochliobolus australiensis, with great potential for the biocontrol of the invasive weed buffelgrass (Cenchrus ciliaris), showed significant anticancer activity in the micromolar range. Furthermore, a SAR study was carried out using radicinin, some natural analogues and hemisynthetic derivatives prepared by synthetic methods developed as part of work aimed at the potential application of these molecules as bioherbicides. This investigation opens new avenues for the design and synthesis of novel radicinin analogues as potential anticancer agents.


Assuntos
Alcaloides , Cenchrus , Neoplasias , Toxinas Biológicas , Alcaloides/farmacologia , Sobrevivência Celular , Cenchrus/química , Curvularia , Pironas , Relação Estrutura-Atividade , Toxinas Biológicas/farmacologia
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