In vitro chemoenzymatic and in vivo biocatalytic syntheses of new beauvericin analogues (original) (raw)
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Synthesis of beauvericin by a multifunctional enzyme
The Journal of Antibiotics, 1988
Beauvericin synthetase, a multifunctional enzyme catalyzing depsipeptide formation in Beauveria bassiana was purified to near homogeneity. The enzymeconsists of a single polypeptide chain with a molecular mass of about 250 kdaltons. The mechanismof beauvericin formation is very similar to that of the cyclohexadepsipeptide enniatin.
Chemistry & Biology, 2008
Beauvericin, a cyclohexadepsipeptide ionophore from the entomopathogen Beauveria bassiana, shows antibiotic, antifungal, insecticidal, and cancer cell antiproliferative and antihaptotactic (cell motility inhibitory) activity in vitro. The bbBeas gene encoding the BbBEAS nonribosomal peptide synthetase was isolated from B. bassiana and confirmed to be responsible for beauvericin biosynthesis by targeted disruption. BbBEAS utilizes D-2-hydroxyisovalerate (D-Hiv) and L-phenylalanine (Phe) for the iterative synthesis of a predicted N-methyl-dipeptidol intermediate, and forms the cyclic trimeric ester beauvericin from this intermediate in an unusual recursive process. Heterologous expression of the bbBeas gene in Escherichia coli to produce the 3189 amino acid, 351.9 kDa BbBEAS enzyme provided a strain proficient in beauvericin biosynthesis. Comparative infection assays with a BbBEAS knockout B. bassiana strain against three insect hosts revealed that beauvericin plays a highly significant but not indispensable role in virulence. 898 Chemistry & Biology 15, 898-907, September 22,
Cell-free synthesis of the depsipeptide beauvericin
The Journal of Antibiotics, 1983
The enzymatic formation of the cyclodepsipeptide beauvericin was demonstrated in cellfree extracts from Beauveria bassiana. In analogy to the enniatin synthetase system formation of beauvericin is strictly dependent on the presence of the constituent amino and hydroxy acid, S-adenosylmethionine, and ATP/Mg".
Beauvericin: The Journey of a Pesticide into a Humanized Drug
Drug discovery has been initially attributed to coincidence or trial and error where the traditional approach was complex, lengthy, and expensive. Conventional drug discovery methods require the costly random screening of synthesized compounds or natural products. Another downside for this approach is the wide dependency on the experimental use of animals for in vi-vo testing. Currently, in silico modeling has become a vital tool for drug discovery and repurposing, and molecular docking is being used to find the best matching between a ligand and a molecule. Practical application of in silico docking will predict the biomolecular interactions between the drug and the target host. Beauvericin (BEA) is an emerging mycotoxin produced by the entomopathogenic fungus Beauveria bassiana. Originally investigated for its pesticide capability, BEA is now considered as a molecule of interest for its potentially diverse biotechnological applications in the pharmacological industry and the field...
Science China Life Sciences, 2013
Beauvericin, a cyclohexadepsipeptide-possessing natural product with synergistic antifungal, insecticidal, and cytotoxic activities. We isolated and characterized the fpBeas gene cluster, devoted to beauvericin biosynthesis, from the filamentous fungus Fusarium proliferatum LF061. Targeted inactivation of the F. proliferatum genomic copy of fpBeas abolished the production of beauvericin. Comparative sequence analysis of the FpBEAS showed 74% similarity with the BbBEAS that synthesizes the cyclic trimeric ester beauvericin in Beauveria bassiana, which assembles N-methyl-dipeptidol monomer intermediates by the programmed iterative use of the nonribosomal peptide synthetase modules. Differences between the organization of the beauvericin loci in F. proliferaturm and B. bassiana revealed the mechanism for high production of beauvericin in F. proliferatum. Our work provides new insights into beauvericin biosynthesis, and may lead to beauvericin overproduction and creation of new analogs via synthetic biology approaches.
In silico evidence of beauvericin antiviral activity against SARS-CoV-2
Computers in Biology and Medicine, 2022
BackgroundScientists are still battling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus 2019 (COVID-19) pandemic so human lives can be saved worldwide. Secondary fungal metabolites are of intense interest due to their broad range of pharmaceutical properties. Beauvericin (BEA) is a secondary metabolite produced by the fungus Beauveria bassiana. Although promising anti-viral activity has previously been reported for BEA, studies investigating its therapeutic potential are limited.MethodsThe objective of this study was to assess the potential usage of BEA as an anti-viral molecule via protein–protein docking approaches using MolSoft.ResultsIn-silico results revealed relatively favorable binding energies for BEA to different viral proteins implicated in the vital life stages of this virus. Of particular interest is the capability of BEA to dock to both the main coronavirus protease (Pockets A and B) and spike proteins. These results were validated by molecular dynamic simulation (Gromacs). Several parameters, such as root-mean-square deviation/fluctuation, the radius of gyration, H-bonding, and free binding energy were analyzed. Computational analyses revealed that interaction of BEA with the main protease pockets in addition to the spike glycoprotein remained stable.ConclusionAltogether, our results suggest that BEA might be considered as a potential competitive and allosteric agonist inhibitor with therapeutic options for treating COVID-19 pending in vitro and in vivo validation.
Pharmacological and Therapeutic Potential of Beauvericin: A Short Review
Journal of Proteomics & Bioinformatics, 2017
An entomopathogenic fungus, Beauveria spp. has been known to have numerous pharmacological and therapeutic implications, especially, in terms of human health making it a suitable for ethnopharmacological use. Beauvericin is a cyclic hexadepsipeptide mycotoxin, a novel bio-metabolite derived from this fungus, exhibiting a very potent anticancer, cytotoxic activities, antiplatelet aggregation and antimicrobial activities. The current review discusses the therapeutic potential of beauvericin including pharmacological and biological activities which will certainly draw the attention of scientific community to improve the production of beauvericin for its use in medical fields. Figure 1: Illustration of the different interactions of beauvericin in biochemical processes, including metastasis, apoptosis, antiplatelet aggregation and antimicrobial activity.
Hinnuliquinone, a C2-symmetric dimeric non-peptide fungal metabolite inhibitor of HIV-1 protease
Biochemical and Biophysical Research Communications, 2004
HIV-1 protease is one of several key enzymes required for the replication and maturation of HIV-1 virus. An almost two-decade research effort by academic and pharmaceutical institutions resulted in the successful commercialization of seven drugs that are potent inhibitors of HIV-1 protease activity and which, if used correctly, are highly effective in managing viral load. However, identification of clinical viral isolates that are resistant to these drugs indicates that this is a significant problem and that new classes of inhibitors are continually needed. Screening of microbial extracts followed by bioassay-guided isolation led to the discovery of a natural hinnuliquinone, a C 2 -symmetric bis-indolyl quinone natural product that inhibited the wild-type and a clinically resistant (A44) strain of HIV-1 protease with K i values of 0.97 and 1.25 lM, respectively. Crystallographic analysis of the inhibitor-bound HIV-1 protease helped explain the importance of the C 2 -symmetry of hinnuliquinone for activity. Details of the isolation, biological activity, and crystallographic analysis of the inhibitor-bound protease are herein described.
Chemistry & Biology, 1998
Background: Penicillins and cephalosporins constitute a major class of clinically useful antibiotics. A key step in their biosynthesis involves the oxidative cyclisation of 6-(L-a-aminoadipoyl)-L-cysteinyl-o-valine to isopenicillin N by isopenicillin N synthase (IPNS). This chemically remarkable transformation has been extensively studied using substrate analogues. The conversion of an analogue in which the valine is replaced by a-aminobutyrate results in three products, two epimeric penams and a cepham. The ratio of ttiese products in reactions catalysed by four different IPNS isozymes has been used previously to probe the thermicity of the chemical mechanism. But how IPNS restricts the products from the natural substrate to a single penam (isopenicillin N) has remained unknown. Results: A key active-site residue, Leu223, identified according to a model of enzyme-substrate binding, has been altered to sterically less demanding residues. As the steric constraints on the upper part of the active site are reduced, the ratio of the P-methyl penam to the cepham increases when the a-aminobutyrate-containing substrate analogue is used. These results suggest a mechanism for processing of the natural substrate in which IPNS uses steric control to restrict the conformational freedom of an intermediate such that the only product is the penam. Conclusions: Using steric pressure to control conformation, and hence to disfavour reactions leading to alternate products, is probably the result of evolutionary selection for a biologically active product at the expense of biologically inactive byproducts. It is likely that this sort of enzymatic catalysis is used in situations where substrate conversion is highly exothermic and a variety of products are possible.
Angewandte Chemie, 2015
Described herein is the synthesis of BMS-986001 by employing two novel organocatalytic transformations:1)a highly selective pyranose to furanose ring tautomerization to access an advanced intermediate,a nd 2) an unprecedented small-molecule-mediated dynamic kinetic resolution to access av ariety of enantiopure pyranones,o ne of which served as av ersatile building blockf or the multigram, stereoselective, and chromatography-free synthesis of BMS-986001. The synthesis required five chemical transformations and resulted in a4 4% overall yield.