Peptide name : Bassianolide nonribosomal cyclodepsipeptide synthetase

Source/Organism : White muscardine disease fungus

Linear/Cyclic : Cyclic

Chirality : Mix

Peptide length: 3146

C-terminal modification: Cyclic

N-terminal modification : Not found

Non-natural peptide information: None

Assay type : Not specified

Assay time : Not found

Activity : Not found

Cell line : MDA-MB-231

Cancer type : Breast cancer

Other activity : Anti-parasitic activity

Amino acid composition bar chart :

Molecular mass : 348268.002 Dalton

Aliphatic index : 0.917

Instability index : 43.7591

Hydrophobicity (GRAVY) : -0.145

Isoelectric point : 5.2729

Charge (pH 7) : -99.9223

Aromaticity : 0.078

Molar extinction coefficient (cysteine, cystine): (310670, 313170)

Hydrophobic/hydrophilic ratio : 1.06299212

hydrophobic moment : 0.0144

Missing amino acid : None

Most occurring amino acid : L

Most occurring amino acid frequency : 312

Least occurring amino acid : n

Least occurring amino acid frequency : 2

Secondary structure fraction (Helix, Turn, Sheet): (0.3, 0.2, 0.3)

SMILES Notation: 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1 : Steiniger C, et al. Probing Exchange Units for Combining Iterative and Linear Fungal Nonribosomal Peptide Synthetases. Cell Chem Biol. 2019; 26:1526-1534.e2. doi: 10.1016/j.chembiol.2019.08.005

2 : Fidan O and Zhan J. Discovery and engineering of an endophytic Pseudomonas strain from Taxus chinensis for efficient production of zeaxanthin diglucoside. J Biol Eng. 2019; 13:66. doi: 10.1186/s13036-019-0196-x

3 : Lobo LS, et al. Assessing gene expression during pathogenesis: Use of qRT-PCR to follow toxin production in the entomopathogenic fungus Beauveria bassiana during infection and immune response of the insect host Triatoma infestans. J Invertebr Pathol. 2015; 128:14-21. doi: 10.1016/j.jip.2015.04.004

4 : Steiniger C, et al. Harnessing fungal nonribosomal cyclodepsipeptide synthetases for mechanistic insights and tailored engineering. Chem Sci. 2017; 8:7834-7843. doi: 10.1039/c7sc03093b

5 : Mun B, et al. Synthesis and antitumor activity of (-)-bassianolide in MDA-MB 231 breast cancer cells through cell cycle arrest. Bioorg Chem. 2016; 69:64-70. doi: 10.1016/j.bioorg.2016.09.008

6 : Yu D, et al. Engineered production of fungal anticancer cyclooligomer depsipeptides in Saccharomyces cerevisiae. Metab Eng. 2013; 18:60-8. doi: 10.1016/j.ymben.2013.04.001

7 : Xu Y, et al. Biosynthesis of the cyclooligomer depsipeptide bassianolide, an insecticidal virulence factor of Beauveria bassiana. Fungal Genet Biol. 2009; 46:353-64. doi: 10.1016/j.fgb.2009.03.001

8 : Yu D, et al. Functional dissection and module swapping of fungal cyclooligomer depsipeptide synthetases. Chem Commun (Camb). 2013; 49:6176-8. doi: 10.1039/c3cc42425a

Paper title : Probing Exchange Units for Combining Iterative and Linear Fungal Nonribosomal Peptide Synthetases.

Doi : https://doi.org/10.1016/j.chembiol.2019.08.005

Abstract : A considerable number of complex peptides are synthesized by nonribosomal peptide synthetases (NRPSs). Due to their multimodular architecture and widely understood basic biosynthetic reactions, these synthetases represent a promising target for compound diversification by active reprogramming. Nevertheless, the limited knowledge about mechanistic details such as C domain specificity hampers rational synthetase engineering. Here, we present a systematic investigation of three fungal NRPS exchange units (C-A-Mt-T, C_CTD-A-Mt-T, and A-Mt-T) focusing on the influence of C domains at heterologous domain junctions. By functionally integrating units from linear cyclosporine synthetase into iterative cyclodepsipeptide synthetases in vivo, we demonstrate that fungal NRPSs of different assembly types can be combined using different swapping sites, while respecting the C domain integrity and specificity. Based on 24 hybrid synthetases, we suggest exchange rules for efficient fungal NRPS engineering. The findings are of importance for rational synthetase design and provide a new set of options for combinatorial reprogramming.

Paper title : Discovery and engineering of an endophytic Pseudomonas strain from Taxus chinensis for efficient production of zeaxanthin diglucoside.

Doi : https://doi.org/10.1186/s13036-019-0196-x

Abstract : BACKGROUND: Endophytic microorganisms are a rich source of bioactive natural products. They are considered as promising biofertilizers and biocontrol agents due to their growth-promoting interactions with the host plants and their bioactive secondary metabolites that can help manage plant pathogens. Identification of new endophytes may lead to the discovery of novel molecules or provide new strains for production of valuable compounds. RESULTS: In this study, we isolated an endophytic bacterium from the leaves of Taxus chinensis, which was identified as Pseudomonas sp. 102515 based on the 16S rRNA gene sequence and physiological characteristics. Analysis of its secondary metabolites revealed that this endophytic strain produces a major product zeaxanthin diglucoside, a promising antioxidant natural product that belongs to the family of carotenoids. A carotenoid (Pscrt) biosynthetic gene cluster was amplified from this strain, and the functions of PsCrtI and PsCrtY in the biosynthesis of zeaxanthin diglucoside were characterized in Escherichia coli BL21(DE3). The entire Pscrt biosynthetic gene cluster was successfully reconstituted in E. coli BL21(DE3) and Pseudomonas putida KT2440. The production of zeaxanthin diglucoside in Pseudomonas sp. 102515 was improved through the optimization of fermentation conditions such as medium, cultivation temperature and culture time. The highest yield under the optimized conditions reached 206 mg/L. The engineered strain of P. putida KT2440 produced zeaxanthin diglucoside at 121 mg/L in SOC medium supplemented with 0.5% glycerol at 18 °C, while the yield of zeaxanthin diglucoside in E. coli BL21(DE3) was only 2 mg/L. To further enhance the production, we introduced an expression plasmid harboring the Pscrt biosynthetic gene cluster into Pseudomonas sp. 102515. The yield in this engineered strain reached 380 mg/L, 85% higher than the wild type. Through PCR, we also discovered the presence of a turnerbactin biosynthetic gene cluster in Pseudomonas sp. 102515. Because turnerbactin is involved in nitrogen fixation, this endophytic strain might have a role in promoting growth of the host plant. CONCLUSIONS: We isolated and identified an endophytic strain of Pseudomonas from T. chinensis. A zeaxanthin diglucoside biosynthetic gene cluster was discovered and characterized in this bacterium. Through fermentation and genetic engineering, the engineered strain produced zeaxanthin diglucoside at 380 ± 12 mg/L, representing a promising strain for the production of this antioxidant natural product. Additionally, Pseudomonas sp. 102515 might also be utilized as a plant-promoting strain for agricultural applications.

Paper title : Assessing gene expression during pathogenesis: Use of qRT-PCR to follow toxin production in the entomopathogenic fungus Beauveria bassiana during infection and immune response of the insect host Triatoma infestans.

Doi : https://doi.org/10.1016/j.jip.2015.04.004

Abstract : Entomopathogenic fungi secrete toxic secondary metabolites during the invasion of the insect hemocoel as part of the infection process. Although these compounds have been frequently mentioned as virulence factors, the roles of many of them remain poorly understood, including the question of whether they are expressed during the infection process. A major hurdle to this issue remains the low sensitivity of biochemical detection techniques (e.g., HPLC) within the complex samples that may contain trace quantities of fungal molecules inside the insect. In this study, quantitative reverse transcription real-time PCR (qRT-PCR) was used to measure the transcript levels within the insect fungal pathogen Beauveria bassiana, that encode for the synthetase enzymes of the secondary metabolites tenellin (BbtenS), beauvericin (BbbeaS) and bassianolide (BbbslS) during the infection of Triatoma infestans, a Chagas disease insect vector. Absolute quantification was performed at different time periods after insect treatment with various concentrations of propagules, either by immersing the insects in conidial suspensions or by injecting them with blastospores. Both BbtenS and BbbeaS were highly expressed in conidia-treated insects at days 3 and 12 post-treatment. In blastospore-injected insects, BbtenS and BbbeaS expression peaked at 24h post-injection and were also highly expressed in insect cadavers. The levels of BbbslS transcripts were much lower in all conditions tested. The expression patterns of insect genes encoding proteins that belong to the T. infestans humoral immune system were also evaluated with the same technique. This qPCR-based methodology can contribute to decifering the dynamics of entomopathogenic fungal infection at the molecular level.

Paper title : Harnessing fungal nonribosomal cyclodepsipeptide synthetases for mechanistic insights and tailored engineering.

Doi : https://doi.org/10.1039/c7sc03093b

Abstract : Nonribosomal peptide synthetases represent potential platforms for the design and engineering of structurally complex peptides. While previous focus has been centred mainly on bacterial systems, fungal synthetases assembling drugs like the antifungal echinocandins, the antibacterial cephalosporins or the anthelmintic cyclodepsipeptide (CDP) PF1022 await in-depth exploitation. As various mechanistic features of fungal CDP biosynthesis are only partly understood, effective engineering of NRPSs has been severely hampered. By combining protein truncation, in trans expression and combinatorial swapping, we assigned important functional segments of fungal CDP synthetases and assessed their in vivo biosynthetic capabilities. Hence, artificial assembly line components comprising of up to three different synthetases were generated. Using Aspergillus niger as a heterologous expression host, we obtained new-to-nature octa-enniatin (4 mg L-1) and octa-beauvericin (10.8 mg L-1), as well as high titers of the hybrid CDP hexa-bassianolide (1.3 g L-1) with an engineered ring size. The hybrid compounds showed up to 12-fold enhanced antiparasitic activity against Leishmania donovani and Trypanosoma cruzi compared to the reference drugs miltefosine and benznidazole, respectively. Our findings thus contribute to a rational engineering of iterative nonribosomal assembly lines.

Paper title : Synthesis and antitumor activity of (-)-bassianolide in MDA-MB 231 breast cancer cells through cell cycle arrest.

Doi : https://doi.org/10.1016/j.bioorg.2016.09.008

Abstract : The high level of interest in the cyclodepsipeptides family in the natural products stems from their diverse range of biological activities. One of the cyclodepsipeptides, (-)-bassianolide, represents rich pharmacophores with diverse biological activities including potential cytotoxicity to various cancer cells. Efficient total synthesis of (-)-bassianolide was designed and achieved in nine steps, with significant improvements in the overall yield of 46.8% (vs. 7.2% yield in previous synthesis) using Ghosez's chloroenamine reagent under mild conditions. The cytotoxicity of the (-)-bassianolide was evaluated against five human tumor cells, and the results showed that the (-)-bassianolide displayed significant cytotoxicity against A549, SK-OV-3, HepG2, HCT-15, MCF-7 and MDA-MB 231 cell lines with IC₅₀ values of 7.24, 8.44, 15.39, 6.40, 11.42 and 3.98 μg/mL respectively. Specifically, (-)-bassianolide induced G0/G1 arrest associated with a decrease of cyclin A, D1 and an increase of p53, MDM2, and p21 expression in MDA-MB 231 cells. These results demonstrate that (-)-bassianolide possesses antitumor activities via arresting of the cell cycle and the synthetic approach features an efficient and mild method for the formation of amide bonds through three inter- and intramolecular coupling reactions.

Paper title : Engineered production of fungal anticancer cyclooligomer depsipeptides in Saccharomyces cerevisiae.

Doi : https://doi.org/10.1016/j.ymben.2013.04.001

Abstract : Two fungal cyclooligomer depsipeptide synthetases(CODSs), BbBEAS (352 kDa) and BbBSLS (348 kDa) from Beauveria bassiana ATCC7159, were reconstituted in Saccharomyces cerevisiae BJ5464-NpgA, leading to the production of the corresponding anticancer natural products, beauvericins and bassianolide, respectively. The titers of beauvericins (33.8 ± 1.4 mg/l) and bassianolide (21.7± 0.1 mg/l) in the engineered S. cerevisiae BJ5464-NpgA strains were comparable to those in the native producer B. bassiana. Feeding D-hydroxyisovaleric acid (D-Hiv) and the corresponding L-amino acid precursors improved the production of beauvericins and bassianolide. However, the high price of D-Hiv limits its application in large-scale production of these cyclooligomer depsipeptides. Alternatively, we engineered another enzyme, ketoisovalerate reductase (KIVR) from B. bassiana, into S. cerevisiae BJ5464-NpgA for enhanced in situ synthesis of this expensive substrate. Co-expression of BbBEAS and KIVR in the yeast led to significant improvement of the production of beauvericins.The total titer of beauvericin and its congeners (beauvericins A-C) was increased to 61.7 ± 3.0 mg/l and reached 2.6-fold of that in the native producer B. bassiana ATCC7159. Supplement of L-Val at 10 mM improved the supply of ketoisovalerate, the substrate of KIVR, which consequently further increased the total titer of beauvericins to 105.8 ± 2.1 mg/l. Using this yeast system,we functionally characterized an unknown CODS from Fusarium venenatum NRRL 26139 as a beauvericin synthetase, which was named as FvBEAS. Our work thus provides a useful approach for functional reconstitution and engineering of fungal CODSs for efficient production of this family of anticancer molecules.

Paper title : Biosynthesis of the cyclooligomer depsipeptide bassianolide, an insecticidal virulence factor of Beauveria bassiana.

Doi : https://doi.org/10.1016/j.fgb.2009.03.001

Abstract : Beauveria bassiana is a facultative entomopathogen with an extremely broad host range that is used as a commercial biopesticide for the control of insects of agricultural, veterinary and medical significance. B. bassiana produces bassianolide, a cyclooligomer depsipeptide secondary metabolite. We have cloned the bbBsls gene of B. bassiana encoding a nonribosomal peptide synthetase (NRPS). Targeted inactivation of the B. bassiana genomic copy of bbBsls abolished bassianolide production, but did not affect the biosynthesis of beauvericin, another cyclodepsipeptide produced by the strain. Comparative sequence analysis of the BbBSLS bassianolide synthetase revealed enzymatic domains for the iterative synthesis of an enzyme-bound dipeptidol monomer intermediate from d-2-hydroxyisovalerate and l-leucine. Further BbBSLS domains are predicted to catalyze the formation of the cyclic tetrameric ester bassianolide by recursive condensations of this monomer. Comparative infection assays against three selected insect hosts established bassianolide as a highly significant virulence factor of B. bassiana.

Paper title : Functional dissection and module swapping of fungal cyclooligomer depsipeptide synthetases.

Doi : https://doi.org/10.1039/c3cc42425a

Abstract : BbBSLS and BbBEAS were dissected and reconstituted in Saccharomyces cerevisiae. The intermodular linker is essential for the reconstitution of the separate modules. Module 1 can be swapped between BbBEAS and BbBSLS, while modules 2 and 3 control the product profiles. BbBSLS is a flexible enzyme that also synthesizes beauvericins.