Peptide name : Bassianolide nonribosomal cyclodepsipeptide synthetase (BSLS)

Source/Organism : White muscardine disease fungus

Linear/Cyclic : Cyclic

Chirality : Mix

Peptide length: 3147

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 : HUVEC-2

Cancer type : Prostate cancer

Other activity : Not found

Amino acid composition bar chart :

Molecular mass : 348342.120 Dalton

Aliphatic index : 0.918

Instability index : 44.0009

Hydrophobicity (GRAVY) : -0.140

Isoelectric point : 5.2597

Charge (pH 7) : -103.676

Aromaticity : 0.077

Molar extinction coefficient (cysteine, cystine): (303680, 306305)

Hydrophobic/hydrophilic ratio : 1.06364829

hydrophobic moment : 0.0399

Missing amino acid : None

Most occurring amino acid : L

Most occurring amino acid frequency : 313

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 : 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

2 : 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

3 : Seicol BJ, et al. Neuromodulation of metabolic functions: from pharmaceuticals to bioelectronics to biocircuits. J Biol Eng. 2019; 13:67. doi: 10.1186/s13036-019-0194-z

4 : 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

5 : 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

6 : 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

7 : 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

8 : 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

9 : Xiao G, et al. Genomic perspectives on the evolution of fungal entomopathogenicity in Beauveria bassiana. Sci Rep. 2012; 2:483. doi: 10.1038/srep00483

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.

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 : Neuromodulation of metabolic functions: from pharmaceuticals to bioelectronics to biocircuits.

Doi : https://doi.org/10.1186/s13036-019-0194-z

Abstract : Neuromodulation of central and peripheral neural circuitry brings together neurobiologists and neural engineers to develop advanced neural interfaces to decode and recapitulate the information encoded in the nervous system. Dysfunctional neuronal networks contribute not only to the pathophysiology of neurological diseases, but also to numerous metabolic disorders. Many regions of the central nervous system (CNS), especially within the hypothalamus, regulate metabolism. Recent evidence has linked obesity and diabetes to hyperactive or dysregulated autonomic nervous system (ANS) activity. Neural regulation of metabolic functions provides access to control pathology through neuromodulation. Metabolism is defined as cellular events that involve catabolic and/or anabolic processes, including control of systemic metabolic functions, as well as cellular signaling pathways, such as cytokine release by immune cells. Therefore, neuromodulation to control metabolic functions can be used to target metabolic diseases, such as diabetes and chronic inflammatory diseases. Better understanding of neurometabolic circuitry will allow for targeted stimulation to modulate metabolic functions. Within the broad category of metabolic functions, cellular signaling, including the production and release of cytokines and other immunological processes, is regulated by both the CNS and ANS. Neural innervations of metabolic (e.g. pancreas) and immunologic (e.g. spleen) organs have been understood for over a century, however, it is only now becoming possible to decode the neuronal information to enable exogenous controls of these systems. Future interventions taking advantage of this progress will enable scientists, engineering and medical doctors to more effectively treat metabolic diseases.

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 : 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 : 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 : 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 : 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 : Genomic perspectives on the evolution of fungal entomopathogenicity in Beauveria bassiana.

Doi : https://doi.org/10.1038/srep00483

Abstract : The ascomycete fungus Beauveria bassiana is a pathogen of hundreds of insect species and is commercially produced as an environmentally friendly mycoinsecticide. We sequenced the genome of B. bassiana and a phylogenomic analysis confirmed that ascomycete entomopathogenicity is polyphyletic, but also revealed convergent evolution to insect pathogenicity. We also found many species-specific virulence genes and gene family expansions and contractions that correlate with host ranges and pathogenic strategies. These include B. bassiana having many more bacterial-like toxins (suggesting an unsuspected potential for oral toxicity) and effector-type proteins. The genome also revealed that B. bassiana resembles the closely related Cordyceps militaris in being heterothallic, although its sexual stage is rarely observed. A high throughput RNA-seq transcriptomic analysis revealed that B. bassiana could sense and adapt to different environmental niches by activating well-defined gene sets. The information from this study will facilitate further development of B. bassiana as a cost-effective mycoinsecticide.