Cyclosporine Biosynthesis in
            <i>Tolypocladium inflatum</i>
            Benefits Fungal Adaptation to the Environment

Yang, Xiuqing; Peng, Feng; Yin, Ying; Bushley, Kathryn E.; Spatafora, Joseph W.; Wang, Chengshu

doi:10.1128/mbio.01211-18

Cited by 72 publications

(83 citation statements)

References 47 publications

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“…Certain non-SM domains like phosphotransferase enzyme family (PF01636.23), syntaxinlike protein (PF14523.6) and SNARE domain (PF05739.19), and Erg28-like protein (PF03694.13) are found and significantly enriched in single clades 2, 3, and 7, respectively (Figure 6 and Supplementary Table S24). These proteins could play a different role in self-protection against a toxic compound as decoy, a function that has been found encoded within a few fungal BGCs (Yeh et al, 2016;Yang et al, 2018;Kjaerbølling et al, 2019). Some proteins with unknown functions could also play a biosynthetic role, as shown for DUF1772 proteins in emodin-like BGCs, which was found to exhibit an anthrone oxidase activity (Lim et al, 2012a,b).…”

Section: Discussionmentioning

confidence: 99%

Evolutionary Histories of Type III Polyketide Synthases in Fungi

Navarro-Muñoz

Collemare

2020

Front. Microbiol.

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Type III polyketide synthases (PKSs) produce secondary metabolites with diverse biological activities, including antimicrobials. While they have been extensively studied in plants and bacteria, only a handful of type III PKSs from fungi has been characterized in the last 15 years. The exploitation of fungal type III PKSs to produce novel bioactive compounds requires understanding the diversity of these enzymes, as well as of their biosynthetic pathways. Here, phylogenetic and reconciliation analyses of 522 type III PKSs from 1,193 fungal genomes revealed complex evolutionary histories with massive gene duplications and losses, explaining their discontinuous distribution in the fungal tree of life. In addition, horizontal gene transfer events from bacteria to fungi and, to a lower extent, between fungi, could be inferred. Ancestral gene duplication events have resulted in the divergence of eight phylogenetic clades. Especially, two clades show ancestral linkage and functional co-evolution between a type III PKS and a reducing PKS genes. Investigation of the occurrence of protein domains in fungal type III PKS predicted gene clusters highlighted the diversity of biosynthetic pathways, likely reflecting a large chemical landscape. Type III PKS genes are most often located next to genes encoding cytochrome P450s, MFS transporters and transcription factors, defining ancestral core gene clusters. This analysis also allowed predicting gene clusters for the characterized fungal type III PKSs and provides working hypotheses for the elucidation of the full biosynthetic pathways. Altogether, our analyses provide the fundamental knowledge to motivate further characterization and exploitation of fungal type III PKS biosynthetic pathways.

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Section: Discussionmentioning

confidence: 99%

Evolutionary Histories of Type III Polyketide Synthases in Fungi

Navarro-Muñoz

Collemare

2020

Front. Microbiol.

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“…This cyclic undecapeptide was first isolated from Toplypocladium inflatum, an entomopathogenic fungus, and is synthesised by the NRPS cyclosporine synthetase [100]. Although cyclosporine 41 exhibits broad spectrum antifungal activity [101] its most valuable contribution is as an immunosuppressive drug administrated after organ transplant to avoid rejection. Cyclosporine 41 prevents the mounting of an immune response by inhibiting the activity of calcineurin, a calcium/calmodulin-dependent serine threonine phosphatase which activates transcription factors, therefore regulating the expression of cytokine genes involved in immunity [102].…”

Section: Other Peptidesmentioning

confidence: 99%

Selected Fungal Natural Products with Antimicrobial Properties

Jakubczyk

Dussart

2020

Molecules

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Fungal natural products and their effects have been known to humankind for hundreds of years. For example, toxic ergot alkaloids produced by filamentous fungi growing on rye poisoned thousands of people and livestock throughout the Middle Ages. However, their later medicinal applications, followed by the discovery of the first class of antibiotics, penicillins and other drugs of fungal origin, such as peptidic natural products, terpenoids or polyketides, have altered the historically negative reputation of fungal “toxins”. The development of new antimicrobial drugs is currently a major global challenge, mainly due to antimicrobial resistance phenomena. Therefore, the structures, biosynthesis and antimicrobial activity of selected fungal natural products are described here.

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“…For insecticidal and phytotoxic destruxins, around 40 structural analogs with variations in bioactivities can be similarly produced by Metarhizium and other fungal species (4). With the elucidation of cyclodepsipeptide biosynthetic mechanisms, it is clear that the non-ribosomal peptide synthetase (NRPS) can uptake the alternate building blocks of amino acids or hydroxy acids for cyclodepsipeptide biosynthesis (5,6). Taken together with the function of various tailoring enzymes, diverse cyclodepsipeptide analogs can therefore be produced by a single biosynthetic gene cluster (BGC) (2).…”

Section: Abstract Cordycipitaceae Fungi Cyclodepsipeptide Beauveriomentioning

confidence: 99%

Production of diverse beauveriolide analogs in closely related fungi: a rare case of fungal chemodiversity

Yin

Chen

Song

et al. 2020

Preprint

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ABSTRACTFungal chemodiversity is well known in part due to the production of diverse analogous compounds by a single biosynthetic gene cluster (BGCs). Usually, similar metabolites are produced by closely related fungal species. Here we report a rare case of the production of the cyclodepsipeptide beauveriolides (BVDs) in three insect pathogenic fungi. We found that the more closely-related fungi Beauveria bassiana and B. brongniartii produce structurally distinct analogs of BVDs whereas the rather divergently evolved species B. brongniartii and Cordyceps militaris produce structural analogs in a similar pattern. It was verified that a conserved BGC containing four genes is responsible for BVD biosynthesis in three fungi including a polyketide synthase (PKS) for the production of 3-hydroxy fatty acids (FAs) with chain length variations. In contrast to BVD production patterns, phylogenetic analysis of the BGC enzymes or enzyme domains largely resulted in the congruence relationship with fungal speciation. Feeding assays demonstrated that a FA with a chain length of eight carbon atoms was preferentially utilized whereas a FA with a chain longer than 10 carbon atoms could not be used as a substrate for BVD biosynthesis. We also found that addition of D-type amino acids could not enable B. bassiana to produce those analogs biosynthesized by other two fungi. Insect survival assays suggested that the contribution of BVD to fungal virulence might be associated with the susceptibility of insect species. The results of this study enrich the knowledge of fungal secondary metabolic diversity.IMPORTANCEFungal chemotaxonomy is an approach to classify fungi based on fungal production of natural compounds especially the secondary metabolites. We found an atypical example that could question chemical classification of fungi in this study: the more closely-related entomopathogenic species Beauveria bassiana and B. brongniartii produce structurally different analogs of the cyclodepsipeptide beauveriolides whereas the rather divergent species B. brongniartii and Cordyceps militaris biosynthesize similar analogs under the same growth condition. The conserved BGC containing four genes is present in each species and responsible for beauveriolide production. In contrast to the compound formation profiles, the phylogenies of biosynthetic enzymes or enzymatic domains show associations with fungal speciation relationship. Dependent on insect species, production of beauveriolides may contribute to fungal virulence against insect. The findings in this study augment the diversity of fungal secondary metabolisms.

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Cyclosporine Biosynthesis in Tolypocladium inflatum Benefits Fungal Adaptation to the Environment

Cited by 72 publications

References 47 publications

Evolutionary Histories of Type III Polyketide Synthases in Fungi

Evolutionary Histories of Type III Polyketide Synthases in Fungi

Selected Fungal Natural Products with Antimicrobial Properties

Production of diverse beauveriolide analogs in closely related fungi: a rare case of fungal chemodiversity

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