Genomics‐Driven Discovery of a Symbiont‐Specific Cyclopeptide from Bacteria Residing in the Rice Seedling Blight Fungus

Niehs, Sarah P.; Dose, Benjamin; Scherlach, Kirstin; Roth, Martin; Hertweck, Christian

doi:10.1002/cbic.201800400

Cited by 27 publications

(24 citation statements)

References 42 publications

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“…5c, Supplementary Fig. 35) 46 . All frs C starter domains form a deeply rooted clade, supporting their close relationship and highlighting differences to the other domains in the database, even from the same taxa.…”

Section: Characterization Of a Cultivable Fr Producermentioning

confidence: 99%

Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359

et al. 2021

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The potent and selective Gq protein inhibitor depsipeptide FR900359 (FR), originally discovered as the product of an uncultivable plant endosymbiont, is synthesized by a complex biosynthetic system comprising two nonribosomal peptide synthetase (NRPS) assembly lines. Here we characterize a cultivable bacterial FR producer, enabling detailed investigations into biosynthesis and attachment of the functionally important FR side chain. We reconstitute side chain assembly by the monomodular NRPS FrsA and the non-heme monooxygenase FrsH, and characterize intermolecular side chain transesterification to the final macrocyclic intermediate FR-Core, mediated by the FrsA thioesterase domain. We harness FrsA substrate promiscuity to generate FR analogs with altered side chains and demonstrate indispensability of the FR side chain for efficient Gq inhibition by comparative bioactivity, toxicity and docking studies. Finally, evolution of FR and side chain biosynthesis is discussed based on bioinformatics analyses. Side chain transesterification boosts potency and target affinity of selective Gq inhibitor natural products.

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Section: Characterization Of a Cultivable Fr Producermentioning

confidence: 99%

Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359

et al. 2021

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“…5). For example, by a combination of genome mining and chemical analytics, a number of nonribosomally synthesized peptides were identified from the endosymbiont of the plant-pathogenic fungus Rhizopus microsporus that are involved in the bacterial-fungal interaction and/or serve an ecological function [117][118][119] . The endofungal bacteria also produce cytotoxic necroximes (e.g., necroxime A, 33) in symbiosis with the fungal host.…”

Section: Genome-guided Discovery Of Natural Products From Ecological Interactionsmentioning

confidence: 99%

Mining and unearthing hidden biosynthetic potential

2021

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Genetically encoded small molecules (secondary metabolites) play eminent roles in ecological interactions, as pathogenicity factors and as drug leads. Yet, these chemical mediators often evade detection, and the discovery of novel entities is hampered by low production and high rediscovery rates. These limitations may be addressed by genome mining for biosynthetic gene clusters, thereby unveiling cryptic metabolic potential. The development of sophisticated data mining methods and genetic and analytical tools has enabled the discovery of an impressive array of previously overlooked natural products. This review shows the newest developments in the field, highlighting compound discovery from unconventional sources and microbiomes.

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“…Investigations on the mucoromycete Rhizopus microsporus revealed that its D-amino acid-containing peptides rhizonin and heptarhizin are not produced by the fungus but by its in-host endosymbiotic proteobacterium Paraburkholderia rhizoxinica (31,32). Similarly, Burkholderia-related (BRE) endosymbionts such as Mycoavidus cysteinexigens are frequently observed in Mortierellales (33,34).…”

Section: Introductionmentioning

confidence: 99%

Bacterial-Like Nonribosomal Peptide Synthetases Produce Cyclopeptides in the Zygomycetous Fungus Mortierella alpina

Wurlitzer

Stanišić

Wasmuth

et al. 2021

Appl Environ Microbiol

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Fungi are traditionally considered as reservoir of biologically active natural products. However, an active secondary metabolism has long not been attributed to early diverging fungi such as Mortierella spec. Here, we report on the biosynthesis of two series of cyclic pentapeptides, the malpicyclins and malpibaldins, as products of Mortierella alpina ATCC32222. The molecular structures of malpicyclins were elucidated by HR-MS/MS, Marfey's method, and 1D and 2D NMR spectroscopy. In addition, malpibaldin biosynthesis was confirmed by HR-MS. Genome mining and comparative qRT-PCR expression analysis pointed at two pentamodular nonribosomal peptide synthetases (NRPS), malpicyclin synthetase MpcA and malpibaldin synthetase MpbA, as candidate biosynthetic enzymes. Heterologous production of the respective adenylation domains and substrate specificity assays proved promiscuous substrate selection and confirmed their respective biosynthetic roles. In stark contrast to known fungal NRPSs, MpbA and MpcA contain bacterial-like dual epimerase/condensation domains allowing the racemization of enzyme-tethered l-amino acids and the subsequent incorporation of d-amino acids into the metabolites. Phylogenetic analyses of both NRPS genes indicate a bacterial origin and a horizontal gene transfer into the fungal genome. We report on the as yet unexplored nonribosomal peptide biosynthesis in basal fungi which highlights this paraphylum as novel and underrated resource of natural products. IMPORTANCE Fungal natural compounds are industrially produced with application in antibiotic treatment, cancer medications and crop plant protection. Traditionally, higher fungi have been intensively investigated concerning their metabolic potential, but re-identification of already known compounds is frequently observed. Hence, alternative strategies to acquire novel bioactive molecules are required. We present the genus Mortierella as representative of the early diverging fungi as an underestimated resource of natural products. Mortierella alpina produces two families of cyclopeptides, denoted malpicyclins and malpibaldins, respectively, via two pentamodular nonribosomal peptide synthetases (NRPSs). These enzymes are much closer related to bacterial than to other fungal NRPSs, suggesting a bacterial origin of these NRPS genes in Mortierella. Both enzymes were biochemically characterized and are involved in as yet unknown biosynthetic pathways of natural products in basal fungi. Hence, this report establishes early diverging fungi as prolific natural compound producers and sheds light on the origin of their biosynthetic capacity.

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Genomics‐Driven Discovery of a Symbiont‐Specific Cyclopeptide from Bacteria Residing in the Rice Seedling Blight Fungus

Cited by 27 publications

References 42 publications

Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359

Thioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359

Mining and unearthing hidden biosynthetic potential

Bacterial-Like Nonribosomal Peptide Synthetases Produce Cyclopeptides in the Zygomycetous Fungus Mortierella alpina

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