Hancockiamides: phenylpropanoid piperazines from <i>Aspergillus hancockii</i> are biosynthesised by a versatile dual single-module NRPS pathway

Li, Hang; Lacey, Alastair E.; Shu, Si; Kalaitzis, John A.; Vuong, Daniel; Crombie, Andrew; Hu, Jinyu; Gilchrist, Cameron L.M.; Lacey, Ernest; Piggott, Andrew M.; Chooi, Yit‐Heng

doi:10.1039/d0ob02243h

Cited by 31 publications

(61 citation statements)

References 44 publications

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“…Examples for monomodular NRPSs can be found as part of the biosynthetic pathway to the conidiophore pigment 17 as well as the route to hancockiamides. 18 It should be noted, however, that not all products of NRPSs are peptides, since the A/C domains may also generate C-O and C-C bonds. 19 2.2 Thiotemplated, freestanding peptide synthetases: type II Various peptide synthetases deviate from the modular architecture of the type I NRPSs by employing catalytic units that are not covalently linked to each other and are thus termed type II NRPSs.…”

Section: A Possible Binning System For Ribosome-independent Peptide Assembly Systemsmentioning

confidence: 99%

Ribosome-independent peptide biosynthesis: the challenge of a unifying nomenclature

2022

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Section: A Possible Binning System For Ribosome-independent Peptide Assembly Systemsmentioning

confidence: 99%

Ribosome-independent peptide biosynthesis: the challenge of a unifying nomenclature

2022

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“…This is one of the first steps when taking a ‘retro-biosynthetic’ approach to identifying a BGC [ 17 ]. Indeed, we have used this approach to identify the megasynthases encoding numerous compounds isolated from Australian fungi [ 18 – 21 ]. Inversely, we can predict that synthases with unique domain architectures could potentially produce unique compounds.…”

Section: Introductionmentioning

confidence: 99%

Synthaser: a CD-Search enabled Python toolkit for analysing domain architecture of fungal secondary metabolite megasynth(et)ases

Gilchrist

Chooi

2021

Fungal Biol Biotechnol

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Background Fungi are prolific producers of secondary metabolites (SMs), which are bioactive small molecules with important applications in medicine, agriculture and other industries. The backbones of a large proportion of fungal SMs are generated through the action of large, multi-domain megasynth(et)ases such as polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The structure of these backbones is determined by the domain architecture of the corresponding megasynth(et)ase, and thus accurate annotation and classification of these architectures is an important step in linking SMs to their biosynthetic origins in the genome. Results Here we report synthaser, a Python package leveraging the NCBI’s conserved domain search tool for remote prediction and classification of fungal megasynth(et)ase domain architectures. Synthaser is capable of batch sequence analysis, and produces rich textual output and interactive visualisations which allow for quick assessment of the megasynth(et)ase diversity of a fungal genome. Synthaser uses a hierarchical rule-based classification system, which can be extensively customised by the user through a web application (http://gamcil.github.io/synthaser). We show that synthaser provides more accurate domain architecture predictions than comparable tools which rely on curated profile hidden Markov model (pHMM)-based approaches; the utilisation of the NCBI conserved domain database also allows for significantly greater flexibility compared to pHMM approaches. In addition, we demonstrate how synthaser can be applied to large scale genome mining pipelines through the construction of an Aspergillus PKS similarity network. Conclusions Synthaser is an easy to use tool that represents a significant upgrade to previous domain architecture analysis tools. It is freely available under a MIT license from PyPI (https://pypi.org/project/synthaser) and GitHub (https://github.com/gamcil/synthaser).

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“…Filamentous fungi from the genus Aspergillus are prolific producers of secondary metabolites which display a diverse range of bioactivities. 1 As part of our ongoing chemotaxonomic exploration of rare and talented Australian Aspergilli, [3][4][5][6][7][8][9][10] we recently reported the novel species Aspergillus burnettii, isolated from soil collected in Queensland, Australia. 4 Chemical profiling of A. burnettii revealed a variety of unprecedented secondary metabolites, including the polyketide-peptide hybrid burnettramic acids, 6 which displayed potent antifungal activity.…”

Section: Introductionmentioning

confidence: 99%

Characterisation and heterologous biosynthesis of burnettiene A, a new polyene-decalin polyketide from Aspergillus burnettii

Roux

Bowles²,

Kalaitzis

et al. 2021

Preprint

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Chemical exploration of the recently described Australian fungus, Aspergillus burnettii, uncovered a new metabolite, burnettiene A. Here, we characterise the structure of burnettiene A as a polyene-decalin polyketide. Bioinformatic analysis of the genome of A. burnettii identified a putative biosynthetic gene cluster for burnettiene A (bue), consisting of eight genes and sharing similarity to the fusarielin gene cluster. Introduction of the reassembled bue gene cluster into Aspergillus nidulans for heterologous expression resulted in the production of burnettiene A under native promoters. Omission of bueE encoding a cytochrome P450 led to the production of preburnettiene A, confirming that BueE is responsible for catalysing the regiospecific multi-oxidation of terminal methyl groups to carboxylic acids. Similarly, bueF was shown to encode an ester-forming methyltransferase, with its omission resulting in the production of the tricarboxylic acid, preburnettiene B. Introduction of an additional copy of the transcription factor bueR under the regulation of the gpdA promoter significantly improved the heterologous production of the burnettienes. Burnettiene A displayed strong in vitro cytotoxicity against mouse myeloma NS-1 cells (MIC 0.8 µg/mL).

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Hancockiamides: phenylpropanoid piperazines from Aspergillus hancockii are biosynthesised by a versatile dual single-module NRPS pathway

Abstract: The hancockiamides are an unusual new family of N-cinnamoylated piperazines from the Australian soil fungus Aspergillus hancockii, originating from mixed nonribosomal peptide and phenylpropanoid pathways.

Cited by 31 publications

References 44 publications

Ribosome-independent peptide biosynthesis: the challenge of a unifying nomenclature

Ribosome-independent peptide biosynthesis: the challenge of a unifying nomenclature

Synthaser: a CD-Search enabled Python toolkit for analysing domain architecture of fungal secondary metabolite megasynth(et)ases

Characterisation and heterologous biosynthesis of burnettiene A, a new polyene-decalin polyketide from Aspergillus burnettii

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