Three previously unrecognised classes of biosynthetic enzymes revealed during the production of xenovulene A

Schor, Raissa; Schotte, Carsten; Wibberg, Daniel; Kalinowski, Jörn; Cox, Russell J.

doi:10.1038/s41467-018-04364-9

Cited by 89 publications

(108 citation statements)

References 40 publications

(38 reference statements)

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“…Similar rearrangements have been suggested in the cases of aspyrone 23 42 and bartanol 24 43 (Fig. 7b ), and are also involved in ring-contracting mechanisms in the case of xenovulene A 44 , 45 . Tang and co-workers very recently reported a family of CrtC-type (carotenoid 1,2-hydratase) enzymes, which can catalyse rearrangements of epoxides.…”

Section: Discussionsupporting

confidence: 78%

“…The retro-Claisen removal of the β-aldehyde of 26 links this step to the proposed oxidative ring contractions involved during xenovulene A biosynthesis that are also catalysed by FAD-dependent enzymes 45 . However, bioinformatic analysis shows no significant homology between Str9 and AsR4 and AsR6 that are responsible for these reactions in Sarocladium schorii 45 . There is also no significant homology between Str9, or any other protein encoded by the str BGC, and PenF, suggesting that Str9 accomplishes both the oxidation of 11 and the rearrangement to form 26 .…”

Section: Discussionmentioning

confidence: 91%

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Strobilurin biosynthesis in Basidiomycete fungi

et al. 2018

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Strobilurins from fungi are the inspiration for the creation of the β-methoxyacrylate class of agricultural fungicides. However, molecular details of the biosynthesis of strobilurins have remained cryptic. Here we report the sequence of genomes of two fungi that produce strobilurins and show that each contains a biosynthetic gene cluster, which encodes a highly reducing polyketide synthase with very unusual C-terminal hydrolase and methyltransferase domains. Expression of stpks1 in Aspergillus oryzae leads to the production of prestrobilurin A when the fermentation is supplemented with a benzoyl coenzyme A (CoA) analogue. This enables the discovery of a previously unobserved route to benzoyl CoA. Reconstruction of the gene cluster in A. oryzae leads to the formation of prestrobilurin A, and addition of the gene str9 encoding an FAD-dependent oxygenase leads to the key oxidative rearrangement responsible for the creation of the β-methoxyacrylate toxophore. Finally, two methyltransferases are required to complete the synthesis.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 91%

Strobilurin biosynthesis in Basidiomycete fungi

et al. 2018

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“…Biochemical analysis of such residues, however, is a prerequisite to further confirm their role in the catalytic activity of such enzymes. Like us, Cox and co-workers could not draw a definite conclusion of motifs responsible for their humulene synthase (AsR6) catalytic activity [27].…”

Section: Discussionmentioning

confidence: 82%

The Biogenetic Origin of the Biologically Active Naematolin of Hypholoma Species Involves an Unusual Sesquiterpene Synthase

et al. 2019

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Naematolin is a biologically active sesquiterpene produced by Hypholoma species. Low titres and complex structure constrain the exploitation of this secondary metabolite. Here, we de novo sequenced the H. fasciculare genome to identify a candidate biosynthetic gene cluster for production of naematolin. Using Aspergillus oryzae as a heterologous host for gene expression, the activity of several sesquiterpene synthases were investigated, highlighting one atypical sesquiterpene synthase apparently capable of catalysing the 1,11 and subsequent 2,10 ring closures, which primes the synthesis of the distinctive structure of caryophyllene derivatives. Co-expression of the cyclase with an FAD oxidase adjacent within the gene cluster generated four oxidised caryophyllene-based sesquiterpenes: 5β,6α,8β-trihydroxycariolan, 5β,8β-dihydroxycariolan along with two previously unknown caryophyllene derivatives 2 and 3. This represents the first steps towards heterologous production of such basidiomycete-derived caryophyllene-based sesquiterpenes, opening a venue for potential novel antimicrobials via combinatorial biosynthesis.

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“…In combination with its advantageously limited set of native compounds A. oryzae has been successfully developed as a heterologous expression system for fungal secondary metabolites [ 2 , 3 ]. This system has been important in the discovery and functional analysis of various biosynthetic gene clusters (BGC) including xenovulenes, pleuromutilins, maleidrides and aphidicolin [ 4 , 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Oryzines A & B, Maleidride Congeners from Aspergillus oryzae and Their Putative Biosynthesis

Wasil

Kuhnert

Simpson

et al. 2018

JoF

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Aspergillus oryzae is traditionally used in East Asia for the production of food and brewing. In addition, it has been developed into a suitable host for the heterologous expression of natural product biosynthetic genes and gene clusters, enabling the functional analysis of the encoded enzymes. A. oryzae shares a 99.5% genome homology with Aspergillus flavus, but their secondary metabolomes differ significantly and various compounds unique to A. oryzae have been reported. While using A. oryzae as a host for heterologous expression experiments we discovered two new metabolites in extracts of A. oryzae M-2-3 with an unusual maleidride backbone, which were named oryzine A and B. Their structures were elucidated by high resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) analysis. Their structural relationships with known maleidrides implied involvement of a citrate synthase (CS) and a polyketide (PKS) or fatty acid synthase (FAS) in their biosynthesis. Analysis of the A. oryzae genome revealed a single putative biosynthetic gene cluster (BGC) consistent with the hypothetical biosynthesis of the oryzines. These findings increase knowledge of the chemical potential of A. oryzae and are the first attempt to link a novel product of this fungus with genomic data.

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Three previously unrecognised classes of biosynthetic enzymes revealed during the production of xenovulene A

Cited by 89 publications

References 40 publications

Strobilurin biosynthesis in Basidiomycete fungi

Strobilurin biosynthesis in Basidiomycete fungi

The Biogenetic Origin of the Biologically Active Naematolin of Hypholoma Species Involves an Unusual Sesquiterpene Synthase

Oryzines A & B, Maleidride Congeners from Aspergillus oryzae and Their Putative Biosynthesis

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