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Isolation of a gene cluster from Armillaria gallica for the synthesis of armillyl orsellinate–type sesquiterpenoids

Engels, Benedikt ; Heinig, Uwe ; McElroy, Christopher ; Meusinger, Reinhard ; Grothe, Torsten ; Stadler, Marc ; Jennewein, Stefan (2021)
Isolation of a gene cluster from Armillaria gallica for the synthesis of armillyl orsellinate–type sesquiterpenoids.
In: Applied Microbiology and Biotechnology, 105 (1)
doi: 10.1007/s00253-020-11006-y
Article, Bibliographie

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Abstract

Melleolides and armillyl orsellinates are protoilludene-type aryl esters that are synthesized exclusively by parasitic fungi of the globally distributed genus Armillaria (Agaricomycetes, Physalacriaceae). Several of these compounds show potent antimicrobial and cytotoxic activities, making them promising leads for the development of new antibiotics or drugs for the treatment of cancer. We recently cloned and characterized the Armillaria gallica gene Pro1 encoding protoilludene synthase, a sesquiterpene cyclase catalyzing the pathway-committing step to all protoilludene-type aryl esters. Fungal enzymes representing secondary metabolic pathways are sometimes encoded by gene clusters, so we hypothesized that the missing steps in the pathway to melleolides and armillyl orsellinates might be identified by cloning the genes surrounding Pro1. Here we report the isolation of an A. gallica gene cluster encoding protoilludene synthase and four cytochrome P450 monooxygenases. Heterologous expression and functional analysis resulted in the identification of protoilludene-8α-hydroxylase, which catalyzes the first committed step in the armillyl orsellinate pathway. This confirms that ∆-6-protoilludene is a precursor for the synthesis of both melleolides and armillyl orsellinates, but the two pathways already branch at the level of the first oxygenation step. Our results provide insight into the synthesis of these valuable natural products and pave the way for their production by metabolic engineering.

Item Type: Article
Erschienen: 2021
Creators: Engels, Benedikt ; Heinig, Uwe ; McElroy, Christopher ; Meusinger, Reinhard ; Grothe, Torsten ; Stadler, Marc ; Jennewein, Stefan
Type of entry: Bibliographie
Title: Isolation of a gene cluster from Armillaria gallica for the synthesis of armillyl orsellinate–type sesquiterpenoids
Language: English
Date: January 2021
Place of Publication: Berlin ; Heidelberg ; New York
Publisher: Springer
Journal or Publication Title: Applied Microbiology and Biotechnology
Volume of the journal: 105
Issue Number: 1
DOI: 10.1007/s00253-020-11006-y
Corresponding Links:
Abstract:

Melleolides and armillyl orsellinates are protoilludene-type aryl esters that are synthesized exclusively by parasitic fungi of the globally distributed genus Armillaria (Agaricomycetes, Physalacriaceae). Several of these compounds show potent antimicrobial and cytotoxic activities, making them promising leads for the development of new antibiotics or drugs for the treatment of cancer. We recently cloned and characterized the Armillaria gallica gene Pro1 encoding protoilludene synthase, a sesquiterpene cyclase catalyzing the pathway-committing step to all protoilludene-type aryl esters. Fungal enzymes representing secondary metabolic pathways are sometimes encoded by gene clusters, so we hypothesized that the missing steps in the pathway to melleolides and armillyl orsellinates might be identified by cloning the genes surrounding Pro1. Here we report the isolation of an A. gallica gene cluster encoding protoilludene synthase and four cytochrome P450 monooxygenases. Heterologous expression and functional analysis resulted in the identification of protoilludene-8α-hydroxylase, which catalyzes the first committed step in the armillyl orsellinate pathway. This confirms that ∆-6-protoilludene is a precursor for the synthesis of both melleolides and armillyl orsellinates, but the two pathways already branch at the level of the first oxygenation step. Our results provide insight into the synthesis of these valuable natural products and pave the way for their production by metabolic engineering.

Uncontrolled Keywords: Antibiotics, Chemotherapy, Drug discovery, Melleolide, Natural product biosynthesis, Terpenoid
Additional Information:

Key points:

• Protoilludene-type aryl esters are bioactive metabolites produced by Armillaria spp.

• The pathway-committing step to these compounds is catalyzed by protoilludene synthase.

• We characterized CYP-type enzymes in the cluster and identified novel intermediates.

Classification DDC: 500 Science and mathematics > 540 Chemistry
500 Science and mathematics > 570 Life sciences, biology
Divisions: 07 Department of Chemistry
07 Department of Chemistry > Clemens-Schöpf-Institut
Date Deposited: 02 May 2024 07:39
Last Modified: 02 May 2024 07:39
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