Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis

Katherine Williams; Agnieszka J Szwalbe; Nicholas P Mulholland; Jason L Vincent; Andy Bailey; Christine L Willis; Thomas J Simpson; Russell J Cox

doi:10.1002/anie.201511882

Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis

Katherine Williams, Agnieszka J Szwalbe, Nicholas P Mulholland, Jason L Vincent, Andy Bailey, Christine L Willis, Thomas J Simpson, Russell J Cox

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Abstract

Fungal maleidrides are an important family of bioactive secondary metabolites that consist of 7, 8, or 9-membered carbocycles with one or two fused maleic anhydride moieties. The biosynthesis of byssochlamic acid (a nonadride) and agnestadride A (a heptadride) was investigated through gene disruption and heterologous expression experiments. The results reveal that the precursors for cyclization are formed by an iterative highly reducing fungal polyketide synthase supported by a hydrolase, together with two citrate-processing enzymes. The enigmatic ring formation is catalyzed by two proteins with homology to ketosteroid isomerases, and assisted by two proteins with homology to phosphatidylethanolamine-binding proteins.

Original language	English
Pages (from-to)	6784-6788
Number of pages	5
Journal	Angewandte Chemie - International Edition
Volume	55
Issue number	23
Early online date	21 Apr 2016
DOIs	https://doi.org/10.1002/anie.201511882
Publication status	Published - 1 Jun 2016

Keywords

biosynthesis
cyclization
enzymes
maleidride
polyketides

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10.1002/anie.201511882

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This is the final published version of the article (version of record). It first appeared online via Wiley at onlinelibrary.wiley.com/doi/10.1002/anie.201511882/abstract. Please refer to any applicable terms of use of the publisher.
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This is the final published version of the article (version of record). It first appeared online via Wiley at onlinelibrary.wiley.com/doi/10.1002/anie.201511882/abstract. Please refer to any applicable terms of use of the publisher.
Final published version, 2.02 MBLicence: CC BY

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3-month Core Capability for Chemistry Research
Crosby, J. (Principal Investigator)
1/01/13 → 1/04/13
Project: Research
CHEMICAL ANALYSIS OF HYBRID FUNGAL MEGASYNTHASES
Cox, R. J. (Principal Investigator)
1/10/08 → 1/10/12
Project: Research

Dr Andy M Bailey
- Andy.Baileybristol.acuk
- School of Biological Sciences - Reader in Molecular Mycology
- Cabot Institute for the Environment
- Infection and Immunity
- Plant and Agricultural Sciences
Person: Academic , Member
Professor Chris L Willis
- Chris.Willisbristol.acuk
- School of Chemistry - Professor of Organic Chemistry
Person: Academic

Cite this

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title = "Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis",

abstract = "Fungal maleidrides are an important family of bioactive secondary metabolites that consist of 7, 8, or 9-membered carbocycles with one or two fused maleic anhydride moieties. The biosynthesis of byssochlamic acid (a nonadride) and agnestadride A (a heptadride) was investigated through gene disruption and heterologous expression experiments. The results reveal that the precursors for cyclization are formed by an iterative highly reducing fungal polyketide synthase supported by a hydrolase, together with two citrate-processing enzymes. The enigmatic ring formation is catalyzed by two proteins with homology to ketosteroid isomerases, and assisted by two proteins with homology to phosphatidylethanolamine-binding proteins.",

keywords = "biosynthesis, cyclization, enzymes, maleidride, polyketides",

author = "Katherine Williams and Szwalbe, {Agnieszka J} and Mulholland, {Nicholas P} and Vincent, {Jason L} and Andy Bailey and Willis, {Christine L} and Simpson, {Thomas J} and Cox, {Russell J}",

note = "{\textcopyright} 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.",

year = "2016",

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doi = "10.1002/anie.201511882",

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T1 - Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis

AU - Williams, Katherine

AU - Szwalbe, Agnieszka J

AU - Mulholland, Nicholas P

AU - Vincent, Jason L

AU - Bailey, Andy

AU - Willis, Christine L

AU - Simpson, Thomas J

AU - Cox, Russell J

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Fungal maleidrides are an important family of bioactive secondary metabolites that consist of 7, 8, or 9-membered carbocycles with one or two fused maleic anhydride moieties. The biosynthesis of byssochlamic acid (a nonadride) and agnestadride A (a heptadride) was investigated through gene disruption and heterologous expression experiments. The results reveal that the precursors for cyclization are formed by an iterative highly reducing fungal polyketide synthase supported by a hydrolase, together with two citrate-processing enzymes. The enigmatic ring formation is catalyzed by two proteins with homology to ketosteroid isomerases, and assisted by two proteins with homology to phosphatidylethanolamine-binding proteins.

AB - Fungal maleidrides are an important family of bioactive secondary metabolites that consist of 7, 8, or 9-membered carbocycles with one or two fused maleic anhydride moieties. The biosynthesis of byssochlamic acid (a nonadride) and agnestadride A (a heptadride) was investigated through gene disruption and heterologous expression experiments. The results reveal that the precursors for cyclization are formed by an iterative highly reducing fungal polyketide synthase supported by a hydrolase, together with two citrate-processing enzymes. The enigmatic ring formation is catalyzed by two proteins with homology to ketosteroid isomerases, and assisted by two proteins with homology to phosphatidylethanolamine-binding proteins.

KW - biosynthesis

KW - cyclization

KW - enzymes

KW - maleidride

KW - polyketides

U2 - 10.1002/anie.201511882

DO - 10.1002/anie.201511882

M3 - Article (Academic Journal)

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JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

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Heterologous Production of Fungal Maleidrides Reveals the Cryptic Cyclization Involved in their Biosynthesis

Abstract

Keywords

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Projects

3-month Core Capability for Chemistry Research

CHEMICAL ANALYSIS OF HYBRID FUNGAL MEGASYNTHASES

Profiles

Dr Andy M Bailey

Professor Chris L Willis

Cite this