Ketoreductase Domain-Catalyzed Polyketide Chain Release in Fungal Alkyl Salicylaldehyde Biosynthesis

Run Yang; Jian Feng; Hao Xiang; Bin Cheng; Li-Dong Shao; Yan-Ping Li; Hang Wang; Qiu-Fen Hu; Wei-Lie Xiao; Yudai Matsuda; Wei-Guang Wang

doi:10.1021/jacs.3c02011

Ketoreductase Domain-Catalyzed Polyketide Chain Release in Fungal Alkyl Salicylaldehyde Biosynthesis

Run Yang (Co-first Author), Jian Feng (Co-first Author), Hao Xiang (Co-first Author), Bin Cheng (Co-first Author), Li-Dong Shao, Yan-Ping Li, Hang Wang, Qiu-Fen Hu, Wei-Lie Xiao^*, Yudai Matsuda^*, Wei-Guang Wang^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

12 Citations (Scopus)

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Abstract

Alkyl salicylaldehyde derivatives are polyketide natural products, which are widely distributed in fungi and exhibit great structural diversity. Their biosynthetic mechanisms have recently been intensively studied; however, how the polyketide synthases (PKSs) involved in the fungal alkyl salicylaldehyde biosyntheses release their products remained elusive. In this study, we discovered an orphan biosynthetic gene cluster of salicylaldehyde derivatives in the fungus Stachybotrys sp. g12. Intriguingly, the highly reducing PKS StrA, encoded by the gene cluster, performs a reductive polyketide chain release, although it lacks a C-terminal reductase domain, which is typically required for such a reductive release. Our study revealed that the chain release is achieved by the ketoreductase (KR) domain of StrA, which also conducts cannonical β-keto reductions during polyketide chain elongation. Furthermore, we found that the cupin domain-containing protein StrC plays a critical role in the aromatization reaction. Collectively, we have provided an unprecedented example of a KR domain-catalyzed polyketide chain release and a clearer image of how the salicylaldehyde scaffold is generated in fungi. © 2023 American Chemical Society.

Original language	English
Pages (from-to)	11293–11300
Journal	Journal of the American Chemical Society
Volume	145
Issue number	20
Online published	12 May 2023
DOIs	https://doi.org/10.1021/jacs.3c02011
Publication status	Published - 24 May 2023

Funding

This work was supported by grants from the National Natural Science Foundation of China (Project nos. 21907083 and 31960095), grants from the National Natural Science Foundation of Yunnan Province and Jiangsu Province (nos. 202101AS070022 and BK20210434), the Yunnan Ten-thousand Talents Program to W.G.W., the General Research Fund grant (Project no. 11301321) from the Research Grants Council (RGC) of Hong Kong, and Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform (Project no. 2022YKZY001).

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COPYRIGHT TERMS OF DEPOSITED POSTPRINT FILE: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright © 2023 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/jacs.3c02011.

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GRF: Broadening the Chemical Space of Fungal Meroterpenoids and the Enzymatic Repertoire for Their Biosynthesis
MATSUDA, Y. (Principal Investigator / Project Coordinator)
1/01/22 → …
Project: Research

Cite this

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title = "Ketoreductase Domain-Catalyzed Polyketide Chain Release in Fungal Alkyl Salicylaldehyde Biosynthesis",

abstract = "Alkyl salicylaldehyde derivatives are polyketide natural products, which are widely distributed in fungi and exhibit great structural diversity. Their biosynthetic mechanisms have recently been intensively studied; however, how the polyketide synthases (PKSs) involved in the fungal alkyl salicylaldehyde biosyntheses release their products remained elusive. In this study, we discovered an orphan biosynthetic gene cluster of salicylaldehyde derivatives in the fungus Stachybotrys sp. g12. Intriguingly, the highly reducing PKS StrA, encoded by the gene cluster, performs a reductive polyketide chain release, although it lacks a C-terminal reductase domain, which is typically required for such a reductive release. Our study revealed that the chain release is achieved by the ketoreductase (KR) domain of StrA, which also conducts cannonical β-keto reductions during polyketide chain elongation. Furthermore, we found that the cupin domain-containing protein StrC plays a critical role in the aromatization reaction. Collectively, we have provided an unprecedented example of a KR domain-catalyzed polyketide chain release and a clearer image of how the salicylaldehyde scaffold is generated in fungi. {\textcopyright} 2023 American Chemical Society.",

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Ketoreductase Domain-Catalyzed Polyketide Chain Release in Fungal Alkyl Salicylaldehyde Biosynthesis. / Yang, Run (Co-first Author); Feng, Jian (Co-first Author); Xiang, Hao (Co-first Author) et al.
In: Journal of the American Chemical Society, Vol. 145, No. 20, 24.05.2023, p. 11293–11300.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Ketoreductase Domain-Catalyzed Polyketide Chain Release in Fungal Alkyl Salicylaldehyde Biosynthesis

AU - Yang, Run

AU - Feng, Jian

AU - Xiang, Hao

AU - Cheng, Bin

AU - Shao, Li-Dong

AU - Li, Yan-Ping

AU - Wang, Hang

AU - Hu, Qiu-Fen

AU - Xiao, Wei-Lie

AU - Matsuda, Yudai

AU - Wang, Wei-Guang

PY - 2023/5/24

Y1 - 2023/5/24

N2 - Alkyl salicylaldehyde derivatives are polyketide natural products, which are widely distributed in fungi and exhibit great structural diversity. Their biosynthetic mechanisms have recently been intensively studied; however, how the polyketide synthases (PKSs) involved in the fungal alkyl salicylaldehyde biosyntheses release their products remained elusive. In this study, we discovered an orphan biosynthetic gene cluster of salicylaldehyde derivatives in the fungus Stachybotrys sp. g12. Intriguingly, the highly reducing PKS StrA, encoded by the gene cluster, performs a reductive polyketide chain release, although it lacks a C-terminal reductase domain, which is typically required for such a reductive release. Our study revealed that the chain release is achieved by the ketoreductase (KR) domain of StrA, which also conducts cannonical β-keto reductions during polyketide chain elongation. Furthermore, we found that the cupin domain-containing protein StrC plays a critical role in the aromatization reaction. Collectively, we have provided an unprecedented example of a KR domain-catalyzed polyketide chain release and a clearer image of how the salicylaldehyde scaffold is generated in fungi. © 2023 American Chemical Society.

AB - Alkyl salicylaldehyde derivatives are polyketide natural products, which are widely distributed in fungi and exhibit great structural diversity. Their biosynthetic mechanisms have recently been intensively studied; however, how the polyketide synthases (PKSs) involved in the fungal alkyl salicylaldehyde biosyntheses release their products remained elusive. In this study, we discovered an orphan biosynthetic gene cluster of salicylaldehyde derivatives in the fungus Stachybotrys sp. g12. Intriguingly, the highly reducing PKS StrA, encoded by the gene cluster, performs a reductive polyketide chain release, although it lacks a C-terminal reductase domain, which is typically required for such a reductive release. Our study revealed that the chain release is achieved by the ketoreductase (KR) domain of StrA, which also conducts cannonical β-keto reductions during polyketide chain elongation. Furthermore, we found that the cupin domain-containing protein StrC plays a critical role in the aromatization reaction. Collectively, we have provided an unprecedented example of a KR domain-catalyzed polyketide chain release and a clearer image of how the salicylaldehyde scaffold is generated in fungi. © 2023 American Chemical Society.

U2 - 10.1021/jacs.3c02011

DO - 10.1021/jacs.3c02011

M3 - RGC 21 - Publication in refereed journal

SN - 0002-7863

VL - 145

SP - 11293

EP - 11300

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 20

ER -

Ketoreductase Domain-Catalyzed Polyketide Chain Release in Fungal Alkyl Salicylaldehyde Biosynthesis

Abstract

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GRF: Broadening the Chemical Space of Fungal Meroterpenoids and the Enzymatic Repertoire for Their Biosynthesis

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