Reconstructing the chemical diversity of labdane-type diterpene biosynthesis in yeast

Codruta Ignea; Efstathia Ioannou; Panagiota Georgantea; Sofia Loupassaki; Fotini A. Trikka; Angelos K. Kanellis; Antonios M. Makris; Vassilios Roussis; Sotirios C. Kampranis

doi:10.1016/j.ymben.2014.12.001

Reconstructing the chemical diversity of labdane-type diterpene biosynthesis in yeast

Codruta Ignea, Efstathia Ioannou, Panagiota Georgantea, Sofia Loupassaki, Fotini A. Trikka, Angelos K. Kanellis, Antonios M. Makris, Vassilios Roussis, Sotirios C. Kampranis

47 Citations (Scopus)

Abstract

Terpenes are a large class of natural products, many of which are used in cosmetics, pharmaceuticals, or biofuels. However, terpene[U+05F3]s industrial application is frequently hindered by limited availability of natural sources or low yields of chemical synthesis. In this report, we developed a modular platform based on standardized and exchangeable parts to reproduce and potentially expand the diversity of terpene structures in Saccharomyces cerevisiae. By combining different module-specific parts, we exploited the substrate promiscuity of class I diterpene synthases to produce an array of labdane-type scaffolds. These were subsequently modified by a scaffold decoration module consisting of a mutant library of a promiscuous cytochrome P450 to afford a range of hydroxylated diterpenes. Further P450 protein engineering yielded dedicated and efficient catalysts for specific products. Terpenes produced include precursors of pharmacologically important compounds, molecules that are difficult to obtain from natural sources, or new natural products. The approach described here provides a platform on which additional gene mining, combinatorial biosynthesis, and protein engineering efforts can be integrated to sustainably explore the terpene chemical space.

Original language	English
Journal	Metabolic Engineering
Volume	28
Pages (from-to)	91-103
Number of pages	13
ISSN	1096-7176
DOIs	https://doi.org/10.1016/j.ymben.2014.12.001
Publication status	Published - 1 Mar 2015
Externally published	Yes

Keywords

Cytochrome P-450 Enzyme System
Diterpenes
Hydroxylation
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins

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10.1016/j.ymben.2014.12.001Licence: CC BY-NC-ND

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title = "Reconstructing the chemical diversity of labdane-type diterpene biosynthesis in yeast",

abstract = "Terpenes are a large class of natural products, many of which are used in cosmetics, pharmaceuticals, or biofuels. However, terpene[U+05F3]s industrial application is frequently hindered by limited availability of natural sources or low yields of chemical synthesis. In this report, we developed a modular platform based on standardized and exchangeable parts to reproduce and potentially expand the diversity of terpene structures in Saccharomyces cerevisiae. By combining different module-specific parts, we exploited the substrate promiscuity of class I diterpene synthases to produce an array of labdane-type scaffolds. These were subsequently modified by a scaffold decoration module consisting of a mutant library of a promiscuous cytochrome P450 to afford a range of hydroxylated diterpenes. Further P450 protein engineering yielded dedicated and efficient catalysts for specific products. Terpenes produced include precursors of pharmacologically important compounds, molecules that are difficult to obtain from natural sources, or new natural products. The approach described here provides a platform on which additional gene mining, combinatorial biosynthesis, and protein engineering efforts can be integrated to sustainably explore the terpene chemical space.",

keywords = "Cytochrome P-450 Enzyme System, Diterpenes, Hydroxylation, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins",

author = "Codruta Ignea and Efstathia Ioannou and Panagiota Georgantea and Sofia Loupassaki and Trikka, {Fotini A.} and Kanellis, {Angelos K.} and Makris, {Antonios M.} and Vassilios Roussis and Kampranis, {Sotirios C.}",

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AU - Ignea, Codruta

AU - Ioannou, Efstathia

AU - Georgantea, Panagiota

AU - Loupassaki, Sofia

AU - Trikka, Fotini A.

AU - Kanellis, Angelos K.

AU - Makris, Antonios M.

AU - Roussis, Vassilios

AU - Kampranis, Sotirios C.

PY - 2015/3/1

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N2 - Terpenes are a large class of natural products, many of which are used in cosmetics, pharmaceuticals, or biofuels. However, terpene[U+05F3]s industrial application is frequently hindered by limited availability of natural sources or low yields of chemical synthesis. In this report, we developed a modular platform based on standardized and exchangeable parts to reproduce and potentially expand the diversity of terpene structures in Saccharomyces cerevisiae. By combining different module-specific parts, we exploited the substrate promiscuity of class I diterpene synthases to produce an array of labdane-type scaffolds. These were subsequently modified by a scaffold decoration module consisting of a mutant library of a promiscuous cytochrome P450 to afford a range of hydroxylated diterpenes. Further P450 protein engineering yielded dedicated and efficient catalysts for specific products. Terpenes produced include precursors of pharmacologically important compounds, molecules that are difficult to obtain from natural sources, or new natural products. The approach described here provides a platform on which additional gene mining, combinatorial biosynthesis, and protein engineering efforts can be integrated to sustainably explore the terpene chemical space.

AB - Terpenes are a large class of natural products, many of which are used in cosmetics, pharmaceuticals, or biofuels. However, terpene[U+05F3]s industrial application is frequently hindered by limited availability of natural sources or low yields of chemical synthesis. In this report, we developed a modular platform based on standardized and exchangeable parts to reproduce and potentially expand the diversity of terpene structures in Saccharomyces cerevisiae. By combining different module-specific parts, we exploited the substrate promiscuity of class I diterpene synthases to produce an array of labdane-type scaffolds. These were subsequently modified by a scaffold decoration module consisting of a mutant library of a promiscuous cytochrome P450 to afford a range of hydroxylated diterpenes. Further P450 protein engineering yielded dedicated and efficient catalysts for specific products. Terpenes produced include precursors of pharmacologically important compounds, molecules that are difficult to obtain from natural sources, or new natural products. The approach described here provides a platform on which additional gene mining, combinatorial biosynthesis, and protein engineering efforts can be integrated to sustainably explore the terpene chemical space.

KW - Cytochrome P-450 Enzyme System

KW - Diterpenes

KW - Hydroxylation

KW - Saccharomyces cerevisiae

KW - Saccharomyces cerevisiae Proteins

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DO - 10.1016/j.ymben.2014.12.001

M3 - Journal article

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VL - 28

SP - 91

EP - 103

JO - Metabolic Engineering

JF - Metabolic Engineering

ER -

Reconstructing the chemical diversity of labdane-type diterpene biosynthesis in yeast

Abstract

Keywords

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