Substrate promiscuity of enzymes from the sesquiterpene biosynthetic pathways from Artemisia annua and Tanacetum parthenium allows for novel combinatorial sesquiterpene production

Arman Beyraghdar Kashkooli, Alexander R. van der Krol, Patrick Rabe, Jeroen S. Dickschat, Harro Bouwmeester

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

The therapeutic properties of complex terpenes often depend on the stereochemistry of their functional groups. However, stereospecific chemical synthesis of terpenes is challenging. To overcome this challenge, metabolic engineering can be employed using enzymes with suitable stereospecific catalytic activity. Here we used a combinatorial metabolic engineering approach to explore the stereospecific modification activity of the Artemisia annua artemisinic aldehyde ∆11(13) double bond reductase2 (AaDBR2) on products of the feverfew sesquiterpene biosynthesis pathway (GAS, GAO, COS and PTS). This allowed us to produce dihydrocostunolide and dihydroparthenolide. For dihydroparthenolide we demonstrate that the preferred order of biosynthesis of dihydroparthenolide is by reduction of the exocyclic methylene of parthenolide, rather than through C4-C5 epoxidation of dihydrocostunolide. Moreover, we demonstrate a promiscuous activity of feverfew CYP71CB1 on dihydrocostunolide and dihydroparthenolide for the production of 3β-hydroxy-dihydrocostunolide and 3β-hydroxy-dihydroparthenolide, respectively. Combined, these results offer new opportunities for engineering novel sesquiterpene lactones with potentially improved medicinal value.

LanguageEnglish
Pages12-23
JournalMetabolic Engineering
Volume54
DOIs
Publication statusPublished - 1 Jul 2019

Fingerprint

Tanacetum parthenium
Artemisia annua
Terpenes
Metabolic engineering
Metabolic Engineering
Sesquiterpenes
Biosynthesis
Biosynthetic Pathways
Enzymes
Stereochemistry
Epoxidation
Lactones
Substrates
Aldehydes
Functional groups
Catalyst activity
Therapeutics

Keywords

  • Combinatorial metabolic engineering
  • Dihydroparthenolide
  • Double bond reductase
  • Feverfew
  • Sesquiterpene lactone
  • Sweet wormwood

Cite this

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title = "Substrate promiscuity of enzymes from the sesquiterpene biosynthetic pathways from Artemisia annua and Tanacetum parthenium allows for novel combinatorial sesquiterpene production",
abstract = "The therapeutic properties of complex terpenes often depend on the stereochemistry of their functional groups. However, stereospecific chemical synthesis of terpenes is challenging. To overcome this challenge, metabolic engineering can be employed using enzymes with suitable stereospecific catalytic activity. Here we used a combinatorial metabolic engineering approach to explore the stereospecific modification activity of the Artemisia annua artemisinic aldehyde ∆11(13) double bond reductase2 (AaDBR2) on products of the feverfew sesquiterpene biosynthesis pathway (GAS, GAO, COS and PTS). This allowed us to produce dihydrocostunolide and dihydroparthenolide. For dihydroparthenolide we demonstrate that the preferred order of biosynthesis of dihydroparthenolide is by reduction of the exocyclic methylene of parthenolide, rather than through C4-C5 epoxidation of dihydrocostunolide. Moreover, we demonstrate a promiscuous activity of feverfew CYP71CB1 on dihydrocostunolide and dihydroparthenolide for the production of 3β-hydroxy-dihydrocostunolide and 3β-hydroxy-dihydroparthenolide, respectively. Combined, these results offer new opportunities for engineering novel sesquiterpene lactones with potentially improved medicinal value.",
keywords = "Combinatorial metabolic engineering, Dihydroparthenolide, Double bond reductase, Feverfew, Sesquiterpene lactone, Sweet wormwood",
author = "{Beyraghdar Kashkooli}, Arman and {van der Krol}, {Alexander R.} and Patrick Rabe and Dickschat, {Jeroen S.} and Harro Bouwmeester",
year = "2019",
month = "7",
day = "1",
doi = "10.1016/j.ymben.2019.01.007",
language = "English",
volume = "54",
pages = "12--23",
journal = "Metabolic Engineering",
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publisher = "Elsevier",

}

Substrate promiscuity of enzymes from the sesquiterpene biosynthetic pathways from Artemisia annua and Tanacetum parthenium allows for novel combinatorial sesquiterpene production. / Beyraghdar Kashkooli, Arman; van der Krol, Alexander R.; Rabe, Patrick; Dickschat, Jeroen S.; Bouwmeester, Harro.

In: Metabolic Engineering, Vol. 54, 01.07.2019, p. 12-23.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Substrate promiscuity of enzymes from the sesquiterpene biosynthetic pathways from Artemisia annua and Tanacetum parthenium allows for novel combinatorial sesquiterpene production

AU - Beyraghdar Kashkooli, Arman

AU - van der Krol, Alexander R.

AU - Rabe, Patrick

AU - Dickschat, Jeroen S.

AU - Bouwmeester, Harro

PY - 2019/7/1

Y1 - 2019/7/1

N2 - The therapeutic properties of complex terpenes often depend on the stereochemistry of their functional groups. However, stereospecific chemical synthesis of terpenes is challenging. To overcome this challenge, metabolic engineering can be employed using enzymes with suitable stereospecific catalytic activity. Here we used a combinatorial metabolic engineering approach to explore the stereospecific modification activity of the Artemisia annua artemisinic aldehyde ∆11(13) double bond reductase2 (AaDBR2) on products of the feverfew sesquiterpene biosynthesis pathway (GAS, GAO, COS and PTS). This allowed us to produce dihydrocostunolide and dihydroparthenolide. For dihydroparthenolide we demonstrate that the preferred order of biosynthesis of dihydroparthenolide is by reduction of the exocyclic methylene of parthenolide, rather than through C4-C5 epoxidation of dihydrocostunolide. Moreover, we demonstrate a promiscuous activity of feverfew CYP71CB1 on dihydrocostunolide and dihydroparthenolide for the production of 3β-hydroxy-dihydrocostunolide and 3β-hydroxy-dihydroparthenolide, respectively. Combined, these results offer new opportunities for engineering novel sesquiterpene lactones with potentially improved medicinal value.

AB - The therapeutic properties of complex terpenes often depend on the stereochemistry of their functional groups. However, stereospecific chemical synthesis of terpenes is challenging. To overcome this challenge, metabolic engineering can be employed using enzymes with suitable stereospecific catalytic activity. Here we used a combinatorial metabolic engineering approach to explore the stereospecific modification activity of the Artemisia annua artemisinic aldehyde ∆11(13) double bond reductase2 (AaDBR2) on products of the feverfew sesquiterpene biosynthesis pathway (GAS, GAO, COS and PTS). This allowed us to produce dihydrocostunolide and dihydroparthenolide. For dihydroparthenolide we demonstrate that the preferred order of biosynthesis of dihydroparthenolide is by reduction of the exocyclic methylene of parthenolide, rather than through C4-C5 epoxidation of dihydrocostunolide. Moreover, we demonstrate a promiscuous activity of feverfew CYP71CB1 on dihydrocostunolide and dihydroparthenolide for the production of 3β-hydroxy-dihydrocostunolide and 3β-hydroxy-dihydroparthenolide, respectively. Combined, these results offer new opportunities for engineering novel sesquiterpene lactones with potentially improved medicinal value.

KW - Combinatorial metabolic engineering

KW - Dihydroparthenolide

KW - Double bond reductase

KW - Feverfew

KW - Sesquiterpene lactone

KW - Sweet wormwood

U2 - 10.1016/j.ymben.2019.01.007

DO - 10.1016/j.ymben.2019.01.007

M3 - Article

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SP - 12

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JO - Metabolic Engineering

T2 - Metabolic Engineering

JF - Metabolic Engineering

SN - 1096-7176

ER -