Kauniolide synthase is a P450 with unusual hydroxylation and cyclization-elimination activity

Qing Liu, Arman Beyraghdar Kashkooli*, David Manzano, Irini Pateraki, Lea Richard, Pim Kolkman, Maria Fátima Lucas, Victor Guallar, Ric C.H. de Vos, Maurice C.R. Franssen, Alexander van der Krol, Harro Bouwmeester

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

Abstract

Guaianolides are an important class of sesquiterpene lactones with unique biological and pharmaceutical properties. They have been postulated to be derived from germacranolides, but for years no progress has been made in the elucidation of their biosynthesis that requires an unknown cyclization mechanism. Here we demonstrate the isolation and characterization of a cytochrome P450 from feverfew (Tanacetum parthenium), kauniolide synthase. Kauniolide synthase catalyses the formation of the guaianolide kauniolide from the germacranolide substrate costunolide. Unlike most cytochrome P450s, kauniolide synthase combines stereoselective hydroxylation of costunolide at the C3 position, with water elimination, cyclization and regioselective deprotonation. This unique mechanism of action is supported by in silico modelling and docking experiments. The full kauniolide biosynthesis pathway is reconstructed in the heterologous hosts Nicotiana benthamiana and yeast, paving the way for biotechnological production of guaianolide-type sesquiterpene lactones.

Original languageEnglish
Article number4657
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 7 Nov 2018

Fingerprint

Tanacetum parthenium
Hydroxylation
biosynthesis
cytochromes
Cyclization
Biosynthesis
Lactones
Guaiane Sesquiterpenes
elimination
Thermodynamic properties
Deprotonation
Sesquiterpenes
yeast
Cytochromes
Computer Simulation
Yeast
Cytochrome P-450 Enzyme System
Tobacco
isolation
Yeasts

Cite this

Liu, Q., Beyraghdar Kashkooli, A., Manzano, D., Pateraki, I., Richard, L., Kolkman, P., ... Bouwmeester, H. (2018). Kauniolide synthase is a P450 with unusual hydroxylation and cyclization-elimination activity. Nature Communications, 9(1), [4657]. https://doi.org/10.1038/s41467-018-06565-8
Liu, Qing ; Beyraghdar Kashkooli, Arman ; Manzano, David ; Pateraki, Irini ; Richard, Lea ; Kolkman, Pim ; Lucas, Maria Fátima ; Guallar, Victor ; de Vos, Ric C.H. ; Franssen, Maurice C.R. ; van der Krol, Alexander ; Bouwmeester, Harro. / Kauniolide synthase is a P450 with unusual hydroxylation and cyclization-elimination activity. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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abstract = "Guaianolides are an important class of sesquiterpene lactones with unique biological and pharmaceutical properties. They have been postulated to be derived from germacranolides, but for years no progress has been made in the elucidation of their biosynthesis that requires an unknown cyclization mechanism. Here we demonstrate the isolation and characterization of a cytochrome P450 from feverfew (Tanacetum parthenium), kauniolide synthase. Kauniolide synthase catalyses the formation of the guaianolide kauniolide from the germacranolide substrate costunolide. Unlike most cytochrome P450s, kauniolide synthase combines stereoselective hydroxylation of costunolide at the C3 position, with water elimination, cyclization and regioselective deprotonation. This unique mechanism of action is supported by in silico modelling and docking experiments. The full kauniolide biosynthesis pathway is reconstructed in the heterologous hosts Nicotiana benthamiana and yeast, paving the way for biotechnological production of guaianolide-type sesquiterpene lactones.",
author = "Qing Liu and {Beyraghdar Kashkooli}, Arman and David Manzano and Irini Pateraki and Lea Richard and Pim Kolkman and Lucas, {Maria F{\'a}tima} and Victor Guallar and {de Vos}, {Ric C.H.} and Franssen, {Maurice C.R.} and {van der Krol}, Alexander and Harro Bouwmeester",
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Liu, Q, Beyraghdar Kashkooli, A, Manzano, D, Pateraki, I, Richard, L, Kolkman, P, Lucas, MF, Guallar, V, de Vos, RCH, Franssen, MCR, van der Krol, A & Bouwmeester, H 2018, 'Kauniolide synthase is a P450 with unusual hydroxylation and cyclization-elimination activity', Nature Communications, vol. 9, no. 1, 4657. https://doi.org/10.1038/s41467-018-06565-8

Kauniolide synthase is a P450 with unusual hydroxylation and cyclization-elimination activity. / Liu, Qing; Beyraghdar Kashkooli, Arman; Manzano, David; Pateraki, Irini; Richard, Lea; Kolkman, Pim; Lucas, Maria Fátima; Guallar, Victor; de Vos, Ric C.H.; Franssen, Maurice C.R.; van der Krol, Alexander; Bouwmeester, Harro.

In: Nature Communications, Vol. 9, No. 1, 4657, 07.11.2018.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Kauniolide synthase is a P450 with unusual hydroxylation and cyclization-elimination activity

AU - Liu, Qing

AU - Beyraghdar Kashkooli, Arman

AU - Manzano, David

AU - Pateraki, Irini

AU - Richard, Lea

AU - Kolkman, Pim

AU - Lucas, Maria Fátima

AU - Guallar, Victor

AU - de Vos, Ric C.H.

AU - Franssen, Maurice C.R.

AU - van der Krol, Alexander

AU - Bouwmeester, Harro

PY - 2018/11/7

Y1 - 2018/11/7

N2 - Guaianolides are an important class of sesquiterpene lactones with unique biological and pharmaceutical properties. They have been postulated to be derived from germacranolides, but for years no progress has been made in the elucidation of their biosynthesis that requires an unknown cyclization mechanism. Here we demonstrate the isolation and characterization of a cytochrome P450 from feverfew (Tanacetum parthenium), kauniolide synthase. Kauniolide synthase catalyses the formation of the guaianolide kauniolide from the germacranolide substrate costunolide. Unlike most cytochrome P450s, kauniolide synthase combines stereoselective hydroxylation of costunolide at the C3 position, with water elimination, cyclization and regioselective deprotonation. This unique mechanism of action is supported by in silico modelling and docking experiments. The full kauniolide biosynthesis pathway is reconstructed in the heterologous hosts Nicotiana benthamiana and yeast, paving the way for biotechnological production of guaianolide-type sesquiterpene lactones.

AB - Guaianolides are an important class of sesquiterpene lactones with unique biological and pharmaceutical properties. They have been postulated to be derived from germacranolides, but for years no progress has been made in the elucidation of their biosynthesis that requires an unknown cyclization mechanism. Here we demonstrate the isolation and characterization of a cytochrome P450 from feverfew (Tanacetum parthenium), kauniolide synthase. Kauniolide synthase catalyses the formation of the guaianolide kauniolide from the germacranolide substrate costunolide. Unlike most cytochrome P450s, kauniolide synthase combines stereoselective hydroxylation of costunolide at the C3 position, with water elimination, cyclization and regioselective deprotonation. This unique mechanism of action is supported by in silico modelling and docking experiments. The full kauniolide biosynthesis pathway is reconstructed in the heterologous hosts Nicotiana benthamiana and yeast, paving the way for biotechnological production of guaianolide-type sesquiterpene lactones.

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DO - 10.1038/s41467-018-06565-8

M3 - Article

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 4657

ER -

Liu Q, Beyraghdar Kashkooli A, Manzano D, Pateraki I, Richard L, Kolkman P et al. Kauniolide synthase is a P450 with unusual hydroxylation and cyclization-elimination activity. Nature Communications. 2018 Nov 7;9(1). 4657. https://doi.org/10.1038/s41467-018-06565-8