Elucidation and in planta reconstitution of the parthenolide biosynthetic pathway

Q. Liu, D. Manzano, N. Tanic, M. Pesic, J. Bankovic, I. Pateraki, L. Ricard, A. Ferrer, R.C.H. de Vos, A.R. van der Krol, H.J. Bouwmeester

Research output: Contribution to journalArticleAcademicpeer-review

33 Citations (Scopus)

Abstract

Parthenolide, the main bioactive compound of the medicinal plant feverfew (Tanacetum parthenium), is a promising anti-cancer drug. However, the biosynthetic pathway of parthenolide has not been elucidated yet. Here we report on the isolation and characterization of all the genes from feverfew that are required for the biosynthesis of parthenolide, using a combination of 454 sequencing of a feverfew glandular trichome cDNA library, co-expression analysis and metabolomics. When parthenolide biosynthesis was reconstituted by transient co-expression of all pathway genes in Nicotiana benthamiana, up to 1.4 µg g-1 parthenolide was produced, mostly present as cysteine and glutathione conjugates. These relatively polar conjugates were highly active against colon cancer cells, with only slightly lower activity than free parthenolide. In addition to these biosynthetic genes, another gene encoding a costunolide and parthenolide 3ß-hydroxylase was identified opening up further options to improve the water solubility of parthenolide and therefore its potential as a drug.
Original languageEnglish
Pages (from-to)145-153
JournalMetabolic Engineering
Volume23
DOIs
Publication statusPublished - 2014

Fingerprint

Biosynthetic Pathways
Tanacetum parthenium
Genes
Biosynthesis
Gene encoding
Solubility
Cells
Trichomes
Metabolomics
parthenolide
Water
Medicinal Plants
Mixed Function Oxygenases
Gene Library
Pharmaceutical Preparations
Colonic Neoplasms
Tobacco
Glutathione
Cysteine

Keywords

  • sesquiterpene lactone parthenolide
  • myelogenous leukemia stem
  • germacrene-a synthase
  • factor-kappa-b
  • tanacetum-parthenium
  • yeast expression
  • progenitor cells
  • cancer
  • chicory
  • apoptosis

Cite this

Liu, Q., Manzano, D., Tanic, N., Pesic, M., Bankovic, J., Pateraki, I., ... Bouwmeester, H. J. (2014). Elucidation and in planta reconstitution of the parthenolide biosynthetic pathway. Metabolic Engineering, 23, 145-153. https://doi.org/10.1016/j.ymben.2014.03.005
Liu, Q. ; Manzano, D. ; Tanic, N. ; Pesic, M. ; Bankovic, J. ; Pateraki, I. ; Ricard, L. ; Ferrer, A. ; de Vos, R.C.H. ; van der Krol, A.R. ; Bouwmeester, H.J. / Elucidation and in planta reconstitution of the parthenolide biosynthetic pathway. In: Metabolic Engineering. 2014 ; Vol. 23. pp. 145-153.
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abstract = "Parthenolide, the main bioactive compound of the medicinal plant feverfew (Tanacetum parthenium), is a promising anti-cancer drug. However, the biosynthetic pathway of parthenolide has not been elucidated yet. Here we report on the isolation and characterization of all the genes from feverfew that are required for the biosynthesis of parthenolide, using a combination of 454 sequencing of a feverfew glandular trichome cDNA library, co-expression analysis and metabolomics. When parthenolide biosynthesis was reconstituted by transient co-expression of all pathway genes in Nicotiana benthamiana, up to 1.4 µg g-1 parthenolide was produced, mostly present as cysteine and glutathione conjugates. These relatively polar conjugates were highly active against colon cancer cells, with only slightly lower activity than free parthenolide. In addition to these biosynthetic genes, another gene encoding a costunolide and parthenolide 3{\ss}-hydroxylase was identified opening up further options to improve the water solubility of parthenolide and therefore its potential as a drug.",
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Liu, Q, Manzano, D, Tanic, N, Pesic, M, Bankovic, J, Pateraki, I, Ricard, L, Ferrer, A, de Vos, RCH, van der Krol, AR & Bouwmeester, HJ 2014, 'Elucidation and in planta reconstitution of the parthenolide biosynthetic pathway', Metabolic Engineering, vol. 23, pp. 145-153. https://doi.org/10.1016/j.ymben.2014.03.005

Elucidation and in planta reconstitution of the parthenolide biosynthetic pathway. / Liu, Q.; Manzano, D.; Tanic, N.; Pesic, M.; Bankovic, J.; Pateraki, I.; Ricard, L.; Ferrer, A.; de Vos, R.C.H.; van der Krol, A.R.; Bouwmeester, H.J.

In: Metabolic Engineering, Vol. 23, 2014, p. 145-153.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Elucidation and in planta reconstitution of the parthenolide biosynthetic pathway

AU - Liu, Q.

AU - Manzano, D.

AU - Tanic, N.

AU - Pesic, M.

AU - Bankovic, J.

AU - Pateraki, I.

AU - Ricard, L.

AU - Ferrer, A.

AU - de Vos, R.C.H.

AU - van der Krol, A.R.

AU - Bouwmeester, H.J.

PY - 2014

Y1 - 2014

N2 - Parthenolide, the main bioactive compound of the medicinal plant feverfew (Tanacetum parthenium), is a promising anti-cancer drug. However, the biosynthetic pathway of parthenolide has not been elucidated yet. Here we report on the isolation and characterization of all the genes from feverfew that are required for the biosynthesis of parthenolide, using a combination of 454 sequencing of a feverfew glandular trichome cDNA library, co-expression analysis and metabolomics. When parthenolide biosynthesis was reconstituted by transient co-expression of all pathway genes in Nicotiana benthamiana, up to 1.4 µg g-1 parthenolide was produced, mostly present as cysteine and glutathione conjugates. These relatively polar conjugates were highly active against colon cancer cells, with only slightly lower activity than free parthenolide. In addition to these biosynthetic genes, another gene encoding a costunolide and parthenolide 3ß-hydroxylase was identified opening up further options to improve the water solubility of parthenolide and therefore its potential as a drug.

AB - Parthenolide, the main bioactive compound of the medicinal plant feverfew (Tanacetum parthenium), is a promising anti-cancer drug. However, the biosynthetic pathway of parthenolide has not been elucidated yet. Here we report on the isolation and characterization of all the genes from feverfew that are required for the biosynthesis of parthenolide, using a combination of 454 sequencing of a feverfew glandular trichome cDNA library, co-expression analysis and metabolomics. When parthenolide biosynthesis was reconstituted by transient co-expression of all pathway genes in Nicotiana benthamiana, up to 1.4 µg g-1 parthenolide was produced, mostly present as cysteine and glutathione conjugates. These relatively polar conjugates were highly active against colon cancer cells, with only slightly lower activity than free parthenolide. In addition to these biosynthetic genes, another gene encoding a costunolide and parthenolide 3ß-hydroxylase was identified opening up further options to improve the water solubility of parthenolide and therefore its potential as a drug.

KW - sesquiterpene lactone parthenolide

KW - myelogenous leukemia stem

KW - germacrene-a synthase

KW - factor-kappa-b

KW - tanacetum-parthenium

KW - yeast expression

KW - progenitor cells

KW - cancer

KW - chicory

KW - apoptosis

U2 - 10.1016/j.ymben.2014.03.005

DO - 10.1016/j.ymben.2014.03.005

M3 - Article

VL - 23

SP - 145

EP - 153

JO - Metabolic Engineering

JF - Metabolic Engineering

SN - 1096-7176

ER -