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

40 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

Keywords

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

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