Elucidation and in planta reconstitution of the parthenolide biosynthetic pathway.
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 1.4μgg(-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 3β-hydroxylase was identified opening up further options to improve the water solubility of parthenolide and therefore its potential as a drug.
Laboratory of Plant Physiology, Wageningen University, Wageningen, The Netherlands.
Qing
Q
Liu
Department of Molecular Genetics, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus UAB Bellaterra, E-08193 Barcelona, Spain; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain.
David
D
Manzano
Department of Neurobiology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Serbia.
Nikola
N
Tanić
Department of Neurobiology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Serbia.
Milica
M
Pesic
Department of Neurobiology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Serbia.
Jasna
J
Bankovic
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain; Department of Plant and Environmental Sciences, Faculty of Science, University of Copenhagen, Thorvaldsensvej 40, Frederiksberg C, Copenhagen, Denmark.
Irini
I
Pateraki
Laboratory of Plant Physiology, Wageningen University, Wageningen, The Netherlands.
Lea
L
Ricard
Department of Molecular Genetics, Centre for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus UAB Bellaterra, E-08193 Barcelona, Spain; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain.
Albert
A
Ferrer
Plant Research International, Wageningen, The Netherlands; Centre for BioSystems Genomics, Wageningen, The Netherlands; Netherlands Metabolomics Centre, Leiden, The Netherlands.
Ric
R
de Vos
Laboratory of Plant Physiology, Wageningen University, Wageningen, The Netherlands.
Sander
S
van de Krol
Laboratory of Plant Physiology, Wageningen University, Wageningen, The Netherlands. Electronic address: harro.bouwmeester@wur.nl.
Harro
H
Bouwmeester
D055432:Metabolomics / Q000379:methods; D010940:Plant Proteins / Q000235:genetics / Q000378:metabolism; D030821:Plants, Genetically Modified / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism*; D020903:Tanacetum parthenium / Q000201:enzymology / Q000235:genetics; D014026:Nicotiana / Q000235:genetics / Q000378:metabolism
D010940:Plant Proteins; D012717:Sesquiterpenes; C002669:parthenolide
Biosynthetic pathway reconstitution; Feverfew; Metabolic engineering; Parthenolide