Elucidation and in planta reconstitution of the parthenolide biosynthetic pathway

TY - JOUR

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

AU - Liu, Qing

AU - Manzano, David

AU - Tanić, Nikola

AU - Pesic, Milica

AU - Bankovic, Jasna

AU - Pateraki, Irini

AU - Ricard, Lea

AU - Ferrer, Albert

AU - de Vos, Ric

AU - de Krol, Sander van

AU - Bouwmeester, Harro

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 1.4μgg-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.

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 1.4μgg-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.

KW - Biosynthetic pathway reconstitution

KW - Feverfew

KW - Metabolic engineering

KW - Parthenolide

U2 - 10.1016/j.ymben.2014.03.005

DO - 10.1016/j.ymben.2014.03.005

M3 - Journal article

C2 - 24704560

AN - SCOPUS:84898867034

SN - 1096-7176

VL - 23

SP - 145

EP - 153

JO - Metabolic Engineering

JF - Metabolic Engineering

ER -