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discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
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Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
for maintenance.
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
for maintenance.
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discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
12/28 - 12/31
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MetaCyc Pathway: costunolide biosynthesis

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Biosynthesis Secondary Metabolites Biosynthesis Terpenoids Biosynthesis Sesquiterpenoids Biosynthesis Sesquiterpene Lactone Biosynthesis

Some taxa known to possess this pathway include ? : Artemisia annua , Barnadesia spinosa , Cichorium intybus , Helianthus annuus , Lactuca sativa , Pogostemon cablin , Solidago canadensis , Tanacetum parthenium Inferred from experiment [Majdi11]

Expected Taxonomic Range: cellular organisms , Viridiplantae

Summary:
Wild chicory (Cichorium intybus) is a blue-flowered composite plant that has spread all over the world from the Mediterranean and east Asia. Since the seventeenth century it has been cultivated (var sativum) for its bitter roots that were roasted and used in hot coffee-like beverages. Although the use of these roots was displaced by genuine coffee from Coffea arabica, sprouts of the plant that are grown in the dark became popular as a vegetable (Belgian endive) halfway through the nineteenth century, and are widely used in Mediterranean cuisine.

Chicory roots contain a number of bitter-tasting compounds called sesquiterpene lactones that are postulated to originate from a common germacranolide, (+)-costunolide. Sesquiterpenoid lactones are a major class of plant secondary metabolites mainly found in Asteraceae. The sesquiterpene lactones in chicory act as antifeedants towards insects and also suspected to act as antifungal and antibacterial agents [Franssen05]. Several thousand sesquiterpenoid lactones are known, all of them contain either guaiane, eudesmane, or a germacrane structure of which (+)-costunolide is structurally the simplest and is generally accepted as the parent compound of guaianolides, eudesmanolides, or germacranolides [deKraker02].

Most of the enzymatic steps of costunolide biosynthesis have been experimentally proven [deKraker01, deKraker02]. In Chicory the most abundant lactones are guaianolides called lactucin and lactucopicrin. The biosynthesis of lactucin is suggested to occur via the (+)-costunolide pathway [Franssen05]. The costunolide synthase in Lactuca sativa was shown to produce 6α-hydroxy-germacra-1(10),4,11(13)-trien-12-oate from germacra-1(10),4,11(13)-trien-12-oate which is then non-enzymatically converted to (+)-costunolide. The homolog identified in Helianthus annuus catalyzes the 8β-hydroxylation of germacra-1(10),4,11(13)-trien-12-oate which yielded the corresponding 8β-hydroxy-germacra-1(10),4,11(13)-trien-12-oate. It remains to be shown if this compound can be further metabolized to (+)-costunolide catalyzed by a yet unknown costunolide synthase or if 8β-hydroxy-germacra-1(10),4,11(13)-trien-12-oate represents the entrance compound into sesquiterpene lactones (STLs) other than (+)-costunolide [Ikezawa11].

Three of the steps of this pathway are catalyzed by the same enzyme namely, germacrene A oxidase (GAO1). The pathway is evolutionarily conserved in the three main subfamilies of Asteraceae as well as the basal phylogenetic species; Barnadesia spinosa. The authors also demonstrated the capacity of GAO1 enzymes to catalyze the non-natural substrate amphordiene to artemisinic acid. The amorphodiene oxidase enzyme showed little activity towards the oxidation of germacrene A, indicating that the ancestral GAO1 retained catalytic plasticity, whereas the diverged AMO1 had lost that capacity [Nguyen10a].

Credits:
Created 06-Jul-2010 by Pujar A , Boyce Thompson Institute
Revised 07-Apr-2014 by Foerster H , Boyce Thompson Institute


References

deKraker01: de Kraker JW, Franssen MC, Dalm MC, de Groot A, Bouwmeester HJ (2001). "Biosynthesis of germacrene A carboxylic acid in chicory roots. Demonstration of a cytochrome P450 (+)-germacrene a hydroxylase and NADP+-dependent sesquiterpenoid dehydrogenase(s) involved in sesquiterpene lactone biosynthesis." Plant Physiol 125(4);1930-40. PMID: 11299372

deKraker02: de Kraker JW, Franssen MC, Joerink M, de Groot A, Bouwmeester HJ (2002). "Biosynthesis of costunolide, dihydrocostunolide, and leucodin. Demonstration of cytochrome p450-catalyzed formation of the lactone ring present in sesquiterpene lactones of chicory." Plant Physiol 129(1);257-68. PMID: 12011356

Franssen05: Franssen, M.C.R, Alessandrini, L, Terraneo, G (2005). "Biocatalytic production of flavors and fragrances." Pure Appl. Chem, 77, 273-279.

Ikezawa11: Ikezawa N, Gopfert JC, Nguyen DT, Kim SU, O'Maille PE, Spring O, Ro DK (2011). "Lettuce costunolide synthase (CYP71BL2) and its homolog (CYP71BL1) from sunflower catalyze distinct regio- and stereoselective hydroxylations in sesquiterpene lactone metabolism." J Biol Chem 286(24);21601-11. PMID: 21515683

Majdi11: Majdi M, Liu Q, Karimzadeh G, Malboobi MA, Beekwilder J, Cankar K, Vos Rd, Todorovic S, Simonovic A, Bouwmeester H (2011). "Biosynthesis and localization of parthenolide in glandular trichomes of feverfew (Tanacetum parthenium L. Schulz Bip.)." Phytochemistry 72(14-15);1739-50. PMID: 21620424

Nguyen10a: Nguyen DT, Gopfert JC, Ikezawa N, Macnevin G, Kathiresan M, Conrad J, Spring O, Ro DK (2010). "Biochemical conservation and evolution of germacrene A oxidase in asteraceae." J Biol Chem 285(22);16588-98. PMID: 20351109

Prosser02: Prosser I, Phillips AL, Gittings S, Lewis MJ, Hooper AM, Pickett JA, Beale MH (2002). "(+)-(10R)-Germacrene A synthase from goldenrod, Solidago canadensis; cDNA isolation, bacterial expression and functional analysis." Phytochemistry 60(7);691-702. PMID: 12127586

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Bennett02: Bennett MH, Mansfield JW, Lewis MJ, Beale MH (2002). "Cloning and expression of sesquiterpene synthase genes from lettuce (Lactuca sativa L.)." Phytochemistry 60(3);255-61. PMID: 12031443

Bertea06: Bertea CM, Voster A, Verstappen FW, Maffei M, Beekwilder J, Bouwmeester HJ (2006). "Isoprenoid biosynthesis in Artemisia annua: cloning and heterologous expression of a germacrene A synthase from a glandular trichome cDNA library." Arch Biochem Biophys 448(1-2);3-12. PMID: 16579958

Bouwmeester02: Bouwmeester HJ, Kodde J, Verstappen FW, Altug IG, de Kraker JW, Wallaart TE (2002). "Isolation and characterization of two germacrene A synthase cDNA clones from chicory." Plant Physiol 129(1);134-44. PMID: 12011345

Deguerry06: Deguerry F, Pastore L, Wu S, Clark A, Chappell J, Schalk M (2006). "The diverse sesquiterpene profile of patchouli, Pogostemon cablin, is correlated with a limited number of sesquiterpene synthases." Arch Biochem Biophys 454(2);123-36. PMID: 16970904

Kumeta10: Kumeta Y, Ito M (2010). "Characterization of {delta}-Guaiene Synthases from Cultured Cells of Aquilaria, Responsible for the Formation of the Sesquiterpenes in Agarwood." Plant Physiol 154(4);1998-2007. PMID: 20959422

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Liu14: Liu Q, Manzano D, Tanic N, Pesic M, Bankovic J, Pateraki I, Ricard L, Ferrer A, de Vos R, de Krol Sv, Bouwmeester H (2014). "Elucidation and in planta reconstitution of the parthenolide biosynthetic pathway." Metab Eng 23;145-53. PMID: 24704560

Paul60: Paul, A., Bawdekar, A.S., Joshi, R.S., Somesekar Roa, A, Kelkar, G.R., Bhattacharyya, S.C. (1960). "Terpenoids XX: examination of costus root oil." Perfume Essential Oil Rec 15:115-120.

Steele98: Steele CL, Crock J, Bohlmann J, Croteau R (1998). "Sesquiterpene synthases from grand fir (Abies grandis). Comparison of constitutive and wound-induced activities, and cDNA isolation, characterization, and bacterial expression of delta-selinene synthase and gamma-humulene synthase." J Biol Chem 273(4);2078-89. PMID: 9442047


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Mon Dec 22, 2014, BIOCYC14B.