If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Secondary Metabolites Biosynthesis → Xanthones Biosynthesis|
Expected Taxonomic Range: Tracheophyta
Xanthones are yellow pigments of phenolic origin restricted in occurrence to only a few families of higher plants and some fungi and lichens. The majority of xanthones is rarely glucosylated and has been found in basically two families of higher plants, the Clusiaceae (syn. Guttiferae) and Gentianaceae [Hostettmann89] [Bennett89].
Xanthones can be classified based on their oxygenation, prenylation and glucosylation pattern. The majority of xanthones isolated so far are of the tetraoxygenated-type which have been intensively studied in plants of the Guttiferae and Gentianaceae [Peres00].
Xanthones posses a number of remarkable pharmacological traits and bioactivities (summarized in [Peres00]) and have been used as, e.g. cardiovascular protective agents [Jiang04] and antitumor promotors [Ito98]. Tetrahydroxylated xanthones can be induced by phytopathogens [Jankovic02] and accumulate in calli and cell suspension upon treatment with plant hormones and supplements, such as naphtaleneacetic acid (NAA) in combination with kinetin [Dias00].
About This Pathway
The biosynthesis of plant xanthones originates mainly from a mixed shikimate-acetate pathway, however xanthones entirely derived from acetate have also been reported in lower plants [Peres00] [Hostettmann89]. The main steps in the xanthone biosynthesis involve the condensation of shikimate and acetate moieties which constitute a benzophenone intermediate followed by a regioselective, oxidative mediated intra-molecular coupling to form the xanthone ring [Peters98].
The shikimate derivatives used as entry compounds for the tetrahydroxyxanthone biosynthesis differ in relation to the investigated plants (Hypericum androsaemum vs Centaurium erythraea) [Abd01] [Abd02]. These plants belong to different families that seem to have developed biosynthetic variants of the tetrahydroxyxanthone synthesis which involves enzymes of diverse regioselectivity and substrate preference and leads to varying intermediates [Peters98] [Schmidt97].
The biosynthesis of tetrahydroxyxanthone via 3-hydroxybenzoate in Centaurium erythraea is obtained by the stepwise condensation of 3 malonyl-CoA and 3-hydroxybenzoyl-CoA to form an intermediate tetrahydroxybenzophenone. The biosynthesis of tetrahydroxyxanthone via benzoate in Hypericum androsaemum is different from the Centaurium erythraea variant (tetrahydroxyxanthone biosynthesis (from 3-hydroxybenzoate)) with regard to the regiospecificity and substrate usage of the involved enzymes. The benzophenone synthase prefers benzoyl-CoA [Liu03], which in turn is provided by the catalytic action of a 3-hydroxybenzoate:coenzyme A ligase using benzoic acid [Beuerle02] [Schmidt97]. The new intermediate, 2,4,6-trihydroxybenzophenone is further hydroxylated and converted to the 2,3',4,6-tetrahydroxyphenone intermediate, common to both pathways.
The crucial step in this biosynthesis is the cyclization of the benzophenone to a xanthone, catalyzed by xanthon synthases. While in Centaurium erythraea the xanthone synthase converts this tetrahydroxybenzophenone intermediate regioselective to 1,3,5-trihydroxyxanthone the xanthone synthase of Hypericum androsaemum converts it to the 1,3,7-trihydroxyxanthone.
The last step in the biosynthesis of the tetrahydroxyxanthones is the introduction of a hydroxyl group to the C-ring of the xanthone skeleton. This reaction is carried out by the plant-specific Cytochrome P450-dependend monooxygenase xanthone-6-hydroxylase to form 1,3,5,6-tetrahydroxyxanthone in Centaurium erythraea and 1,3,6,7-tetrahydroxyxanthone in Hypericum androsaemum [Schmidt00].
Another representative of the Gentianaceae, chirayta (Swertia chirata), again hydroxylates 1,3,5-trihydroxyxanthone in the 8-position of the C-ring resulting in the major xanthone of this species 1,3,5,8-tetrahydroxyxanthone [Wang03b]. However, the enzyme and corresponding reaction involved remains to be characterized.
Abd01: Abd El-Mawla AM, Schmidt W, Beerhues L (2001). "Cinnamic acid is a precursor of benzoic acids in cell cultures of Hypericum androsaemum L. but not in cell cultures of Centaurium erythraea RAFN." Planta 212(2);288-93. PMID: 11216850
Dias00: Dias ACP, Seabra RM, Andrade PB, Ferreres F, Fernandes-Ferreira M (2000). "Xanthone biosynthesis and accumulation in calli and suspended cells of Hypericum androsaemum." Plant Science, 150, 93-101.
Hostettmann89: Hostettmann K, Hostettmann M (1989). "Xanthones." In: Dey, PM., Harborne JB (eds) Methods in Plant biochemistry, Harborne JB (editor) Vol 1, Plant Phenolics; Academic Press, London, San Diego, New York, Berkeley, Boston, Sydney, Tokyo, Toronto, 493-508.
Ito98: Ito C, Itoigawa M, Furukawa H, Rao KS, Enjo F, Bu P, Takayasu J, Tokuda H, Nishino H (1998). "Xanthones as inhibitors of Epstein-Barr virus activation." Cancer Lett 132(1-2);113-7. PMID: 10397461
Jankovic02: Jankovic T, Krstic D, Savikin-Fodulovic K, Menkovic N, Grubisic D (2002). "Xanthones and secoiridoids from hairy root cultures of Centaurium erythraea and C. pulchellum." Planta Med 68(10);944-6. PMID: 12391565
Liu03: Liu B, Falkenstein-Paul H, Schmidt W, Beerhues L (2003). "Benzophenone synthase and chalcone synthase from Hypericum androsaemum cell cultures: cDNA cloning, functional expression, and site-directed mutagenesis of two polyketide synthases." Plant J 34(6);847-55. PMID: 12795704
Peters98: Peters S, Schmidt W, Beerhues L (1998). "Regioselective oxidative phenol couplings of 2,3',4,6-tetrahydroxybenzophenone in cell cultures of Centaurium erythraea RAFN and Hypericum androsaemum L." Planta, 204: 64-69.
Wang03b: Wang CZ, Maier UH, Keil M, Zenk MH, Bacher A, Rohdich F, Eisenreich W (2003). "Phenylalanine-independent biosynthesis of 1,3,5,8-tetrahydroxyxanthone. A retrobiosynthetic NMR study with root cultures of Swertia chirata." Eur J Biochem 270(14);2950-8. PMID: 12846828
Altenschmidt91: Altenschmidt U, Oswald B, Fuchs G (1991). "Purification and characterization of benzoate-coenzyme A ligase and 2-aminobenzoate-coenzyme A ligases from a denitrifying Pseudomonas sp." J Bacteriol 1991;173(17);5494-501. PMID: 1885526
Altenschmidt93: Altenschmidt U, Oswald B, Steiner E, Herrmann H, Fuchs G (1993). "New aerobic benzoate oxidation pathway via benzoyl-coenzyme A and 3-hydroxybenzoyl-coenzyme A in a denitrifying Pseudomonas sp." J Bacteriol 175(15);4851-8. PMID: 8335640
Geissler88: Geissler JF, Harwood CS, Gibson J (1988). "Purification and properties of benzoate-coenzyme A ligase, a Rhodopseudomonas palustris enzyme involved in the anaerobic degradation of benzoate." J Bacteriol 1988;170(4);1709-14. PMID: 3350788
Gibson94: Gibson J, Dispensa M, Fogg GC, Evans DT, Harwood CS (1994). "4-Hydroxybenzoate-coenzyme A ligase from Rhodopseudomonas palustris: purification, gene sequence, and role in anaerobic degradation." J Bacteriol 176(3);634-41. PMID: 8300518
Kliebenstein07: Kliebenstein DJ, D'Auria JC, Behere AS, Kim JH, Gunderson KL, Breen JN, Lee G, Gershenzon J, Last RL, Jander G (2007). "Characterization of seed-specific benzoyloxyglucosinolate mutations in Arabidopsis thaliana." Plant J 51(6);1062-76. PMID: 17651367
Mohamed01: Mohamed ME, Zaar A, Ebenau-Jehle C, Fuchs G (2001). "Reinvestigation of a new type of aerobic benzoate metabolism in the proteobacterium Azoarcus evansii." J Bacteriol 183(6);1899-908. PMID: 11222587
Nualkaew12: Nualkaew N, Morita H, Shimokawa Y, Kinjo K, Kushiro T, De-Eknamkul W, Ebizuka Y, Abe I (2012). "Benzophenone synthase from Garcinia mangostana L. pericarps." Phytochemistry 77;60-9. PMID: 22390826
Rubio06: Rubio S, Larson TR, Gonzalez-Guzman M, Alejandro S, Graham IA, Serrano R, Rodriguez PL (2006). "An Arabidopsis mutant impaired in coenzyme A biosynthesis is sugar dependent for seedling establishment." Plant Physiol 140(3);830-43. PMID: 16415216
Schuhle03: Schuhle K, Gescher J, Feil U, Paul M, Jahn M, Schagger H, Fuchs G (2003). "Benzoate-coenzyme A ligase from Thauera aromatica: an enzyme acting in anaerobic and aerobic pathways." J Bacteriol 185(16);4920-9. PMID: 12897012
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