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MetaCyc Pathway: superpathway of tetrahydroxyxanthone biosynthesis

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

Superclasses: Biosynthesis Secondary Metabolites Biosynthesis Xanthones Biosynthesis
Superpathways

Some taxa known to possess this pathway include ? : Centaurium erythraea , Clarkia breweri , Hypericum androsaemum

Expected Taxonomic Range: Tracheophyta

Summary:
General Background

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 [Jiang04a] 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 [Liu03a], 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 [Wang03e]. However, the enzyme and corresponding reaction involved remains to be characterized.

Subpathways: tetrahydroxyxanthone biosynthesis (from benzoate) , tetrahydroxyxanthone biosynthesis (from 3-hydroxybenzoate)

Credits:
Created 07-Sep-2006 by Foerster H , TAIR


References

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

Abd02: Abd El-Mawla AM, Beerhues L (2002). "Benzoic acid biosynthesis in cell cultures of Hypericum androsaemum." Planta 214(5);727-33. PMID: 11882941

Bennett89: Bennett GJ, Lee H-H (1989). "Xanthones from Guttiferae." Phytochemistry, 28(4), 967-998.

Beuerle02: Beuerle T, Pichersky E (2002). "Purification and characterization of benzoate:coenzyme A ligase from Clarkia breweri." Arch Biochem Biophys 400(2);258-64. PMID: 12054436

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

Jiang04a: Jiang DJ, Dai Z, Li YJ (2004). "Pharmacological effects of xanthones as cardiovascular protective agents." Cardiovasc Drug Rev 22(2);91-102. PMID: 15179447

Liu03a: 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

Peres00: Peres V, Nagem TJ, de Oliveira FF (2000). "Tetraoxygenated naturally occurring xanthones." Phytochemistry 55(7);683-710. PMID: 11190384

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.

Schmidt00: Schmidt W, Peters S, Beerhues L (2000). "Xanthone 6-hydroxylase from cell cultures of Centaurium erythraea RAFN and Hypericum androsaemium L." Phytochemistry 53(4);427-31. PMID: 10731018

Schmidt97: Schmidt W, Beerhues L (1997). "Alternative pathways of xanthone biosynthesis in cell cultures of Hypericum androsaemum L." FEBS Lett 420(2-3);143-6. PMID: 9459298

Wang03e: 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

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

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

Barillas00: Barillas W, Beerhues L (2000). "3-Hydroxybenzoate:coenzyme A ligase from cell cultures of Centaurium erythraea: isolation and characterization." Biol Chem 381(2);155-60. PMID: 10746747

Barillas97: Barillas W, Beerhues L (1997). "3-Hydroxybenzoate:coenzyme A ligase and 4-coumarate:coenzyme A ligase from cultured cells of Centaurium erythraea." Planta 202(1);112-6. PMID: 9177055

Beerhues94: Beerhues L, Berger U (1994). "Xanthones in cell suspension cultures of two Centaurium species." Phytochemistry, 35(5), 1227-1231.

Beerhues96: Beerhues L (1996). "Benzophenone synthase from cultured cells of Centaurium erythraea." FEBS Lett 383(3);264-6. PMID: 8925910

Da73: Da Mata Rezende CMA, Gottlieb OR (1973). "Xanthones as Systematic Markers." Biochemical Systematics., 1, 111 - 118.

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

Gescher02: Gescher J, Zaar A, Mohamed M, Schagger H, Fuchs G (2002). "Genes coding for a new pathway of aerobic benzoate metabolism in Azoarcus evansii." J Bacteriol 184(22);6301-15. PMID: 12399500

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

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

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

Nielsen79: Nielsen H, Arends P (1979). "Xanthone constitutents of Hypericum androsaemum." Journal of Natural Products, 42(3), 301-305.

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

Schmidt00a: Schmidt W, Abd el-Mawla AM, Wolfender JL, Hostettmann K, Beerhues L (2000). "Xanthones in cell cultures of Hypericum androsaemum." Planta Med 66(4);380-1. PMID: 10865463

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

Sultanbawa80: Sultanbawa MUS (1980). "Xanthonoids of tropical plants." Tetrahedron, 36, 1465 - 1506.


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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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