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MetaCyc Pathway: anthocyanin biosynthesis (cyanidin 3-O-glucoside)

Enzyme View:

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Biosynthesis Secondary Metabolites Biosynthesis Phenylpropanoid Derivatives Biosynthesis Flavonoids Biosynthesis Anthocyanins Biosynthesis

Some taxa known to possess this pathway include ? : Arabidopsis thaliana col , Freesia hybrid cultivar , Ginkgo biloba Inferred from experiment [Xu08], Glycine max , Senecio , Vitis labrusca , Vitis vinifera

Expected Taxonomic Range: Spermatophyta

Summary:
General Background

Anthocyanins are water-soluble, secondary plant products that constitute a major subgroup (about 15 to 20%) of flavonoids [Andersen06]. Almost all vascular plants possess basic anthocyanins such as pelargonidin-3-O-glucoside and cyaniding-3-O-glucoside (this pathway) responsible for the red to magenta coloration of flowers and fruits and delphinidin-3-O-glucoside (anthocyanin biosynthesis (delphinidin 3-O-glucoside)) introducing blue tones to the floral organs of plants [Harborne00].

Anthocyanins play important roles as pigments of flowers and fruits in numerous plants across the plant kingdom to attract insects for pollination and act as protectants against UV-B irradiation [Kong03]. They also exhibit anti-oxidant activities and therefore may serve as potential anticancer [Cooke05] and anti-arteriosclerosis compounds in human health [Williams04] [Springob03] [WinkelShirley02]. Anthocyanines constitute biological active metabolites that also modulate inter-species relationships being intimately connected with the co-existence of plants with, e.g. insects, mammals, and birds [Whiting01].

About This Pathway

Enzymes: The crucial step in this pathway is the oxidation of leucoanthocyanidins to generate respective cyanidins. Despite of intensive research over the last years (e.g. [Turnbull03] [Welford05]) this enzymatic step is still not completely understood and requires further study. Anthocyanidin synthase (ANS), a 2-oxoglutarate iron-dependent oxygenase, catalyzes the penultimate step in the biosynthesis of the anthocyanin class of flavonoids [Wilmouth02]. Anthocyanidin synthase catalyzes the in vitro conversion of leucoanthocyanidins to dihydroflavonol and flavonol intermediates (cis- and trans-isoforms) and to a minor degree anthocyanidins [Turnbull00]. Moreover, the cyanidin synthase of the gymnosperm Ginkgo biloba (ANS/FLS) has been shown to have bifunctional properties and can also act as flavonol synthase (see flavonol biosynthesis), hence catalyzing key reactions in more than one pathway [Xu08].

The formation of colored anthocyanidins such as pelargonidin and cyanidin from colorless leucoanthocyanidins (leucopelargonidin, leucocyanidin) was detected by the ANS-catalyzed reaction in the presence of ferrous ion, 2-oxoglutarate and ascorbate, being followed by acidification with HCI [Saito99]. It has been shown that recombinant ANSs from several model plant species, snapdragon, petunia, torenia, and maize, catalyze the formation of anthocyanidins in vitro through a 2-oxoglutarate-dependent oxidation of corresponding leucoanthocyanidins [Nakajima01]. Assuming that the site of initial oxidation is the same for anthocyanidin and dihydroflavonol formation, evidence is presented for initial oxidation at the C-3 position of the flavonoid C-ring and for two bifurcating steps during catalysis by anthocyanidin synthase [Welford01].

It is assumed that the anthocyanidin synthase proceeds via stereospecific hydroxylation at the C-3 atom of the leucocyanidins which furthermore spontaneously dehydrate and finally form stable isomers, i.e. anthocyanidin pseudobase (3-flaven-2,3-diol) [Davies06].

The other enzyme of the pathway, UDPG: flavonoid 3-O-glucosyltransferase (3-UGT) is considered as a final enzyme necessary for producing the earliest stable anthocyanin molecules in plant cells [Kitamura06]. Glucosylation is one of the most prominent modifications of compounds involved in plant secondary metabolism and often represents final steps within a pathway [LorencKukula04]. Flavonoid 3-O-glucosyltransferases catalyzing red to magenta colored anthocyanins have been identified in many plant genera such as Arabidopsis [Tohge05] and Gentiana [Tanaka96].

Regulation: The flavonoid biosynthetic pathway belongs to one of the most intensely studied areas of plant secondary metabolism [WinkelShirley01] and provides probably the best-investigated regulatory system in plants [Broun05] [Quattrocchio06]. It has long been suggested that enzymes involved in the phenylpropanoid and flavonoid pathweay form multienzyme complexes that channel substrates towards required metabolic routes and entail a complex regulation [Stafford74] [Hrazdina85].

Anthocyanin and proanthocyanin biosynthesis is basically regulated by transcription factors with MYB or helix-loop-helix (HLH) domains and a WD40 protein. Those proteins are able to mutually interact in response to the demand of the plant resulting in the activation of corresponding structural pigmentation genes [Grotewold06] [Koes05] [Wade03]. Little is known so far what regulates the regulators, but light and plant hormones have been established to be central to the expression of anthocyanin biosynthetic genes [Grotewold06].

Transport: Anthocyanins are known to be accumulated in vacuoles where the acidic environment finally causes the alteration from colorless to colored pigments. A growing body of evidence specifies that flavonoid synthesis takes place in the cytoplasm indicating that a transport step is involved in the overall biosynthesis scheme [Kitamura06] [Grotewold06].

Genes encoding glutathione S-transferases (GST's) linked to the sequestration of anthocyanins into the tonoplast have been found in Petunia (AN9) [Mueller00], carnation [Larsen03] and Arabidopsis (TT19) [Kitamura04]. Besides transporters that bind to certain anthocyanins and carry them to the vacuole special intravacuolar bodies, i.e. anthocyanic vacuolar inclusions (AVIs) have been found to be involved in the transport and/or accumulation of anthocyanins. They appear to serve as anthocyanin traps concentrating the pigments (preferentially anthocyanidin 3,5-diglycosides) to a proteinaceous matrix [Markham00].

Citations: [Wellmann06]

Unification Links: AraCyc:PWY-5125

Credits:
Created 01-Mar-2006 by Foerster H , TAIR
Revised 17-Apr-2013 by Foerster H , Boyce Thompson Institute
Revised 27-Oct-2013 by Foerster H , Boyce Thompson Institute


References

Andersen06: Andersen OM, Jordheim M (2006). "The anthocyanins." In: Flavonoids: Chemistry, biochemistry and applications. Andersen, OM, Markham, KR (eds.), Taylor and Francis, 471- 551.

Broun05: Broun P (2005). "Transcriptional control of flavonoid biosynthesis: a complex network of conserved regulators involved in multiple aspects of differentiation in Arabidopsis." Curr Opin Plant Biol 8(3);272-9. PMID: 15860424

Cooke05: Cooke D, Steward WP, Gescher AJ, Marczylo T (2005). "Anthocyans from fruits and vegetables--does bright colour signal cancer chemopreventive activity?." Eur J Cancer 41(13);1931-40. PMID: 16084717

Davies06: Davies KM, Schwinn KE (2006). "Molecular biology and biotechnology of flavonoid biosynthesis." In: Flavonoids: Chemistry, biochemistry and applications. Andersen, OM, Markham, KR (eds.), Taylor and Francis, 143 - 218.

Grotewold06: Grotewold E (2006). "The Genetics and Biochemistry of Floral Pigments." Annu Rev Plant Biol NIL. PMID: 16464150

Hall12: Hall D, Yuan XX, Murata J, De Luca V (2012). "Molecular cloning and biochemical characterization of the UDP-glucose: flavonoid 3-O-glucosyltransferase from Concord grape (Vitis labrusca)." Phytochemistry 74;90-9. PMID: 22098678

Harborne00: Harborne JB, Williams CA (2000). "Advances in flavonoid research since 1992." Phytochemistry 55(6);481-504. PMID: 11130659

Hrazdina85: Hrazdina G, Wagner GJ (1985). "Metabolic pathways as enzyme complexes: evidence for the synthesis of phenylpropanoids and flavonoids on membrane associated enzyme complexes." Arch Biochem Biophys 237(1);88-100. PMID: 3970546

Kitamura04: Kitamura S, Shikazono N, Tanaka A (2004). "TRANSPARENT TESTA 19 is involved in the accumulation of both anthocyanins and proanthocyanidins in Arabidopsis." Plant J 37(1);104-14. PMID: 14675436

Kitamura06: Kitamura S (2006). "Transport of flavonoids." In: The science of flavonoids. Grotewold E (ed). Springer science and business media Inc., 123 - 146.

Koes05: Koes R, Verweij W, Quattrocchio F (2005). "Flavonoids: a colorful model for the regulation and evolution of biochemical pathways." Trends Plant Sci 10(5);236-42. PMID: 15882656

Kong03: Kong JM, Chia LS, Goh NK, Chia TF, Brouillard R (2003). "Analysis and biological activities of anthocyanins." Phytochemistry 64(5);923-33. PMID: 14561507

Larsen03: Larsen ES, Alfenito MR, Briggs WR, Walbot V (2003). "A carnation anthocyanin mutant is complemented by the glutathione S-transferases encoded by maize Bz2 and petunia An9." Plant Cell Rep 21(9);900-4. PMID: 12789508

LorencKukula04: Lorenc-Kukula K, Korobczak A, Aksamit-Stachurska A, Kostyn K, Lukaszewicz M, Szopa J (2004). "Glucosyltransferase: the gene arrangement and enzyme function." Cell Mol Biol Lett 9(4B);935-46. PMID: 15647808

Markham00: Markham KR, Gould KS, Winefield CS, Mitchell KA, Bloor SJ, Boase MR (2000). "Anthocyanic vacuolar inclusions--their nature and significance in flower colouration." Phytochemistry 55(4);327-36. PMID: 11117881

Mueller00: Mueller LA, Goodman CD, Silady RA, Walbot V (2000). "AN9, a petunia glutathione S-transferase required for anthocyanin sequestration, is a flavonoid-binding protein." Plant Physiol 123(4);1561-70. PMID: 10938372

Nakajima01: Nakajima J, Tanaka Y, Yamazaki M, Saito K (2001). "Reaction mechanism from leucoanthocyanidin to anthocyanidin 3-glucoside, a key reaction for coloring in anthocyanin biosynthesis." J Biol Chem 276(28);25797-803. PMID: 11316805

Ogata98: Ogata J, Teramoto S, Yoshitama K (1998). "Isolation and Characterization of UDP-glucose: Cyanidin 3-O-glucosyltransferase from the Flower Buds of Senecio x hybridus." J. Plant Res. 111:213-216.

Quattrocchio06: Quattrocchio F, Baudry A, Lepiniec L, Grotewold E (2006). "The regulation of flavonoid biosynthesis." In: The science of flavonoids. Grotewold E (ed). Springer science and business media Inc., 97 - 122.

Saito99: Saito K, Kobayashi M, Gong Z, Tanaka Y, Yamazaki M (1999). "Direct evidence for anthocyanidin synthase as a 2-oxoglutarate-dependent oxygenase: molecular cloning and functional expression of cDNA from a red forma of Perilla frutescens." Plant J 17(2);181-9. PMID: 10074715

Springob03: Springob K, Nakajima J, Yamazaki M, Saito K (2003). "Recent advances in the biosynthesis and accumulation of anthocyanins." Nat Prod Rep 20(3);288-303. PMID: 12828368

Stafford74: Stafford HA (1974). "Possible multi-enzyme complexes regulating the formation of C6-C3 phenolic compounds and lignins in higher plants." Rec Adv Phytochem, 8, 53-79.

Sui11: Sui X, Gao X, Ao M, Wang Q, Yang D, Wang M, Fu Y, Wang L (2011). "cDNA cloning and characterization of UDP-glucose: anthocyanidin 3-O-glucosyltransferase in Freesia hybrida." Plant Cell Rep 30(7);1209-18. PMID: 21318353

Tanaka96: Tanaka Y, Yonekura K, Fukuchi-Mizutani M, Fukui Y, Fujiwara H, Ashikari T, Kusumi T (1996). "Molecular and biochemical characterization of three anthocyanin synthetic enzymes from Gentiana triflora." Plant Cell Physiol 37(5);711-6. PMID: 8819318

Tohge05: Tohge T, Nishiyama Y, Hirai MY, Yano M, Nakajima J, Awazuhara M, Inoue E, Takahashi H, Goodenowe DB, Kitayama M, Noji M, Yamazaki M, Saito K (2005). "Functional genomics by integrated analysis of metabolome and transcriptome of Arabidopsis plants over-expressing an MYB transcription factor." Plant J 42(2);218-35. PMID: 15807784

Turnbull00: Turnbull JT, Sobey WJ, Aplin RT, Hassan A, Firmin JL, Schofield CJ, Prescott AJ "Are anthocyanidins the immediate products of anthocyanidin synthase?." Chem. Commun., 2000, (24), 2473 - 2474.

Turnbull03: Turnbull JJ, Nagle MJ, Seibel JF, Welford RW, Grant GH, Schofield CJ (2003). "The C-4 stereochemistry of leucocyanidin substrates for anthocyanidin synthase affects product selectivity." Bioorg Med Chem Lett 13(21);3853-7. PMID: 14552794

Wade03: Wade HK, Sohal AK, Jenkins GI (2003). "Arabidopsis ICX1 is a negative regulator of several pathways regulating flavonoid biosynthesis genes." Plant Physiol 131(2);707-15. PMID: 12586894

Welford01: Welford RW, Turnbull JJ, Claridge TD, Prescott AG, Schofield CJ (2001). "Evidence for oxidation at C-3 of the flavonoid C-ring during anthocyanin biosynthesis." Chem Commun (Camb) NIL(18);1828-9. PMID: 12240335

Welford05: Welford RW, Clifton IJ, Turnbull JJ, Wilson SC, Schofield CJ (2005). "Structural and mechanistic studies on anthocyanidin synthase catalysed oxidation of flavanone substrates: the effect of C-2 stereochemistry on product selectivity and mechanism." Org Biomol Chem 3(17);3117-26. PMID: 16106293

Wellmann06: Wellmann F, Griesser M, Schwab W, Martens S, Eisenreich W, Matern U, Lukacin R (2006). "Anthocyanidin synthase from Gerbera hybrida catalyzes the conversion of (+)-catechin to cyanidin and a novel procyanidin." FEBS Lett 580(6);1642-8. PMID: 16494872

Whiting01: Whiting DA (2001). "Natural phenolic compounds 1900-2000: a bird's eye view of a century's chemistry." Nat Prod Rep 18(6);583-606. PMID: 11820759

Williams04: Williams CA, Grayer RJ (2004). "Anthocyanins and other flavonoids." Nat Prod Rep 21(4);539-73. PMID: 15282635

Wilmouth02: Wilmouth RC, Turnbull JJ, Welford RW, Clifton IJ, Prescott AG, Schofield CJ (2002). "Structure and mechanism of anthocyanidin synthase from Arabidopsis thaliana." Structure (Camb) 2002;10(1);93-103. PMID: 11796114

WinkelShirley01: Winkel-Shirley B (2001). "It takes a garden. How work on diverse plant species has contributed to an understanding of flavonoid metabolism." Plant Physiol 127(4);1399-404. PMID: 11743081

WinkelShirley02: Winkel-Shirley B (2002). "Biosynthesis of flavonoids and effects of stress." Curr Opin Plant Biol 5(3);218-23. PMID: 11960739

Xu08: Xu F, Cheng H, Cai R, Li LL, Chang J, Zhu J, Zhang FX, Chen LJ, Wang Y, Cheng SH, Cheng SY (2008). "Molecular cloning and function analysis of an anthocyanidin synthase gene from Ginkgo biloba, and its expression in abiotic stress responses." Mol Cells 26(6);536-47. PMID: 18779661

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

Ford98: Ford CM, Boss PK, Hoj PB (1998). "Cloning and characterization of Vitis vinifera UDP-glucose:flavonoid 3-O-glucosyltransferase, a homologue of the enzyme encoded by the maize Bronze-1 locus that may primarily serve to glucosylate anthocyanidins in vivo." J Biol Chem 273(15);9224-33. PMID: 9535914

FukuchiMizutani11: Fukuchi-Mizutani M, Akagi M, Ishiguro K, Katsumoto Y, Fukui Y, Togami J, Nakamura N, Tanaka Y (2011). "Biochemical and molecular characterization of anthocyanidin/flavonol 3-glucosylation pathways in Rosa x hybrida." Plant biotechnology 28:239-244.

Hennayake06: Hennayake CK, Takagi S, Nishimura K, Kanechi M, Uno Y, Inagaki N (2006). "Differential expression of anthocyanin biosynthesis genes in suspension culture cells of Rosa hybrida cv. Charleston." Plant biotechnology 23: 379-385.

Hennayake07: Hennayake CK, Kanechi M, Uno Y, Inagaki N (2007). "Differential Expression of Anthocyanin Biosynthetic Genes in 'Charleston' Roses." Acta Hort. 760:643-650.

Kubo04: Kubo A, Arai Y, Nagashima S, Yoshikawa T (2004). "Alteration of sugar donor specificities of plant glycosyltransferases by a single point mutation." Arch Biochem Biophys 429(2);198-203. PMID: 15313223

Kubo07: Kubo H, Nawa N, Lupsea SA (2007). "Anthocyaninless1 gene of Arabidopsis thaliana encodes a UDP-glucose:flavonoid-3-O-glucosyltransferase." J Plant Res 120(3);445-9. PMID: 17277900

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

Lazarowski03: Lazarowski ER, Shea DA, Boucher RC, Harden TK (2003). "Release of cellular UDP-glucose as a potential extracellular signaling molecule." Mol Pharmacol 63(5);1190-7. PMID: 12695547

Pelletier97: Pelletier MK, Murrell JR, Shirley BW (1997). "Characterization of flavonol synthase and leucoanthocyanidin dioxygenase genes in Arabidopsis. Further evidence for differential regulation of "early" and "late" genes." Plant Physiol 1997;113(4);1437-45. PMID: 9112784

Turnbull00a: Turnbull JJ, Sobey WJ, Aplin RT, Hassan A, Firmin JL, Schofield CJ, Prescott AG (2000). "Are anthocyanidins the immediate products of anthocyanidin synthase?." Chem. Commun. 2000(24); 2473-2474.


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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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