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MetaCyc Pathway: curcuminoid biosynthesis

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

Superclasses: Biosynthesis Secondary Metabolites Biosynthesis Polyketides Biosynthesis
Superpathways

Some taxa known to possess this pathway include ? : Curcuma longa

Expected Taxonomic Range: Curcuma

Summary:
General Background

Curcuminoids are a class of diarylheptanoid secondary metabolites produced in turmeric (Curcuma longa) and other related plant species. These yellow pigment compounds appear to offer numerous health benefits based on their anti-inflammatory, antioxidant, anti-tumor, and anti-amyloid properties [Maheshwari06, Ringman05, Weber05a, Strimpakos08]. The rhizome of tumeric has been used both for medicine and as a source of spices for cooking, particularly in Asian societies [Sharma05]. The biosynthesis of three of the most prominent curcuminoids, curcumin, demethoxycurcumin, and bisdemethoxycurcumin is described in this pathway.

About This Pathway

Curcuminoid biosynthesis has been a topic of research for many years. Radiotracer studies have suggested several potential routes for curcuminoid synthesis [Roughley73, Kita08] and complementary research on type III polyketide synthases in several species has provided further insights into potential curcuminoid biosynthetic mechanisms [Schroder97a, Kamo00, Brand06]. In general, these studies suggested that two phenylpropanoid units derived from phenylalanine condense to form the curcumin scaffold. But, it remained unknown whether the hydroxy and methoxy groups were added before or after scaffold formation. A set of labeling experiments suggested that cinnamate (and likely cinnamoyl-CoA) was the primary source of a putative curcumin skeleton intermediate that lacks any functional modifications on either ring (referred to as bisdeshydroxybisdesmethoxycurcumin in [Kita08]). But, the discovery and characterization of four enzymes involved in this pathway, DKS, and CURS1, 2, and 3, led to the proposal that 4-coumaryl-CoA and feruloyl-CoA are likely to be the starter CoA ester substrates used by these enzymes. In this proposed pathway, the hydroxy and methoxy groups are introduced as part of the starter substrates in the first and second condensation reactions to produce a modified diketide intermediate and the final curcuminoid products [Katsuyama09, Katsuyama09a]. It remains to be seen whether the pathway proposed by [Kita08] that calls for later modifications on the curcuminoid skeleton is performed through the activity of any enzymes from Curcuma longa that have not yet been characterized. Although it is not depicted on this pathway, the diketide-CoA esters are predicted to form a β-keto acid intermediate prior to the addition of the second CoA ester [Katsuyama09a].

Regulation of curcuminoid biosynthesis will require further study, but a few hints have emerged from the characterization of these enzymes. DCS, the first enzyme in the pathway, appears to be subject to allosteric regulation. Because both DCS and the downstream CURS enzymes use feruloyl-CoA as a substrate, it may be important to ensure that not all of this compound is consumed by DCS. In comparison to the CURS enzymes, the homotropic activation of DCS may cause a relatively greater decrease in activity in response to reduced levels of feruloyl-CoA and thus promote an adequate flow of both the diketide-CoA esters and feruloyl-CoA to the downstream enzymes [Katsuyama09a]. In addition, differential control of the three CURS (polyketide synthases) may help to account for differences in the levels and distribution of curcuminoids found within different organs and cultivars of tumeric. Although these enzymes are similar in sequence, they fall into two groups, with CURS1 and CURS2 showing similarities in substrate preference and transcript expression patterns that differ from CURS3 [Katsuyama09, Katsuyama09a].

Based on the medicinal importance of these compounds and other structurally related compounds found in other plant species, research on curcuminoid biosynthesis is likely to continue.

Subpathways: trans-cinnamoyl-CoA biosynthesis

Unification Links: PlantCyc:6432

Credits:
Created 12-Feb-2010 by Dreher KA , TAIR


References

Brand06: Brand S, Holscher D, Schierhorn A, Svatos A, Schroder J, Schneider B (2006). "A type III polyketide synthase from Wachendorfia thyrsiflora and its role in diarylheptanoid and phenylphenalenone biosynthesis." Planta 224(2);413-28. PMID: 16496097

Kamo00: Kamo T, Hirai N, Tsuda M, Fujioka D, Ohigashi H (2000). "Changes in the content and biosynthesis of phytoalexins in banana fruit." Biosci Biotechnol Biochem 64(10);2089-98. PMID: 11129580

Katsuyama09: Katsuyama Y, Kita T, Horinouchi S (2009). "Identification and characterization of multiple curcumin synthases from the herb Curcuma longa." FEBS Lett 583(17);2799-803. PMID: 19622354

Katsuyama09a: Katsuyama Y, Kita T, Funa N, Horinouchi S (2009). "Curcuminoid biosynthesis by two type III polyketide synthases in the herb Curcuma longa." J Biol Chem 284(17);11160-70. PMID: 19258320

Kita08: Kita T, Imai S, Sawada H, Kumagai H, Seto H (2008). "The biosynthetic pathway of curcuminoid in turmeric (Curcuma longa) as revealed by 13C-labeled precursors." Biosci Biotechnol Biochem 72(7);1789-98. PMID: 18603793

Maheshwari06: Maheshwari RK, Singh AK, Gaddipati J, Srimal RC (2006). "Multiple biological activities of curcumin: a short review." Life Sci 78(18);2081-7. PMID: 16413584

Ringman05: Ringman JM, Frautschy SA, Cole GM, Masterman DL, Cummings JL (2005). "A potential role of the curry spice curcumin in Alzheimer's disease." Curr Alzheimer Res 2(2);131-6. PMID: 15974909

Roughley73: Roughley, P.J., Whiting, D.A. (1973). "Experiments in the biosynthesis of curcumin." Journal of the Chemical Society. Perkin Transactions 1. 1973: 2379.

Schroder97a: Schroder, J. (1997). "A family of plant-specific polyketide synthases: facts and predictions." Trends in Plant Science. 2: 373-378.

Sharma05: Sharma RA, Gescher AJ, Steward WP (2005). "Curcumin: the story so far." Eur J Cancer 41(13);1955-68. PMID: 16081279

Strimpakos08: Strimpakos AS, Sharma RA (2008). "Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials." Antioxid Redox Signal 10(3);511-45. PMID: 18370854

Weber05a: Weber WM, Hunsaker LA, Abcouwer SF, Deck LM, Vander Jagt DL (2005). "Anti-oxidant activities of curcumin and related enones." Bioorg Med Chem 13(11);3811-20. PMID: 15863007

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

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

Austin03: Austin MB, Noel JP (2003). "The chalcone synthase superfamily of type III polyketide synthases." Nat Prod Rep 20(1);79-110. PMID: 12636085

Colquhoun12: Colquhoun TA, Marciniak DM, Wedde AE, Kim JY, Schwieterman ML, Levin LA, Van Moerkercke A, Schuurink RC, Clark DG (2012). "A peroxisomally localized acyl-activating enzyme is required for volatile benzenoid formation in a Petuniaxhybrida cv. 'Mitchell Diploid' flower." J Exp Bot 63(13);4821-33. PMID: 22771854

Gaid12: Gaid MM, Sircar D, Muller A, Beuerle T, Liu B, Ernst L, Hansch R, Beerhues L (2012). "Cinnamate:CoA Ligase Initiates the Biosynthesis of a Benzoate-Derived Xanthone Phytoalexin in Hypericum calycinum Cell Cultures." Plant Physiol 160(3);1267-80. PMID: 22992510

Guranowski10: Guranowski A, Wojdyla AM, Zimny J, Wypijewska A, Kowalska J, Jemielity J, Davis RE, Bieganowski P (2010). "Dual activity of certain HIT-proteins: A. thaliana Hint4 and C. elegans DcpS act on adenosine 5'-phosphosulfate as hydrolases (forming AMP) and as phosphorylases (forming ADP)." FEBS Lett 584(1);93-8. PMID: 19896942

Katsuyama07: Katsuyama Y, Matsuzawa M, Funa N, Horinouchi S (2007). "In vitro synthesis of curcuminoids by type III polyketide synthase from Oryza sativa." J Biol Chem 282(52);37702-9. PMID: 17932040

Katsuyama11: Katsuyama Y, Miyazono K, Tanokura M, Ohnishi Y, Horinouchi S (2011). "Structural and biochemical elucidation of mechanism for decarboxylative condensation of beta-keto acid by curcumin synthase." J Biol Chem 286(8);6659-68. PMID: 21148316

Kim01c: Kim SH, Virmani D, Wake K, MacDonald K, Kronstad JW, Ellis BE (2001). "Cloning and disruption of a phenylalanine ammonia-lyase gene from Ustilago maydis." Curr Genet 40(1);40-8. PMID: 11570515

Klempien12: Klempien A, Kaminaga Y, Qualley A, Nagegowda DA, Widhalm JR, Orlova I, Shasany AK, Taguchi G, Kish CM, Cooper BR, D'Auria JC, Rhodes D, Pichersky E, Dudareva N (2012). "Contribution of CoA ligases to benzenoid biosynthesis in petunia flowers." Plant Cell 24(5);2015-30. PMID: 22649270

Koukol61: Koukol, J., Conn, E.E. (1961). "The metabolism of aromatic compounds in higher plants. IV. Purification and properties of the phenylalanine deaminase of Hordeum vulgare." J Biol Chem 236;2692-8. PMID: 14458851

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

Liu06: Liu R, Xu S, Li J, Hu Y, Lin Z (2006). "Expression profile of a PAL gene from Astragalus membranaceus var. Mongholicus and its crucial role in flux into flavonoid biosynthesis." Plant Cell Rep 25(7);705-10. PMID: 16456646

MacDonald07: MacDonald MJ, D'Cunha GB (2007). "A modern view of phenylalanine ammonia lyase." Biochem Cell Biol 85(3);273-82. PMID: 17612622

Moore02b: Moore BS, Hertweck C, Hopke JN, Izumikawa M, Kalaitzis JA, Nilsen G, O'Hare T, Piel J, Shipley PR, Xiang L, Austin MB, Noel JP (2002). "Plant-like biosynthetic pathways in bacteria: from benzoic acid to chalcone." J Nat Prod 65(12);1956-62. PMID: 12502351

Payton07: Payton F, Sandusky P, Alworth WL (2007). "NMR study of the solution structure of curcumin." J Nat Prod 70(2);143-6. PMID: 17315954

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

Vannelli07: Vannelli T, Wei Qi W, Sweigard J, Gatenby AA, Sariaslani FS (2007). "Production of p-hydroxycinnamic acid from glucose in Saccharomyces cerevisiae and Escherichia coli by expression of heterologous genes from plants and fungi." Metab Eng 9(2);142-51. PMID: 17204442

Xiang02: Xiang L, Moore BS (2002). "Inactivation, complementation, and heterologous expression of encP, a novel bacterial phenylalanine ammonia-lyase gene." J Biol Chem 277(36);32505-9. PMID: 12082112

Xiang03: Xiang L, Moore BS (2003). "Characterization of benzoyl coenzyme A biosynthesis genes in the enterocin-producing bacterium "Streptomyces maritimus"." J Bacteriol 185(2);399-404. PMID: 12511484

Xue07: Xue Z, McCluskey M, Cantera K, Sariaslani FS, Huang L (2007). "Identification, characterization and functional expression of a tyrosine ammonia-lyase and its mutants from the photosynthetic bacterium Rhodobacter sphaeroides." J Ind Microbiol Biotechnol 34(9);599-604. PMID: 17602252


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 Thu Dec 18, 2014, BIOCYC13A.