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MetaCyc Pathway: raspberry ketone biosynthesis
Inferred from experimentTraceable author statement to experimental support

Enzyme View:

Pathway diagram: raspberry ketone biosynthesis

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: BiosynthesisSecondary Metabolites BiosynthesisPolyketides Biosynthesis

Some taxa known to possess this pathway include : Polygonum cuspidatum, Rheum palmatum, Rubus idaeus

Expected Taxonomic Range: Eukaryota

General Background

Raspberry ketone (4-hydroxybutanone) is the key metabolite among 230 volatile compounds that determine the bouquet of raspberry. In contrast to the complex nature of other aromas that alter rapidly if the composition of their multiple compounds is not maintained, raspberry ketone is the single dominant volatile that defines raspberry aroma [Hrazdina06]. Although it occurs only in low concentrations (between 1 to 17 μg/100g FW [BorejszaWysocki92]) raspberry ketone and its glucosidic derivatives [Pabst90] have been found across the plant kingdom [Fronza99] as well as in fungi [Zorn03] and insects [Metcalf83].

Raspberry ketone acts as olfactory stimulant [KengHong05], exerts anti-obese actions, alters lipid metabolism [Morimoto05, Choi06] and shows growth inhibition and antifeedant activity [Chattopadhyay04].

Raspberry ketone is a sought-after aroma that is widely used in the food industry for flavor of beverages and dairy products. The natural product, unlike synthetic adulterations, increases appeal and value for commercial purposes [Fronza98]. Because the low natural occurrence in plants it may cost up to $10.000/kg [Zorn03].

About This Pathway

The pathway for raspberry ketone biosynthesis is a short sequence of two enzymatic conversions. Benzalacetone synthase (BST), a chalcone synthase-like enzyme, catalyzes the one-step decarboxylative condensation of p-coumaroyl-CoA and malonyl-CoA to p-hydroxybenzalacetone. This step is considered rate-limiting. The enzyme has been isolated, cloned and characterized [Chattopadhyay04, Abe01, Abe03] and found to be different from the closely related chalcone synthase (CHS) and stilbene synthase (STS).

The polyketide type III synthase (PKS III) from Polygonum cuspidatum represents yet another type in the PKS type III superfamily. In contrast to almost all PKS III proteins which have 1 intron in their gene structure [Schroder97], the PKS III encoded by PKS2 from Polygonum has 3 introns. Moreover, the highly conserved L-phenylalanine 'gatekeeper' residues Phe215 and Phe265 in the active site of PKS IIIs were replaced by L-leucine and L-cysteine in PKS2. Interestingly, the PKS2 encoded protein shows a different substrate specificity in dependence on the pH conditions, at physiological normal pH (6.5-8.5) the recombinant enzyme acted as p-coumaryltriacetic lactone synthase (CTAS) forming predominantly p-coumaroyltriacetate and p-coumaroyltriacetic acid lactone (see resveratrol biosynthesis). In contrast to that, at a higher pH of 9.0-9.5, the PKS2 mainly catalyzed the formation of 4-hydroxybenzalacetone| after only one round of condensation, hence acting as benzalacetone synthase (BAS) (this pathway) [Ma09].

The second step in the pathway converts p-hydroxyacetone to raspberry ketone (p-hydroxybutanone). The NADPH-dependent enzyme activity that reduces the double bond in the side chain of p-hydroxybenzalacetone has been found in crude extracts of raspberry berries and cell cultures [BorejszaWysocki94]. However, the cloning and enzymatic characterization of this enzyme remains to be accomplished.

Created 09-Nov-2006 by Foerster H, TAIR
Revised 16-Sep-2010 by Pujar A, Boyce Thompson Institute
Reviewed 30-Nov-2012 by Foerster H, Boyce Thompson Institute
Revised 16-Mar-2015 by Foerster H, Boyce Thompson Institute


Abe01: Abe I, Takahashi Y, Morita H, Noguchi H (2001). "Benzalacetone synthase. A novel polyketide synthase that plays a crucial role in the biosynthesis of phenylbutanones in Rheum palmatum." Eur J Biochem 268(11);3354-9. PMID: 11389739

Abe03: Abe I, Sano Y, Takahashi Y, Noguchi H (2003). "Site-directed mutagenesis of benzalacetone synthase. The role of the Phe215 in plant type III polyketide synthases." J Biol Chem 278(27);25218-26. PMID: 12724310

BorejszaWysocki92: Borejsza-Wysocki W, Goers SK, McArdle RN, Hrazdina G (1992). "p-Hydrozyphenylbutanone levels in raspberries determined by chromatographic and organoleptic methods." J. Agric. Food Chem, 40, 1176-1177.

BorejszaWysocki94: Borejsza-Wysocki V, Hrazdina G (1994). "Biosynthesis of phydroxyphenylbutan-2-one in raspberry fruits and tissue cultures." Phytochemistry, 35(3), 623-628.

Chattopadhyay04: Chattopadhyay SK, Srivastava S, Sashidhara KV, Tripathi AK, Bhattacharya AK, Negi AS (2004). "Betuligenol derivative with growth inhibition and antifeedant activity." Bioorg Med Chem Lett 14(7);1729-31. PMID: 15026059

Choi06: Choi HS (2006). "Lipolytic effects of citrus peel oils and their components." J Agric Food Chem 54(9);3254-8. PMID: 16637681

Fronza98: Fronza G, Fuganti C, Guillou C, Reniero F, Joulain D (1998). "Natural Abundance (2)H Nuclear Magnetic Resonance Study of the Origin of Raspberry Ketone." J Agric Food Chem 46(1);248-254. PMID: 10554227

Fronza99: Fronza G, Fuganti C, Pedrocchi-Fantoni G, Serra S, Zucchi G, Fauhl C, Guillou C, Reniero F (1999). "Stable isotope characterization of raspberry ketone extracted from Taxus baccata and obtained by oxidation of the accompanying alcohol (Betuligenol)." J Agric Food Chem 47(3);1150-5. PMID: 10552430

Hrazdina06: Hrazdina G (2006). "Aroma production by tissue cultures." J Agric Food Chem 54(4);1116-23. PMID: 16478225

KengHong05: Keng-Hong T, Nishida R (2005). "Synomone or kairomone?--Bulbophyllum apertum flower releases raspberry ketone to attract Bactrocera fruit flies." J Chem Ecol 31(3);497-507. PMID: 15898497

Ma09: Ma LQ, Pang XB, Shen HY, Pu GB, Wang HH, Lei CY, Wang H, Li GF, Liu BY, Ye HC (2009). "A novel type III polyketide synthase encoded by a three-intron gene from Polygonum cuspidatum." Planta 229(3);457-69. PMID: 18998157

Metcalf83: Metcalf RL, Mitchell WC, Metcalf ER (1983). "Olfactory receptors in the melon fly Dacus cucurbitae and the oriental fruit fly Dacus dorsalis." Proc Natl Acad Sci U S A 80(11);3143-3147. PMID: 16593321

Morimoto05: Morimoto C, Satoh Y, Hara M, Inoue S, Tsujita T, Okuda H (2005). "Anti-obese action of raspberry ketone." Life Sci 77(2);194-204. PMID: 15862604

Pabst90: Pabst A, Barron D, Adda J, Schreier P (1990). "Phenylbutan-2-one β-D-glucosides from raspberry fruit." Phytochemistry, 29(12), 3853-3858.

Schroder97: Schroder J (1997). "A family of plant-specific polyketide synthases: facts and predictions." Trends in plant science 2(10), 373-378.

Zorn03: Zorn H, Fischer-Zorn M, Berger RG (2003). "A labeling study to elucidate the biosynthesis of 4-(4-hydroxyphenyl)-butan-2-one (raspberry ketone) by Nidula niveo-tomentosa." Appl Environ Microbiol 69(1);367-72. PMID: 12514017

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

BorejszaWysocki96: Borejsza-Wysocki W, Hrazdina G (1996). "Aromatic Polyketide Synthases (Purification, Characterization, and Antibody Development to Benzalacetone Synthase from Raspberry Fruits)." Plant Physiol 110(3);791-799. PMID: 12226219

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

Morita10: Morita H, Shimokawa Y, Tanio M, Kato R, Noguchi H, Sugio S, Kohno T, Abe I (2010). "A structure-based mechanism for benzalacetone synthase from Rheum palmatum." Proc Natl Acad Sci U S A 107(2);669-73. PMID: 20080733

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

Zheng08: Zheng D, Hrazdina G (2008). "Molecular and biochemical characterization of benzalacetone synthase and chalcone synthase genes and their proteins from raspberry (Rubus idaeus L.)." Arch Biochem Biophys 470(2);139-45. PMID: 18068110

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 Pathway Tools version 19.5 (software by SRI International) on Fri Feb 12, 2016, biocyc13.