Skip to main content
Log in

Nootkatone—a biotechnological challenge

  • Mini-Review
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

Due to its pleasant grapefruit-like aroma and various further interesting molecular characteristics, (+)-nootkatone represents a highly sought-after specialty chemical. (+)-Nootkatone is accumulated in its producer plants in trace amounts only, and the demand of the food, cosmetics and pharmaceutical industry is currently predominantly met by chemical syntheses. These typically require environmentally critical reagents, catalysts and solvents, and the final product must not be marketed as a “natural flavour” compound. Both the market pull and the technological push have thus inspired biotechnologists to open up more attractive routes towards natural (+)-nootkatone. The multifaceted approaches for the de novo biosynthesis or the biotransformation of the precursor (+)-valencene to (+)-nootkatone are reviewed. Whole-cell systems of bacteria, filamentous fungi and plants, cell extracts or purified enzymes have been employed. A prominent biocatalytic route is the allylic oxidation of (+)-valencene. It allows the production of natural (+)-nootkatone in high yields under mild reaction conditions. The first sequence data of (+)-valencene-converting activities have just become known.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Notes

  1. The cited patent is in Japanese. The parameters and yields given were taken from Huang et al. 2001.

References

  • Andersen NH (1970) Biogenetic implications of the antipodal sesquiterpenes of vetiver oil. Phytochemistry 9:145–151

    CAS  Google Scholar 

  • Baysal T, Demirdöven A (2007) Lipoxygenase in fruits and vegetables: a review. Enzyme Microb Technol 40:491–496

    CAS  Google Scholar 

  • Bouwmeester HJ, de Kraker JW, Schurink M, Bino RJ, de Groot A, Franssen MCR (2007) Plant enzymes for bioconversion. US Patent Application 7214507

  • Chappell J (2004) Valencene synthase—a biochemical magician and harbinger of transgenic aromas. Trends Plant Sci 9:266–269

    CAS  PubMed  Google Scholar 

  • Chappell J, Greenhagen B (2006) Novel sesquiterpene synthase gene and protein. US Patent Application 2006/218661

  • Dastur KP (1973) A stereoselective approach to eremophilane sesquiterpenes. A synthesis of (±)-nootkatone. J Am Chem Soc 95:6509–6510

    CAS  Google Scholar 

  • de Kraker J-W, Schurink M, Franssen MCR, König WA, de Groot A, Bouwmeester HJ (2003) Hydroxylation of sesquiterpenes by enzymes from chicory (Cichorium intybus L.) roots. Tetrahedron 59:409–418

    Google Scholar 

  • del Río JA, Ortuño A, Puig DG, Iborra JL, Sabater F (1991) Accumulation of the sesquiterpenes nootkatone and valencene by callus cultures of Citrus paradisi, Citrus limonia and Citrus aurantium. Plant Cell Rep 10:410–413

    PubMed  Google Scholar 

  • del Río JA, Ortuño A, García-Puig D, Porras I, García-Lidón A, Sabater F (1992) Variations of nootkatone and valencene levels during the development of grapefruit. J Agric Food Chem 40:1488–1490

    Google Scholar 

  • Dhavlikar RS, Albroscheit G (1973) Mikrobiologische Umsetzung von Terpenen: Valencen. Dragoco Rep 12:251–258

    Google Scholar 

  • Drawert F, Berger RG (1982) Über die Biogenese von Aromastoffen bei Pflanzen und Früchten. Chem Mikrobiol Technol Lebensm 7:143–147

    CAS  Google Scholar 

  • Drawert F, Berger RG, Godelmann R (1984) Regioselective biotransformation of valencene in cell suspension cultures of Citrus sp. Plant Cell Rep 3:37–40

    CAS  PubMed  Google Scholar 

  • Erdtman H, Hirose Y (1962) The chemistry of the natural order Cupressales. Acta Chem Scand 16:1311–1314

    CAS  Google Scholar 

  • Fisher C, Scott TR (1997) Food flavours: biology and chemistry. Royal Society of Chemistry, Information Services, Cambridge

    Google Scholar 

  • Flamini G, Cioni PL, Morelli I (2003) Volatiles from leaves, fruits, and virgin oil from Olea europaea Cv. Olivastra Seggianese from Italy. J Agric Food Chem 51:1382–1386

    CAS  PubMed  Google Scholar 

  • Fraatz MA, Kopp SJL, Takenberg M, Krings U, Marx S, Berger RG, Zorn H (2008) Enzymatische Synthese von Nootkaton. German Patent Application; submitted

  • Furusawa M, Hashimoto T, Noma Y, Asakawa Y (2005) Highly efficient production of nootkatone, the grapefruit aroma from valencene, by biotransformation. Chem Pharm Bull (Tokyo) 53:1513–1514

    CAS  Google Scholar 

  • Haring HG, Rijkens F, Boelens H, van der Gen A (1972) Olfactory studies on enantiomeric eremophilane sesquiterpenoids. J Agric Food Chem 20:1018–1021

    CAS  Google Scholar 

  • Huang R, Christenson PA, Labuda IM (2001) Process for the preparation of nootkatone by laccase catalysis. US Patent Application 6200786

  • Hunter GLK, Brogden WB Jr (1965a) Conversion of valencene to nootkatone. J Food Sci 30:876–878

    CAS  Google Scholar 

  • Hunter GLK, Brogden WB Jr (1965b) Analysis of the terpene and sesquiterpene hydrocarbons in some citrus oils. J Food Sci 30:383–387

    CAS  Google Scholar 

  • Iny D, Pinsky A, Cojocoru M, Grossman S (1993) Lipoxygenase of Thermoactinomyces vulgaris, purification and characterization of reaction products. Int J Biochem 25:1313–1323

    CAS  Google Scholar 

  • Kaspera R (2004) Oxyfunktionalisierung von Terpenkohlenwasserstoffen zu aromaaktiven Terpenoiden durch selektive Biokatalyse. Dissertation, Leibniz Universität, Hannover

  • Kaspera R, Krings U, Nanzad T, Berger RG (2005) Bioconversion of (+)-valencene in submerged cultures of the ascomycete Chaetomium globosum. Appl Microbiol Biotechnol 67:477–483

    CAS  PubMed  Google Scholar 

  • Kelsey RG, Hennon PE, Huso M, Karchesy JJ (2005) Changes in heartwood chemistry of dead yellow-cedar trees that remain standing for 80 years or more in southeast Alaska. J Chem Ecol 31:2653–2670

    CAS  PubMed  Google Scholar 

  • Kosjek B, Stampfer W, van Deursen R, Faber K, Kroutil W (2003) Efficient production of raspberry ketone via ‘green’ biocatalytic oxidation. Tetrahedron 59:9517–9521

    CAS  Google Scholar 

  • Kuhn H, Thiele BJ (1999) The diversity of the lipoxygenase family: many sequence data but little information on biological significance. FEBS Lett 449:7–11

    CAS  PubMed  Google Scholar 

  • Kuribayashi T, Kaise H, Uno C, Hara T, Hayakawa T, Joh T (2002) Purification and characterization of lipoxygenase from Pleurotus ostreatus. J Agric Food Chem 50:1247–1253

    CAS  PubMed  Google Scholar 

  • Lynen F (1967) Biosynthetic pathways from acetate to natural products. Pure Appl Chem 14:137–167

    CAS  PubMed  Google Scholar 

  • MacLeod WD Jr, Buigues NM (1964) Sesquiterpenes. I. Nootkatone, a new grapefruit flavor constituent. J Food Sci 29:565–568

    CAS  Google Scholar 

  • MacLeod AJ, MacLeod G, Subramanian G (1988) Volatile aroma constituents of celery. Phytochemistry 27:373–375

    CAS  Google Scholar 

  • Majetich G, Behnke M, Hull K (1985) A stereoselective synthesis of (±)-nootkatone and (±)-valencene via an intramolecular Sakurai reaction. J Org Chem 50:3615–3618

    CAS  Google Scholar 

  • Marshall JA, Ruden RA (1971) The stereoselective total synthesis of racemic nootkatone. J Org Chem 36:594–596

    CAS  Google Scholar 

  • Miyazawa M, Watanabe H, Kameoka H (1997) Inhibition of acetylcholinesterase activity by monoterpenoids with a p-menthane skeleton. J Agric Food Chem 45:677–679

    CAS  Google Scholar 

  • Miyazawa M, Nakamura Y, Ishikawa Y (2000) Insecticidal sesquiterpene from Alpinia oxyphylla against Drosophila melanogaster. J Agric Food Chem 48:3639–3641

    CAS  PubMed  Google Scholar 

  • Miyazawa M, Tougo H, Ishihara M (2001) Inhibition of acetylcholinesterase activity by essential oil from Citrus paradisi. Nat Prod Lett 15:205–210

    CAS  PubMed  Google Scholar 

  • Muller B, Dean C, Schmidt C, Kuhn J-C (1998) Process for the preparation of nootkatone. US Patent Application 5847226

  • Murase T, Minegishi Y (2007) AMPK activating agent. US Patent Application 2007/0054965

  • Njoroge SM, Mungai HN, Koaze H, Phi NTL, Sawamura M (2006) Volatile constituents of mandarin (Citrus reticulata blanco) peel oil from Burundi. J Essent Oil Res 18:659–662

    CAS  Google Scholar 

  • Ohloff G (1971) Präparative Möglichkeiten mit Singulettsauerstoff. Nachr Chem Techn 24:446–448

    Google Scholar 

  • Okuda M, Sonohara H, Takigawa H, Tajima K, Ito S (1994) Nootkatone manufacture with Rhodococcus from valencene. Japanese Patent Application 06303967A

  • Ortuño A, García-Puig D, Fuster MD, Pérez ML, Sabater F, Porras I, García-Lidón A, del Río JA (1995) Flavanone and nootkatone levels in different varieties of grapefruit and pummelo. J Agric Food Chem 43:1–5

    Google Scholar 

  • Panella NA, Dolan MC, Karchesy JJ, Xiong Y, Peralta-Cruz J, Khasawneh M, Montenieri JA, Maupin GO (2005) Use of novel compounds for pest control: insecticidal and acaricidal activity of essential oil components from heartwood of Alaska yellow cedar. J Med Entomol 42:352–358

    CAS  PubMed  Google Scholar 

  • Pesaro M, Bozzato G, Schudel P (1968) Total synthesis of racemic nootkatone. Chem Commun (London) 19:1152–1154

    Google Scholar 

  • Reil G, Berger RG (1996) Accumulation of chlorophyll and essential oils in photomixotrophic cell cultures of Citrus sp. Z Naturforsch, C. J Biosci 51:657–666

    CAS  Google Scholar 

  • Reil G, Berger RG (1997) Variation of chlorophyll and essential oils in photomixotrophic cell cultures of Coleonema album (Thunb.). J Plant Physiol 150:160–166

    CAS  Google Scholar 

  • Rohmer M (1999) The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants. Nat Prod Rep 16:565–574

    CAS  PubMed  Google Scholar 

  • Roussis V, Vagias C, Tsitsimpikou C, Diamantopoulou N (2000) Chemical variability of the volatile metabolites from the Caribbean corals of the genus Gorgonia. Z Naturforsch, C. J Biosci 55:431–441

    CAS  Google Scholar 

  • Sakamaki H, K-i I, Taniai T, Kitanaka S, Takagi Y, Chai W, Horiuchi CA (2005) Biotransformation of valencene by cultured cells of Gynostemma pentaphyllum. J Mol Catal B Enzym 32:103–106

    CAS  Google Scholar 

  • Salvador JAR, Clark JH (2002) The allylic oxidation of unsaturated steroids by tert-butyl hydroperoxide using surface functionalised silica supported metal catalysts. Green Chem 4:352–356

    CAS  Google Scholar 

  • Sauer AM, Crowe WE, Laine RA, Henderson G (2006) Efficient and economic asymmetric synthesis of nootkatone, tetrahydronootkatone, their precursors and derivatives. US Patent Application 7112700

  • Sawamura M, Kuriyama T (1988) Quantitative determination of volatile constituents in the pummelo (Citrus grandis Osbeck forma Tosa-buntan). J Agric Food Chem 36:567–569

    CAS  Google Scholar 

  • Schulte-Elte K-H, Fracheboud MG, Ohloff G (1974) Procédé pour la préparation d’une cétone bicyclique. Swiss Patent Application 541533

  • Shaffer GW, Eschinasi EH, Purzycki KL, Doerr AB (1975) Oxidations of valencene. J Org Chem 40:2181–2185

    CAS  Google Scholar 

  • Sharon-Asa L, Shalit M, Frydman A, Bar E, Holland D, Or E, Lavi U, Lewinsohn E, Eyal Y (2003) Citrus fruit flavor and aroma biosynthesis: isolation, functional characterization, and developmental regulation of Cstps1, a key gene in the production of the sesquiterpene aroma compound valencene. Plant J 36:664–674

    CAS  PubMed  Google Scholar 

  • Shoji N, Umeyama A, Asakawa Y, Takemoto T, Nomoto K, Ohizumi Y (1984) Structural determination of nootkatol, a new sesquiterpene isolated from Alpinia oxyphylla Miquel possessing calcium-antagonistic activity. J Pharm Sci 73:843–844

    CAS  PubMed  Google Scholar 

  • Sowden RJ, Yasmin S, Rees NH, Bell SG, Wong L-L (2005) Biotransformation of the sesquiterpene (+)-valencene by cytochrome P450cam and P450BM-3. Org Biomol Chem 3:57–64

    CAS  PubMed  Google Scholar 

  • Takahashi S, Yeo Y-S, Zhao Y, O’Maille PE, Greenhagen BT, Noel JP, Coates RM, Chappell J (2007) Functional characterization of premnaspirodiene oxygenase, a cytochrome p450 catalyzing regio- and stereo-specific hydroxylations of diverse sesquiterpene substrates. J Biol Chem 282:31744–31754

    CAS  PubMed  Google Scholar 

  • Tassaneeyakul W, Guo L-Q, Fukuda K, Ohta T, Yamazoe Y (2000) Inhibition selectivity of grapefruit juice components on human cytochromes p450. Arch Biochem Biophys 378:356–363

    CAS  PubMed  Google Scholar 

  • Torii S, Inokuchi T, Handa K (1982) Functionalization of trans-decalin. V. A synthesis of (±)-nootkatone and (±)-valencene from 4β,4aβ-dimethyl-Δ6,7-octalin-1-one ethylene acetal. Bull Chem Soc Jpn 55:887–890

    CAS  Google Scholar 

  • van Brink HM, van Gorcom RF, van den Hondel CA, Punt PJ (1998) Cytochrome P450 enzyme systems in fungi. Fungal Genet Biol 23:1–17

    PubMed  Google Scholar 

  • Willershausen H, Graf H (1991) Enzymatische Transformation von Valencen zu Nootkaton. Chemiker-Zeitung 115:358–360

    CAS  Google Scholar 

  • Wilson CWIII, Shaw PE (1978) Synthesis of nootkatone from valencene. J Agric Food Chem 26:1430–1432

    CAS  Google Scholar 

  • Wu S, Schoenbeck MA, Greenhagen BT, Takahashi S, Lee S, Coates RM, Chappell J (2005) Surrogate splicing for functional analysis of sesquiterpene synthase genes. Plant Physiol 138:1322–13333

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yanami T, Miyashita M, Yoshikoshi A (1980) Synthetic study of (+)-nootkatone from (-)-β-pinene. J Org Chem 45:607–612

    CAS  Google Scholar 

  • Zhu BCR, Henderson G, Chen F, Maistrello L, Laine RA (2001) Nootkatone is a repellent for Formosan subterranean termite (Coptotermes formosanus). J Chem Ecol 27:523–531

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Financial support of the project “biotechnological production of natural (+)-nootkatone” (AZ 13187) by the “Deutsche Bundesstiftung Umwelt, DBU” is gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Holger Zorn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fraatz, M.A., Berger, R.G. & Zorn, H. Nootkatone—a biotechnological challenge. Appl Microbiol Biotechnol 83, 35–41 (2009). https://doi.org/10.1007/s00253-009-1968-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-009-1968-x

Keywords

Navigation