Abstract
Terpenoids form the largest group of plant specialized metabolites and exhibit essential functions in plant metabolism, propagation and defence. Since several mono- and sesquiterpenoids, like artemisinin, menthol and nootkatone, have proven beneficial for mankind, they also possess high socio-economic value. The general mechanisms of terpene biosynthesis are understood and enzymes catalysing the formation of the isoprenoid basic carbon skeletons have been described frequently. In the subsequent pathway steps, it is mainly cytochromes P450 that catalyse the decoration of these basic skeletons and thereby contribute significantly to the structural diversity observed. Structure–function relationship, even though discussed intensively, is poorly understood for this enzyme family; even with the phylogenic relationship well established identification of the functionality of the single enzymes is challenging, and, so far, only a few have been characterized. This review provides an overview over cytochromes P450 participating in the biosynthesis of mono- and sesquiterpenes. Only enzymes that have been described thoroughly after purification and heterologous expression are included in this review and their characteristic features are discussed.
Similar content being viewed by others
Abbreviations
- CPR:
-
Cytochrome P450 reductase
- CYP:
-
Cytochrome P450
- GAO:
-
Germacrene acid oxidase
- SRS:
-
Substrate recognition site
- TPS:
-
Terpene synthase
References
Aharoni A, Giri AP, Verstappen FW et al (2004) Gain and loss of fruit flavor compounds produced by wild and cultivated strawberry species. Plant Cell 16(11):3110–3131
Ashour M, Wink M, Gershenzon J (2010) Biochemistry of terpenoids: monoterpenes, sesquiterpenes and diterpenes. Annu Plant Rev 40:258–303
Bak S, Beisson F, Bishop G et al (2011) Cytochromes P450. The Arabidopsis Book e0144
Berger RG (ed) (2007) Flavours and fragrances chemistry, bioprocessing and sustainability, vol XVI. Springer, Heidelberg
Bernhardt R (2006) Cytochromes P450 as versatile biocatalysts. J Biotechnol 124(1):128–145
Berry R, Wagner CJ, Moshonas MG (1967) Flavor studies of nootkatone in grapefruit juice. J Food Sci 32:75–78
Bertea CM, Schalk M, Karp F et al (2001) Demonstration that menthofuran synthase of mint (Mentha) is a cytochrome P450 monooxygenase: cloning, functional expression, and characterization of the responsible gene. Arch Biochem Biophys 390(2):279–286
Bertea CM, Freije JR, van der Woude H et al (2005) Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua. Planta Med 71(1):40–47
Bohlmann J, Keeling CI (2008) Terpenoid biomaterials. Plant J 54(4):656–669
Bohlmann J, Meyer-Gauen G, Croteau R (1998) Plant terpenoid synthases: molecular biology and phylogenetic analysis. PNAS 95(8):4126–4133
Bozak KR, O’Keefe DP, Christoffersen RE (1992) Expression of a ripening-related Avocado (Persea americana) cytochrome P450 in yeast. Plant Phys 100:1976–1981
Buckingham J (2011) Dictionary of natural products. http://www.chemnetbase.com
Cankar K, van Houwelingen A, Bosch D et al (2011) A chicory cytochrome P450 mono-oxygenase CYP71AV8 for the oxidation of (+)-valencene. FEBS Lett 585(1):178–182
Clark IM, Forde BG, Hallahan DL (1997) Spatially distinct expression of two new cytochrome P450s in leaves of Nepeta racemosa: identification of a trichome-specific isoform. Plant Mol Biol 33(5):875–885
Collu G, Unver N, Peltenburg-Looman AM et al (2001) Geraniol 10-hydroxylase, a cytochrome P450 enzyme involved in terpenoid indole alkaloid biosynthesis. FEBS Lett 508(2):215–220
Contin A, Van der Heijden R, Verpoorte R (1999) Accumulation of loganin and secologanin in vacuoles from suspension cultured Catharanthus roseus cells. Plant Sci 147:177–183
Coutinho EM (2002) Gossypol: a contraceptive for men. Contraception 65(4):259–263
Cragg GM, Kingston DGI, Newman DJ (2011) Anticancer agents from natural products, 2nd edn. CRC Press, Boca Raton
Crocoll C (2011) Biosynthesis of the phenolic monoterpenes, thymol and carvacrol, by terpene synthases and cytochrome P450s in oregano and thyme. PhD Thesis, Friedrich-Schiller-Universität
Daviet J, Schalk M (2010) Biotechnology in plant essential oil production: progress and perspective in metabolic engineering of the terpene pathway. Flav Frag J 25:123–127
Devi BSR, Kim YJ, Sathiyamoorthy S et al (2011) Classification and characterization of putative cytochrome P450 genes from Panax ginseng C. A. Meyer. Biochemistry 76(12):1347–1359
Dictionary of Natural Products (2011) Chapman and Hall/CRC. http://www.chemnetbase.com. Accessed Jan 2012
Drew DP, Krichau N, Reichwald K et al (2009) Guaianolides in apiaceae: perspectives on pharmacology and biosynthesis. Phytochem Rev 8(3):581–599
El-Sayed M, Verpoorte R (2007) Catharanthus terpenoid indole alkaloids: biosynthesis and regulation. Phytochem Rev 6(2–3):277–305
Evans WC (2009) Trease and evans: pharmacognosy, 16th edn. Elsevier, London
Gershenzon J, Dudareva N (2007) The function of terpene natural products in the natural world. Nat Chem Biol 3(7):408–414
Gershenzon J, McConkey ME, Croteau RB (2000) Regulation of monoterpene accumulation in leaves of peppermint. Plant Phys 122(1):205–214
Graham SE, Peterson JA (1999) How similar are P450s and what can their differences teach us? Arch Biochem Biophys 369(1):24–29
Greenhagen BT, Griggs P, Takahashi S et al (2003) Probing sesquiterpene hydroxylase activities in a coupled assay with terpene synthases. Arch Biochem Biophys 409(2):385–394
Guengerich FP (2001) Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 14(6):611–650
Hallahan DL, Nugent JH, Hallahan BJ et al (1992) Interactions of Avocado (Persea americana) Cytochrome P-450 with Monoterpenoids. Plant Phys 98(4):1290–1297
Hallahan DL, Lau SM, Harder PA et al (1994) Cytochrome P-450-catalysed monoterpenoid oxidation in catmint (Nepeta racemosa) and avocado (Persea americana); evidence for related enzymes with different activities. Biochim Biophys Acta 1201(1):94–100
Hamberger B, Bak S (2013) Plant P450s as versatile drivers for evolution of species-specific chemical diversity. Phil Trans R Soc B 368(1612):1471–2970
Hamdane D, Zhang H, Hollenberg P (2008) Oxygen activation by cytochrome P450 monooxygenase. Photosynth Res 98(1–3):657–666
Hasemann CA, Kurumbail RG, Boddupalli SS et al (1995) Structure and function of cytochromes P450: a comparative analysis of three crystal structures. Structure 3(1):41–62
Haudenschild C, Schalk M, Karp F et al (2000) Functional expression of regiospecific cytochrome P450 limonene hydroxylases from mint (Mentha spp.) in Escherichia coli and saccharomyces cerevisiae. Arch Biochem Biophys 379(1):127–136
Ikezawa N, Gopfert JC, Nguyen DT et al (2011) Lettuce costunolide synthase (CYP71BL2) and its homolog (CYP71BL1) from sunflower catalyze distinct regio- and stereoselective hydroxylations in sesquiterpene lactone metabolism. J Biol Chem 286(24):21601–21611
Irmler S, Schroder G, St-Pierre B et al (2000) Indole alkaloid biosynthesis in Catharanthus roseus: new enzyme activities and identification of cytochrome P450 CYP72A1 as secologanin synthase. Plant J 24(6):797–804
Kaltenbach M, Schroder G, Schmelzer E et al (1999) Flavonoid hydroxylase from Catharanthus roseus: cDNA, heterologous expression, enzyme properties and cell-type specific expression in plants. Plant J 19(2):183–193
Li X, Ma D, Chen J et al (2012) Biochemical characterization and identification of a cinnamyl alcohol dehydrogenase from Artemisia annua. Plant Sci 193–194:85–95
Liu Q, Majdi M, Cankar K et al (2011) Reconstitution of the costunolide biosynthetic pathway in yeast and Nicotiana benthamiana. PLoS ONE 6(8):e23255
Luo P, Wang YH, Wang GD et al (2001) Molecular cloning and functional identification of (+)-delta-cadinene-8-hydroxylase, a cytochrome P450 mono-oxygenase (CYP706B1) of cotton sesquiterpene biosynthesis. Plant J 28(1):95–104
Lupien S, Karp F, Wildung M et al (1999) Regiospecific cytochrome P450 limonene hydroxylases from mint (Mentha) species: cDNA isolation, characterization, and functional expression of (-)-4S-limonene-3-hydroxylase and (-)-4S-limonene-6-hydroxylase. Arch Biochem Biophys 368(1):181–192
Mahmoud SS, Croteau RB (2001) Metabolic engineering of essential oil yield and composition in mint by altering expression of deoxyxylulose phosphate reductoisomerase and menthofuran synthase. PNAS 98(15):8915–8920
Mau CJD, Croteau R (2006) Cytochrome P450 oxygenases of monoterpene metabolism. Phytochem Rev 5:373–383
Mau CJ, Karp F, Ito M et al (2010) A candidate cDNA clone for (-)-limonene-7-hydroxylase from Perilla frutescens. Phytochemistry 71(4):373–379
Miller B, Madilao LL, Ralph S et al. (2005) Insect-induced conifer defense. White pine weevil and methyl jasmonate induce traumatic resinosis, de novo formed volatile emissions, and accumulation of terpenoid synthase and putative octadecanoid pathway transcripts in Sitka spruce. Plant Phys 137(1):369–382
Mizutani M (2012) Impacts on diversifation of cytochrome P450 on plant metabolism. Biol Pharm Bull 35(6):824–832
Mizutani M, Sato F (2011) Unusual P450 reactions in plant secondary metabolism. Arch Biochem Biophys 507(1):194–203
Mizutani M, Ward E, Ohta D (1997) Plant geraniol/nerol 10-hydroxylase and DNA coding therefor. US Patent
Nelson DR (2011) Progress in tracing the evolutionary paths of cytochrome P450. Biochim Biophys Acta 1814(1):14–18
Nelson D (2012) Personal communication
Nelson D, Werck-Reichhart D (2011) A P450-centric view of plant evolution. Plant J 66(1):194–211
Nguyen DT, Gopfert JC, Ikezawa N et al (2010) Biochemical conservation and evolution of germacrene a oxidase in asteraceae. J Biol Chem 285(22):16588–16598
O’Connor SE, Maresh JJ (2006) Chemistry and biology of monoterpene indole alkaloid biosynthesis. Nat Prod Rep 23(4):532–547
O’Connor SE, McCoy E (2006) Chapter one Terpene indole alkaloid biosynthesis. In: John TR (ed) Integrative plant biochemistry. Recent advances in phytochemistry, vol 40. Elsevier, Amsterdam, pp 1–22
Okamoto S, Yu F, Harada H et al (2011) A short-chain dehydrogenase involved in terpene metabolism from Zingiber zerumbet. FEBS J 278(16):2892–2900
Olofsson L, Engstrom A, Lundgren A et al (2011) Relative expression of genes of terpene metabolism in different tissues of Artemisia annua L. BMC Plant Biol 11(1):45
Omura T, Sato R (1964) The carbon monoxide-binding pigment of liver microsomes. I. Evidence for its hemoprotein nature. J Biol Chem 239:2370–2378
Oudin A, Mahroug S, Courdavault V et al (2007) Spatial distribution and hormonal regulation of gene products from methyl erythritol phosphate and monoterpene-secoiridoid pathways in Catharanthus roseus. Plant Mol Biol 65(1–2):13–30
Peterson JA, Graham SE (1998) A close family resemblance: the importance of structure in understanding cytochromes P450. Structure 6(9):1079–1085
Ralston L, Kwon ST, Schoenbeck M et al (2001) Cloning, heterologous expression, and functional characterization of 5-epi-aristolochene-1,3-dihydroxylase from tobacco (Nicotiana tabacum). Arch Biochem Biophys 393(2):222–235
Ramadan M, Goeters S, Watzer B et al (2006) Chamazulene carboxylic acid and matricin: a natural profen and its natural prodrug, identified through similarity to synthetic drug substances. J Nat Prod 69(7):1041–1045
Ro DK, Paradise EM, Ouellet M et al (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440(7086):940–943
Ro DK, Ouellet M, Paradise EM et al (2008) Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid. BMC Biotechnol 8:83
Robineau T, Batard Y, Nedelkina S et al (1998) The chemically inducible plant cytochrome P450 CYP76B1 actively metabolizes phenylureas and other xenobiotics. Plant Phys 118(3):1049–1056
Schalk M, Croteau R (2000) A single amino acid substitution (F363I) converts the regiochemistry of the spearmint (-)-limonene hydroxylase from a C6- to a C3-hydroxylase. PNAS 97(22):11948–11953
Schuler MA, Werck-Reichhart D (2003) Functional genomics of P450s. Annu Rev Plant Biol 54(1):629–667
Seifert A, Pleiss J (2009) Identification of selectivity-determining residues in cytochrome P450 monooxygenases: a systematic analysis of the substrate recognition site 5. Proteins 74(4):1028–1035
Simonsen HT, Drew DP, Lunde C (2009) Perspectives on using Physcomitrella Patens as an alternative production platform for Thapsigargin and other Terpenoid drug candidates. Perspect Med Chem 3:1–6
Sirim D, Widmann M, Wagner F et al (2010) Prediction and analysis of the modular structure of cytochrome P450 monooxygenases. BMC Struct Biol 10:34
Sono M, Roach MP, Coulter ED et al (1996) Heme-containing oxygenases. Chem Rev 96(7):2841–2888
Sung PH, Huang FC, Do YY et al (2011) Functional expression of geraniol 10-hydroxylase reveals its dual function in the biosynthesis of terpenoid and phenylpropanoid. J Agric Food Chem 59(9):4637–4643
Takahashi S, Zhao Y, O’Maille PE et al (2005) Kinetic and molecular analysis of 5-epiaristolochene 1,3-dihydroxylase, a cytochrome P450 enzyme catalyzing successive hydroxylations of sesquiterpenes. J Biol Chem 280(5):3686–3696
Takahashi S, Yeo YS, Zhao Y et al (2007) Functional characterization of premnaspirodiene oxygenase, a cytochrome P450 catalyzing regio- and stereo-specific hydroxylations of diverse sesquiterpene substrates. J Biol Chem 282(43):31744–31754
Teoh KH, Polichuk DR, Reed DW et al (2006) Artemisia annua L. (Asteraceae) trichome-specific cDNAs reveal CYP71AV1, a cytochrome P450 with a key role in the biosynthesis of the antimalarial sesquiterpene lactone artemisinin. FEBS Lett 580(5):1411–1416
Teoh KH, Polichuk DR, Reed DW et al (2009) Molecular cloning of an aldehyde dehydrogenase implicated in artemisinin biosynthesis in Artemisia annua. Botany 87(6):635–642
van Herpen TW, Cankar K, Nogueira M et al (2010) Nicotiana benthamiana as a production platform for artemisinin precursors. PLoS ONE 5(12):e14222
Wang YH, Essenberg M (2010) Inhibitor and substrate activities of sesquiterpene olefins toward (+)-[delta]-cadinene-8-hydroxylase, a cytochrome P450 monooxygenase (CYP706B1). Phytochemistry 71(16):1825–1831
Wang J, Liu Y, Cai Y et al (2010) Cloning and functional analysis of geraniol 10-hydroxylase, a cytochrome P450 from Swertia mussotii Franch. Biosci Biotechnol Biochem 74(8):1583–1590
Werck-Reichhart D, Feyereisen R (2000) Cytochromes P450: a success story. Genome Biol 1(6):REVIEWS3003
Wust M, Croteau RB (2002) Hydroxylation of specifically deuterated limonene enantiomers by cytochrome p450 limonene-6-hydroxylase reveals the mechanism of multiple product formation. Biochemistry 41(6):1820–1827
Wust M, Little DB, Schalk M et al (2001) Hydroxylation of limonene enantiomers and analogs by recombinant (-)-limonene 3- and 6-hydroxylases from mint (Mentha) species: evidence for catalysis within sterically constrained active sites. Arch Biochem Biophys 387(1):125–136
Yamamoto H, Katano N, Ooi A et al (2000) Secologanin synthase which catalyzes the oxidative cleavage of loganin into secologanin is a cytochrome P450. Phytochemistry 53(1):7–12
Yu F, Okamoto S, Harada H et al (2011) Zingiber zerumbet CYP71BA1 catalyzes the conversion of alpha-humulene to 8-hydroxy-alpha-humulene in zerumbone biosynthesis. Cell Mol Life Sci 68(6):1033–1040
Zwenger S, Basu C (2008) Plant terpenoids: applications and future potentials. Biotechnol Mol Biol Rev 3(1):1–7
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Weitzel, C., Simonsen, H.T. Cytochrome P450-enzymes involved in the biosynthesis of mono- and sesquiterpenes. Phytochem Rev 14, 7–24 (2015). https://doi.org/10.1007/s11101-013-9280-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11101-013-9280-x