Phytochemistry 70 (2009) 1663–1679
Contents lists available at ScienceDirect
Phytochemistry
journal homepage: www.elsevier.com/locate/phytochem
Review Evolution of rosmarinic acid biosynthesis
Maike Petersen *, Yana Abdullah, Johannes Benner, David Eberle, Katja Gehlen, Stephanie Hücherig, Verena Janiak, Kyung Hee Kim, Marion Sander, Corinna Weitzel, Stefan Wolters
Institut für Pharmazeutische Biologie, Philipps-Universität Marburg, Deutschhausstr. 17A, D-35037 Marburg, Germany article info abstract
Article history: Rosmarinic acid and chlorogenic acid are caffeic acid esters widely found in the plant kingdom and pre- Received 24 February 2009 sumably accumulated as defense compounds. In a survey, more than 240 plant species have been Received in revised form 19 May 2009 screened for the presence of rosmarinic and chlorogenic acids. Several rosmarinic acid-containing species Available online 25 June 2009 have been detected. The rosmarinic acid accumulation in species of the Marantaceae has not been known before. Rosmarinic acid is found in hornworts, in the fern family Blechnaceae and in species of several Keywords: orders of mono- and dicotyledonous angiosperms. The biosyntheses of caffeoylshikimate, chlorogenic Rosmarinic acid acid and rosmarinic acid use 4-coumaroyl-CoA from the general phenylpropanoid pathway as hydroxy- Caffeoylshikimic acid cinnamoyl donor. The hydroxycinnamoyl acceptor substrate comes from the shikimate pathway: shiki- Chlorogenic acid Phenylpropanoid metabolism mic acid, quinic acid and hydroxyphenyllactic acid derived from L-tyrosine. Similar steps are involved Acyltransferase in the biosyntheses of rosmarinic, chlorogenic and caffeoylshikimic acids: the transfer of the 4-coumaroyl CYP98A moiety to an acceptor molecule by a hydroxycinnamoyltransferase from the BAHD acyltransferase family and the meta-hydroxylation of the 4-coumaroyl moiety in the ester by a cytochrome P450 monooxygen- ase from the CYP98A family. The hydroxycinnamoyltransferases as well as the meta-hydroxylases show high sequence similarities and thus seem to be closely related. The hydroxycinnamoyltransferase and CYP98A14 from Coleus blumei (Lamiaceae) are nevertheless specific for substrates involved in RA biosyn- thesis showing an evolutionary diversification in phenolic ester metabolism. Our current view is that only a few enzymes had to be ‘‘invented” for rosmarinic acid biosynthesis probably on the basis of genes needed for the formation of chlorogenic and caffeoylshikimic acid while further biosynthetic steps might have been recruited from phenylpropanoid metabolism, tocopherol/plastoquinone biosynthesis and photorespiration. Ó 2009 Elsevier Ltd. All rights reserved.
Contents
1. Rosmarinic acid ...... 1664 1.1. Occurrence of rosmarinic acid in the plant kingdom ...... 1664 1.2. Screening of plant species for the presence of rosmarinic acid and chlorogenic acid ...... 1665 2. Biosynthesis of rosmarinic acid, chlorogenic acid and caffeoylshikimic acid ...... 1666 3. D-isomer-specific 2-hydroxyacid dehydrogenases ...... 1672 3.1. Hydroxy(phenyl)pyruvate reductase from C. blumei ...... 1673 4. CoA-ester-dependent BAHD hydroxycinnamoyltransferases ...... 1673 4.1. Hydroxycinnamoyltransferases in phenolic metabolism ...... 1673 4.2. Properties of hydroxycinnamoyl-CoA:hydroxyphenyllactate hydroxycinnamoyltransferase (rosmarinic acid synthase; RAS) ...... 1675 5. Cytochrome P450 CYP98A ...... 1675 5.1. CYP98A in phenylpropanoid metabolism ...... 1675 5.2. Properties of 4-coumaroyl-4’-hydroxyphenyllactate 3- and 3’-hydroxylase from C. blumei (CYP98A14) ...... 1676 6. Possible evolutionary relationship of caffeoylshikimic/chlorogenic acid and rosmarinic acid biosynthesis...... 1676 Acknowledgement ...... 1677 References ...... 1677
* Corresponding author. Tel.: +49 6421 2825821; fax: +49 6421 2825828. E-mail address: [email protected] (M. Petersen).
0031-9422/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.phytochem.2009.05.010 1664 M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679
COOH COOH
NH2 NH2 HO L-phenylalanine L-tyrosine PAL OH COOH HO TAT O OH HO O COOH COOH t-cinnamic acid C4H homogentisic acid HO O HPPD COOH HO caffeoyl-5'-O-quinic acid = chlorogenic acid 4-hydroxyphenylpyruvic acid
OH HO 4C-S/Q 3H tocopherols HO 4-coumaric acid HPPR O 4CL O plastoquinones OH COOH SCoA O COOH HO H HO HO HO 4-coumaroyl-5'-O-quinic acid 4-coumaroyl-CoA 4-hydroxyphenyllactic acid
+ quinic acid RAS
+ shikimic acid HCS/QT OH O COOH OH H HO O O 4-coumaroyl-4'-hydroxyphenyllactic acid HO O COOH 4C-pHPL 3H 4C-pHPL 3'H
HO OH OH 4-coumaroyl-5'-O-shikimic acid O COOH O COOH H H HO 4C-S/Q 3H OH O O OH
HO caffeoyl-4'-hydroxy- 4-coumaroyl-3',4'-dihydroxy- O HO phenyllactic acid HO phenyllactic acid HO O COOH Caf-pHPL 3'H 4C-DHPL 3H OH O COOH HO H HO caffeoyl-5'-O-shikimic acid O OH + CoA HCS/QT (?) rosmarinic acid caffeoyl-CoA + shikimic acid HO
Fig. 1. Proposed biosynthetic pathways to rosmarinic acid, caffeoylshikimic acid and chlorogenic acid as well as some other phenylpropanoid pathway-derived compounds. The involved enzymes are: PAL = phenylalanine ammonia lyase; C4H = cinnamic acid 4-hydroxylase; 4CL = 4-coumaric acid CoA-ligase; TAT = tyrosine aminotransferase; HPPR = hydroxyphenylpyruvate reductase; RAS = ‘‘rosmarinic acid synthase”, hydroxycinnamoyl-CoA:hydroxyphenyllactate hydroxycinnamoyltransferase; 4C-pHPL 3H, 4C- pHPL 30H = 4-coumaroyl-40-hydroxyphenyllactate 3/30-hydroxylases; Caf-pHPL 30H = caffeoyl-40-hydroxyphenyllactate 30-hydroxylase; 4C-DHPL 3H = 4-coumaroyl-30,40- dihydroxyphenyllactate 3-hydroxylase; HPPD = hydroxyphenylpyruvate dioxygenase; HCS/QT = hydroxycinnamoyl-CoA: shikimate/quinate hydroxycinnamoyltransferase; 4C-S/Q 3H = 4-coumaroylshikimate/quinate 3-hydroxylase.
1. Rosmarinic acid phyletic according to Grayer et al. (2003). The presence of RA in the Lamiaceae outside of the subfamily Nepetoideae was, however, re- 1.1. Occurrence of rosmarinic acid in the plant kingdom ported by Pedersen (2000) in Teucrium scorodonia and Aegiphila mollis of the sub-family Teucrioideae and Hymenopyramis brachiata The tanning compounds of Labiates have been known as Labiate of uncertain affinity within the family (according to Olmstead tannins (‘‘Labiatengerbstoffe”) for a long time. Research into the (2005)). On the other hand, RA was found in many species outside identification of these compounds started around 1950, and a com- the Lamiaceae and Boraginaceae (Petersen and Simmonds, 2003; pound named rosmarinic acid (RA) was isolated from Rosmarinus Table 1). The use of RA occurrence as a chemotaxonomical marker officinalis (Lamiaceae) by Scarpati and Oriente (1958). Rosmarinic therefore is not recommendable. As can be seen from Table 1,RAis acid is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid already present in the Anthocerotaceae (hornworts), one of the (Fig. 1). It was isolated from many species of the families Lamia- earliest land plant families. Own unpublished investigations could ceae and Boraginaceae and was identified as one of the active com- not show the occurrence of RA in the genus Chara of the green al- ponents of several medicinal plants (e.g. Salvia officinalis, Mentha x gae family Charophyceae which is seen as the algal predecessor of piperita, Thymus vulgaris, Melissa officinalis, Symphytum officinale) land plants. Within the land plants RA was found in species of the within these families. Not all members of the Lamiaceae, however, hornworts (family Anthocerotaceae), ferns (family Blechnaceae) as contain RA. The occurrence is mainly restricted to the subfamily well as some orders of the monocotyledonous plants and the Nepetoideae (Litvinenko et al., 1975), which is regarded as mono- rosids and asterids within the eudicotyledonous plants (Fig. 2). M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679 1665
Table 1 Published occurrence of rosmarinic acid in the plant kingdom. Systematics are according to ‘‘Strasburger – Lehrbuch der Botanik” (Bresinsky et al., 2008).
Subclass Order Family Reference Anthocerophytina Anthocerotales Anthocerotaceae Takeda et al. (1990), Petersen (2003) and Vogelsang et al. (2005) Filicophytina Blechnales Blechnaceae Harborne (1966), Bohm (1968) and Häusler et al. (1992) Spermatophytina, class Magnoliopsida Basal orders Chloranthales Chloranthaceae Zhu et al. (2008) Monocoty ledonous Alismatales Araceae Aquino et al. (2001) plants Potamogetonaceae Petersen (unpublished) Zosteraceae Ravn et al. (1994) and Achamlale et al. (2009) Zingiberales Cannaceae Petersen and Simmonds (2003) and Yun et al. (2004) Marantaceae Abdullah et al. (2008) Liliales Melianthaceae Lee et al. (2008) Eudicoty ledons Myrtales Onagraceae Huang et al. (2007) Celastrales Celastraceae Ly et al. (2006) Rosales Rosaceae Amzad Hossain et al. (2009) Cucurbitales Cucurbitaceae De Tommasi et al. (1991) Malvales Malvaceae/Sterculiaceae Satake et al. (1999) Malvaceae/Tiliaceae Lasure et al. (1994) and Ho et al. (1995) Gentianales Rubiaceae Aquino et al. (1990) Lamiales Lamiaceae Scarpati and Oriente (1958), Litvinenko et al. (1975), Janicsak et al. (1999) and Pedersen (2000) Plantaginaceae Kurkin et al. (1988) cited in Holzmannova (1995) and Velazquez Fiz et al. (2000) Acanthaceae Harborne (1966) Scrophulariaceae Fernandez et al. (1995) Unclear Boraginaceae/ Kelley et al. (1975), Harborne (1966) and Petersen (unpublished) Hydrophyllaceae Apiales Apiaceae Hiller (1965), Hiller and Kothe (1967), Parejo et al. (2004), Le Claire et al. (2005), Yoshida et al. (2005) and Olivier et al. (2008) Araliaceae Trute and Nahrstedt (1996) Asterales Asteraceae Rubio et al. (1992) Dipsacales Dipsacaceae Kowalczyk (1996)
Interestingly there is no report about RA in gymnosperms and only RA has been detected in three orders of the monocotyledonous one recent finding of RA derivatives in the basal dicot order Chlo- plants, namely Alismatales, Liliales and Zingiberales (Ravn et al., ranthales in Sarcandra glabra (Chloranthaceae; Zhu et al., 2008). 1994; Aquino et al., 2001; Petersen and Simmonds, 2003; Yun et al., 2004; Lee et al., 2008, and own unpublished results). Re- 1.2. Screening of plant species for the presence of rosmarinic acid and cently, the occurrence of RA in Marantaceae species was shown chlorogenic acid for the first time. Here again the occurrence of RA was not a consis- tent feature of all species of this family (Abdullah et al., 2008). Although several publications have dealt with the detection of Within the order Zingiberales, RA was also detected in the Canna- RA in members of various plant families (see e.g. Litvinenko ceae family (Petersen and Simmonds, 2003; Yun et al., 2004) which et al., 1975; Holzmannová, 1995; Janicsák et al., 1999; Pedersen, is a near sister family to the Marantaceae (Kress et al., 2001). 2000, and others) many other reports only deal with one or a Within the eudicotyledonous plants RA has been found in many few species. We have therefore set out to screen plant species col- orders of the Rosids and the Asterids and thus in the more evolved lected from the wild and from botanical gardens for their RA and orders (Fig. 2, Table 2). In general, however, our own screening chlorogenic acid (CA) content. Accumulation of RA or CA is not only showed RA accumulation in families that have already been mutually exclusive. Many species from several families contain described previously to have species with RA accumulation. Addi- both phenolic compounds (Table 2). tional species of these groups have been detected in our screening. The earliest land plants with RA occurrence are the hornwort RA as natural product is well-known from Lamiaceae species. How- genera Anthoceros and Folioceros (Anthocerotaceae, Anthocero- ever, a massive presence of RA-accumulating species is only ob- tales) which are phylogenetically closely related to each other served in the subfamily Nepetoideae while members of the (Takeda et al., 1990; Petersen, 2003; Vogelsang et al., 2005 and Teucrioideae and Scutellarioideae (as shown in Table 2) and the own unpublished results). Within the pteridophytes, species of other subfamilies mostly are devoid of RA. RA accumulation seems the genus Blechnum (Blechnaceae, Blechnales) (Harborne, 1966; to be a rather consistent feature of species within the Boraginaceae Bohm, 1968; Häusler et al., 1992 and own unpublished results) including the formerly separate family Hydrophyllaceae (Table 2). definitely accumulate RA. Interestingly, of seven examined Blech- Several species of the Apiaceae, namely Centella asiatica, Sanicula num species only two showed RA accumulation. In a survey by europaea, Eryngium alpinum and Foeniculum vulgare, accumulate Bohm (1968) only Blechnum brasiliense contained RA, while all RA (Hiller, 1965; Hiller and Kothe, 1967; Parejo et al., 2004; Le other examined 39 eusporangiate and leptosporangiate fern spe- Claire et al., 2005; Yoshida et al., 2005). We now found Astrantia cies were devoid of this phenolic compound, nine of the investi- major as a new RA-forming species of this family. Helicteres isora gated fern species contained CA. (Malvaceae, formerly: Sterculiaceae) has been reported to accumu- The presence of RA in Sarcandra glabra (Chloranthaceae; Zhu late RA as well as the less hydroxylated precursor isorinic acid et al., 2008) belonging to the primitive angiosperm order Chlorant- (Satake et al., 1999). Helicteres jamaicensis, but no other examined hales prompted us to analyse two Chloranthus species. Leaves of species of the Malvaceae, contained RA in our study. Chloranthus officinalis showed the presence of RA and CA, while All previous studies as well as our own investigations show a Chloranthus spicatus only contained CA. rather scattered occurrence of RA. Moreover, RA is present in plant 1666 M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679
Fig. 2. Phylogenetic relationship in angiosperms (redrawn from Bresinksky et al. (2008)). Orders with members reported to contain RA are marked in bold print.
species of one of the earliest groups of land plants (hornworts) up 2. Biosynthesis of rosmarinic acid, chlorogenic acid and to highly evolved species of the monocotyledonous and eudicoty- caffeoylshikimic acid ledonous plants. Our investigations might – in the long run – give some explanation for this observation. Enzymes involved in the biosynthesis of RA have been eluci- Chlorogenic acid (CA; caffeoyl-50-O-quinic acid) is more widely dated in several plant species of the Lamiaceae and Boraginaceae, distributed in the plant kingdom. It was first detected in 1837 in namely Coleus blumei (Lamiaceae; Petersen et al., 1993; Petersen, coffee (Sondheimer, 1964) and is an ester of caffeic acid and (L)- 1997), M. officinalis (Lamiaceae; Weitzel and Petersen, unpub- quinic acid (Fig. 1) that can occur alone or along with RA (Table lished), Anchusa officinalis (Boraginaceae; De-Eknamkul and Ellis, 2). Several isomeric caffeoylquinic acid esters (30-/40-O-caffeoylqui- 1987), Salvia miltiorrhiza (Lamiaceae; Yan et al., 2006; Huang nic acid) as well as several dicaffeoylquinic acids (e.g. 10,30-dica- et al., 2008) and Lithospermum erythrorhizon (Boraginaceae; ffeoylquinic acid = cynarin from Cynara scolymus) are known Yamamura et al., 2001; Matsuno et al., 2002). The cDNAs encoding from the plant kingdom. In our investigation, CA was found in sev- several biosynthetic enzymes have been isolated as well. eral Blechnaceae species and was abundant in species of the orders The biosynthesis as shown in C. blumei (Fig. 1; Petersen et al., Apiales, Asterales and Dipsacales, whereas the family Boraginaceae 1993; Petersen, 1997; Petersen and Simmonds, 2003 and literature only shows a scattered occurrence of CA. CA was only rarely de- cited therein) starts with the aromatic amino acids L-phenylalanine tected in monocotyledonous plants and in most cases concomi- and L-tyrosine which are separately transformed to the intermedi- tantly with RA. ary precursors 4-coumaroyl-CoA and 4-hydroxyphenyllactic acid. M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679 1667
Table 2 Screening of the plant kingdom for the occurrence of rosmarinic acid (RA) and chlorogenic acid (CA). The presence of the compounds in 70% ethanolic extracts from leaves was verified by HPLC and TLC as described by Abdullah et al. (2008). The plant material was collected in different botanical gardens: D = Botanical Garden of the Heinrich-Heine-Universität Düsseldorf, G = Botanical Garden of the Justus-Liebig-Universität Giessen, K = Botanical Garden of the Christian-Albrechts-Universität Kiel, M = Botanical Garden of the Philipps-Universität Marburg, T = Institut für Pharmazeutische Biologie der Eberhard-Karls-Universität Tübingen. In the family Lamiaceae, subfamilies (as defined by Olmstead, 2005) are indicated: NE = Nepetoideae, TE = Teucrioideae, SC = Scutellarioideae. For species marked with an asterisk (*) the occurrence of RA has – to our best knowledge – not been reported before. Family Genus or species Source RA CA Ferns
Equisetaceae Equisetum arvense D – n.d. Order: Blechnales Blechnaceae Blechnum arcuatum M–+ Blechnum brasiliense M++ Blechnum gibbum*M++ Blechnum occidentale M–+ Blechnum penna-marina D – n.d. Blechnum polypodioides M–– Blechnum spicant M – n.d. Doodia caudata G––
‘‘Basal orders” Order: Chloranthales Chloranthaceae Chloranthus officinalis *M++ Chloranthus spicatus M–+
Monocotyledonous plants Order: Alismatales Araceae Arum italicum M–– Juncaginaceae Triglochin striatum M–– Zosteraceae Zostera marina - + n.d. Potamogetonaceae Potamogeton coloratus* D + n.d. Order: Liliales Hyacinthaceae Chionodoxa luciliae M–– Order: Poales Juncaceae Juncus effusus M–– Juncus subnodulosus M–+ Order: Zingiberales Cannaceae Canna edulis M++ Canna indica M++ Costaceae Costus cuspidatus M–– Heliconiaceae Heliconia humilis M–– Heliconia jacquinii M–– Lowiaceae Orchidantha maxillarioides M–– Musaceae Musa acuminata M–– Musa textilis M–– Marantaceae Ataenidia conferta K–– Calathea argyraea G–– Calathea bachemiana G–– Calathea insignis M–– Calathea kegeljani M–– Calathea lancifolia G–– Calathea lindeniana M–– Calathea lietzei G–– Calathea louisae M–– Calathea makoyana M–– Calathea mediopicta G–– Calathea micans M–– Calathea ornata M–– Calathea picturata G–– Calathea rotundifolia K–– Calathea undulata G–– Calathea variegata M–– Calathea warscewiczii K–– Calathea zebrina M–– Ctenanthe burle-marxii M–– Ctenanthe kummeriana G–– Ctenanthe lubbersiana G–– Ctenanthe pilosa K–– Ctenanthe setosa K–– Maranta arundinacea K–– Maranta depressa*K++ Maranta leuconeura ‘‘Fascinator”* M + + Maranta leuconeura var. kerchoviana*M + + Maranta leuconeura var. massangeana*G + + Maranta noctiflora G–– Marantochloa flexuosa M–– (continued on next page) 1668 M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679
Table 2 (continued) Family Genus or species Source RA CA Megaphrynium macrostachyum M–– Pleiostachya pruinosa M–– Stromanthe amabilis G–+ Stromanthe sanguinea G–– Thalia dealbata M–– Thalia geniculata*M+– Strelitziaceae Strelitzia reginae M–– Zingiberaceae Curcuma longa M–– Globba marantina M–– Zingiber officinale M––
Eudicotyledonous plants Order: Geraniales Geraniaceae Erodium manescavii M–– Geranium sanguineum M–– Geranium swatense M–– Geranium sylvaticum M–+ Order: Myrtales Lythraceae Cuphea procumbens M–– Lythrum alatum M–– Lythrum hyssopifolia M–– Onagraceae Gaura biennis M–– Oenothera missouriensis M–– Lopezia racemosa M–– Order: Celastrales Aquifoliaceae Ilex aquifolium M–+ Celastraceae Euonymus verrucosus M–– Order: Rosales Hydrangeaceae Philadelphus spec. M–+ Order: Cucurbitales Cucurbitaceae Cucurbita pepo var. giromontiina M–– Cucurbita pepo var. oleifera M–– Order: Brassicales Brassicaceae Arabidopsis thaliana M – n.d. Order: Malvales Malvaceae incl. Sterculiaceae, Tiliaceae Abroma augustum M–– Abutilon theophrasti M–– Alcea rosea M–– Alyogyne huegelii M–– Callirhoe involucrata M–– Dombeya rotundifolia M–– Helicteres jamaicensis*M+– Hibiscus cannabinus M–– Hibiscus rosa-sinensis M–– Lavatera trimestris M–– Malope trifida M–– Pavonia X gledhillii M–– Theobroma cacao M–+ Tilia americana M–– Tilia amurensis M–– Tilia cordata M–+ Tilia japonica M–+ Tilia platyphyllos M–+ Tilia tomentosa M–– Thymelaeaceae Daphne mezereum M–– Order: Cornales Cornaceae Cornus alba M–– Cornus mas M–– Cornus officinalis M–– Order: Gentianales Apocynaceae Catharanthus roseus M–+ Asclepiadaceae Asclepias syriaca M–– Gentianaceae Gentiana asclepiadea M–– Gentiana lutea M–– Rubiaceae Galium boreale M–+ Galium rubioides M–+ Phuopsis stylosa M–– Rubia tinctoria M–+ Order: Lamiales Acanthaceae Acanthus hungaricus M–– Acanthus longifolius M–– Barleria micans M–+ M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679 1669
Table 2 (continued) Family Genus or species Source RA CA Jacobinia zelandia M–– Odontonema schomburgkianum M–– Gesneriaceae Phinaea multiflora M–– Streptocarpus caulescens M–– Streptocarpus rexii M–– Lamiaceae Ajuga chamaepitys TE D – n.d. Agastache rugosa NE D + n.d. Calamintha nepeta NE M + – Cedronella canariensis NE D + n.d. Coleus forskohlii (syn. Plectranthus barbatus) NE T + n.d. Collinsonia canadensis NE M + – Dracocephalum spec. NE M + + Elsholtzia stauntonii* NE D + n.d. Glechoma hederacea NE M + + Hormium pyrenaicum* NE D + n.d. Lavandula angustifolia NE M + – Lavandula multifida NE M + – Lycopus europaeus NE - + n.d. Lycopus exaltatus NE D + n.d. Melissa officinalis NE M + – Mentha aquatica NE M + – Micromeria thymifolia NE M + – Monarda punctata* NE D + n.d. Origanum majorana NE M + – Perilla frutescens NE D + n.d. Perovskia abrotanoides NE D + n.d. Plectranthus ciliatus*NEM+– Salvia officinalis NE M + – Salvia splendens*NEM+– Satureja montana NE M + – Lamium album SC D – n.d. Lamium galeobdolon SC D – n.d. Lamium maculatum SC D – n.d. Lamium purpureum SC D – n.d. Leonurus cardiaca SC M – + Marrubium vulgare SC M – – Molucella laevis SC D – n.d. Phlomis russeliana SC D – n.d. Phlomis tuberosa SC M – + Stachys alpina SC D – n.d. Oleaceae Olea europaea M–– Plantaginaceae Digitalis lanata M–– Digitalis lutea M–– Plantago media M–+ Plantago nivalis M–– Plantago schwarzenbergiana M–– Plantago sempervirens M–+ Scrophulariaceae Calceolaria scabiosifolia M–+ Chelone lyonii M–+ Linaria triornithophora M–– Nemesia strumosa M–– Penstemon digitalis M–+ Penstemon hirsutus M–– Penstemon serrulatus M–– Scrophularia nodosa M–– Verbascum phlomoides M–– Verbascum undulatum M–– Veronica longifolia M–– Verbenaceae Lantana camara M–– Verbena spec. M–– Verbena officinalis M–– Verbena rigida M–– Verbena urticifolia M–– Order: Solanales Convolvulaceae Convolvulus tricolor M–+ Menyanthaceae Menyanthes trifoliata M–+ Solanaceae Atropa belladonna M–+ Datura stramonium M–– Lycopersicon esculentum M–+ Nicotiana sylvestris M–+ Petunia hybrida M – n.d. Physalis alkekengi M–– Saracha edulis M–– Withania somnifera M–+ (continued on next page) 1670 M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679
Table 2 (continued) Family Genus or species Source RA CA
Order: Apiales Apiaceae Anthriscus cerefolium M–+ Anthriscus sylvestris M–+ Apium graveolens M–+ Astrantia major *M++ Carum carvi M–+ Cenolophium denudatum M–+ Dorema ammoniacum M–+ Eryngium bourgatii M–+ Foeniculum vulgare M–+ Levisticum officinale M–+ Ligusticum scoticum M–– Peucedanum officinale M–– Sanicula europaea M + n.d. Sanicula marilandica M–– Seseli hippomarathrum M–– Seseli libanotis M–– Araliaceae Aralia californica M–+ Eleutherococcus senticosus M–+ Hedera colchica M–+ Hedera helix M–+ Order: Asterales Asteraceae Achillea millefolium M–+ Arnica chamissonis M–+ Centaurea macrocephala M–+ Cichorium intybus M–+ Helianthus annuus M–+ Tagetes tenuifolia M–– Order: Dipsacales Caprifoliaceae Diervilla lonicera M–+ Diervilla trifolia M–+ Lonicera demissa M–+ Lonicera emphyllocalyx M–+ Lonicera ferdinandi M–+ Lonicera kamtschatica M–+ Lonicera syringantha M–– Viburnum dilatatum M–+ Viburnum hupehense M–+ Viburnum lantana M–+ Dipsacaceae Cephalaria gigantea M–– Dipsacus laciniatus M–+ Knautia dipsacifolia M–+ Scabiosa atropurpurea M–+ Scabiosa caucasia M–+ Succisella inflexa M–+ Uncertain order, Boraginales? Boraginaceae incl. Cerinthe major*M+– Hydrophyllaceae Echium italicum*M++ Heliotropium amplexicaule*M+– Lindelofia longiflora*M+– Lithospermum arvense*M+– Lithospermum erythrorhizon - + n.d. Lithospermum purpureocoeruleum* D + n.d. Nonea lutea*M++ Symphytum asperum*M+– Symphytum officinale M+– Hydrophyllum canadense*M++ Hydrophyllum virginicum*M+– Nemophila menziesii*M++ Phacelia tanacetifolia* D + n.d.
Table 3 Similarities/identities of amino acid sequences of H(P)PR from Coleus blumei (syn. Solenostemon scutellarioides, Lamiaceae) and similar data base entries.
Plant source, assigned function Amino acid sequence Accession number Length Identity (%) Similarity (%) Coleus blumei, HPPR 313 100 100 Salvia miltiorrhiza, putative HPPR Q15KG6 313 90 97 Salvia miltiorrhiza, putative HPPR A7KJR2 313 89 97 Salvia miltiorrhiza, putative HPPR A9CBF7 313 89 96 Vitis vinifera, putative uncharacterised protein A5CAL1 313 77 87 Arabidopsis thaliana, putative D-isomer-specific 2-hydroxyacid dehydrogenase Q9CA90 313 76 87 Populus jackii, putative uncharacterised protein A9PIN2 314 75 85 M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679 1671
The transformation of phenylalanine is catalysed by the enzymes ric acid CoA-ligase (4CL). Tyrosine is transaminated by tyrosine of the general phenylpropanoid pathway phenylalanine ammo- aminotransferase (TAT) with 2-oxoglutarate as cosubstrate to 4- nia-lyase (PAL), cinnamic acid 4-hydroxylase (C4H) and 4-couma- hydroxyphenylpyruvic acid (pHPP) which is then reduced to
Table 4 Hydroxycinnamoyltransferases and their substrate preferences; pHPL = 4-hydroxyphenyllactic acid, DHPL = 3,4-dihydroxyphenyllactic acid, n.d. = not determined.
Plant source (Acc. number) Donor substrate Acceptor substrate Reference Cynara cardunculus ‘‘HCT” [DQ104740] 4-coumaroyl-CoA, caffeoyl-CoA quinic > shikimic acid Comino et al. (2007) Nicotiana tabacum ‘‘HCT” [AJ507825] caffeoyl-CoA > 4-coumaroyl-CoA > feruloyl- shikimic >> quinic acid Hoffmann et al. (2003) CoA > sinapoyl-CoA Nicotiana tabacum ‘‘HQT” [AJ582651] 4-coumaroyl-CoA, caffeoyl-CoA quinic >> shikimic acid Niggeweg et al. (2004) Lycopersicon esculentum ‘‘HQT” n.d. n.d. Niggeweg et al. (2004) [AJ582652] Coffea canephora ‘‘HQT” [EF153930, n.d. n.d. Lepelley et al. (2007) EF153931] Coffea canephora ‘‘HCT” [EF137954, Hydrolysis of chlorogenic acid Lepelley et al. (2007) EF153929] Coffea arabica ‘‘HCT” [EF143341] n.d. n.d. Lepelley et al. (2007) Coleus blumei ‘‘HST” 4-coumaroyl-CoA, caffeoyl-CoA shikimic >> quinic acid; not accepted: Sander and Petersen pHPL, DHPL (unpublished) Coleus blumei ‘‘RAS” [AM283092] 4-coumaroyl-CoA, caffeoyl-CoA pHPL, DHPL; not accepted: shikimic acid, Berger et al. (2006) quinic acid Melissa officinalis ‘‘RAS” 4-coumaroyl-CoA, caffeoyl-CoA pHPL, DHPL; not accepted: shikimic acid, Weitzel and Petersen quinic acid (unpublished) Plectranthus fruticosus ‘‘RAS” 4-coumaroyl-CoA, caffeoyl-CoA pHPL, DHPL; not accepted: shikimic acid, Gehlen and Petersen quinic acid (unpublished) Coleus forskohlii ‘‘RAS” 4-coumaroyl-CoA, caffeoyl-CoA pHPL, DHPL; not accepted: shikimic acid, Petersen (unpublished) quinic acid
Fig. 3. Phylogenetic tree from 27 hydroxycinnamoyltransferase amino acid sequences with assigned activities constructed with the neighbor joining program of the MEGA 4.0 software package, bootstrapping with 500 replicates (Tamura et al., 2007). HCS/QT = hydroxycinnamoyl-CoA:shikimate/quinate hydroxycinnamoyltransferase, RAS = rosmarinic acid synthase, HCBT = hydroxycinnamoyl/benzoyltransferase. 1672 M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679
4-hydroxyphenyllactic acid (pHPL) by hydroxyphenylpyruvate with quinic and shikimic acid. Hydroxycinnamoyl-CoA:shikimic/ reductase (HPPR). The two intermediary precursors are coupled quinic acid hydroxycinnamoyltransferases have been detected on by ester formation and with release of coenzyme A and 4-couma- enzyme level (Stöckigt and Zenk, 1974; Ulbrich and Zenk, 1979, royl-40-hydroxyphenyllactic acid (4C-pHPL) is formed. The reaction 1980) and the respective genes characterised recently (Hoffmann is catalysed by ‘‘rosmarinic acid synthase” (RAS; 4-coumaroyl- et al., 2003; Niggeweg et al., 2004). An alternative pathway has CoA:40-hydroxyphenyllactic acid 4-coumaroyltransferase). The 3- been detected in sweet potato (Ipomoea batatas, Convolvulaceae) and 30-hydroxyl groups are finally introduced by cytochrome where 4-coumaroylglucose serves as donor for the 4-coumaroyl P450-dependent monooxygenase reactions. Looking at the eight moiety (Kojima and Villegas, 1984). The meta-hydroxylation of enzymatic activities involved in this biosynthetic pathway, only a the 4-coumaroyl part of the ester is mediated by cytochrome maximum of four of them might be specific for RA biosynthesis. P450 monooxygenases as described on enzyme level by Heller The enzymes of the general phenylpropanoid pathway (PAL, C4H, and Kühnl (1985) and Kühnl et al. (1987). The first evidence for this 4CL) are ubiquitous in land plants since they provide the precur- hydroxylase on gene level was from Arabidopsis thaliana (Schoch sors for the formation of supporting material like lignin and et al., 2001; Anterola et al., 2002; Franke et al., 2002; Nair et al., UV-protecting phenolic pigments. TAT is a primary enzyme as well 2002). CA can be accumulated up to high levels as defense com- because it forms pHPP that is needed for the biosynthesis of toc- pound, e.g. in coffee, while CS was not found in high concentrations opherols and plastoquinones (Hess, 1993; Douce and Joyard, in most plants (Sondheimer, 1964). In the current hypothesis CS 1996). A reaction similar to the stereospecific reduction of pHPP might serve as donor for caffeoyl moieties after re-transfer to coen- is active in photorespiration where hydroxypyruvate is reduced zyme A (Fig. 1). to glycerate by either a NADH-dependent peroxisomal hydroxy- pyruvate reductase (HPR) or a cytosolic NADPH-dependent HPR 3. D-isomer-specific 2-hydroxyacid dehydrogenases (Timm et al., 2008). Thus, HPPR might be identical or closely re- lated to this cytosolic HPR (see below), which is currently under The family of D-isomer-specific 2-hydroxyacid dehydrogenases investigation. was defined by Grant (1989). Members of this family catalyse the The remaining three enzymes, rosmarinic acid synthase (RAS) NAD(P)H-dependent reduction of 2-oxoacids to the corresponding 0 and the 3-and 3 -hydroxylases, have been characterised in protein D-isomers of 2-hydroxyacids as well as the reverse reaction. Most and microsome preparations of suspension cells of C. blumei (Pet- known members of this family are involved in primary metabolism ersen et al., 1993; Petersen, 1997). Recently, cDNAs encoding RAS and are predominantly from prokaryotic organisms, examples are 0 and a cytochrome P450 catalysing the 3- as well as the 3 -hydrox- D-lactate dehydrogenase (D-LDH), D-3-phosphoglycerate dehydro- ylation (CYP98A14) have been cloned and heterologously ex- genase or hydroxypyruvate reductase (HPR). The proteins are char- pressed (Berger et al., 2006; Eberle et al., 2009). Both acterised by two domains, a substrate-binding or catalytic domain heterologously expressed proteins revealed a strict specificity for and a cosubstrate-binding domain. The majority of enzymes prefer substrates involved in RA biosynthesis although they showed high NADH as cosubstrate. The catalytic cleft is located between the two similarities to 4-coumaroyl-CoA:quinate/shikimate hydroxy- domains. Active enzymes mostly are homodimers. In rare cases a cinnamoyltransferases and 4-coumaroylshikimate/quinate 3- third domain and a quarternary structure as homotetramer are ob- hydroxylases, respectively (see below). served, as for example for D-3-phosphoglycerate dehydrogenase The biosynthesis of CA and caffeoylshikimic acid (CS) also from Escherichia coli (Schuller et al., 1995). It should be stressed branches off the general phenylpropanoid pathway (Fig. 1). 4-Cou- that enzymes catalysing the homologous reactions with L-isomers maroyl-CoA is the hydroxycinnamoyl donor for the esterification of the 2-hydroxyacids belong to different protein families. Several
Table 5 Cytochrome P450 amino acid sequences of the CYP98A family and their assigned functions; * = catalytic activity not shown, n.f.a. = no function assigned. The identities/ similarities are related to CYP98A14 from Solenostemon scutellarioides.
Amino acid sequence Accession number Length Identity (%) Similarity (%) CYP98A14 Solenostemon scutellarioides 4C-DHPL 30-hydroxylase, Caf-pHPL 3-hydroxylase Q84VU3 507 100 100 CYP98A13v2 Ocimum basilicum, 4C-shikimate 3-hydroxylase, 4C-pHPL 3-hydroxylase Q8L5H7 509 80 90 CYP98A13v1 Ocimum basilicum, 4C-shikimate 3-hydroxylase, 4C-pHPL 3-hydroxylase Q8L5H8 512 79 90 Capsicum annuum, putative 4C 3-hydroxylase* B5LAT7 511 77 88 Vitis vinifera, cytochrome P450, n.f.a. A7PTC8 508 76 87 Populus trichocarpa, coumaroyl 3-hydroxylase* B2Z6P3 508 77 87 Populus alba x P. grandidentata, 4C-CoA 3-hydroxylase B0LXE6 508 77 87 CYP98A2 Glycine max, n.f.a. O48922 509 77 87 CYP98A46 Coptis japonica var. dissecta, n.f.a. A9ZT63 511 77 88 CYP98A37 Medicago truncatula, n.f.a. Q2MJ10 509 75 86 CYP98A21 Ammi majus, n.f.a. Q6QNI3 509 73 87 CYP98A-C2 Coffea canephora, p-coumaroyl ester 3-hydroxylase Q2Q093 508 75 88 CYP98A3 Arabidopsis thaliana, 4-coumaroyl ester 3-hydroxylase Q940C7 508 74 85 Arabidopsis thaliana, cyt. P450-like protein, n.f.a. Q0WWH4 508 74 85 Camptotheca acuminata, cyt. P450, n.f.a. Q5QIB0 509 71 85 Coffea canephora, p-coumaroyl quinate/shikimate 3-hydroxylase A4ZKM5 508 70 85 CYP98A-C1 Coffea canephora, putative p-coumaroyl 3-hydroxylase Q2Q094 508 69 85 Pinus taeda, p-coumarate 3-hydroxylase Q8VZH6 512 70 83 CYP98A33v1 Nicotiana tabacum, n.f.a. A1XEI4 508 69 84 CYP98A33v2 Nicotiana tabacum, n.f.a. A1XEI5 520 69 84 Ginkgo biloba, 4-coumarate 3-hydroxylase* B1WAN6 512 70 83 Sesamum indicum, p-coumarate 3-hydroxylase* Q8VWQ9 509 66 81 CYP98A6 Lithospermum erythrorhizon, 4C-pHPL 3-hydroxylase Q8GSQ6 506 65 81 CYP98A1 Sorghum bicolor, cyt. P450 O48956 512 66 81 M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679 1673 crystal structures of D-isomer-specific 2-hydroxyacid dehydrogen- from glucose esters in plant secondary metabolism is catalysed ases have been solved, e.g. D-LDH from Lactobacillus helveticus by a different protein family, namely members of the serine car- (2dld, Bernard et al., 1995)orLactobacillus bulgaricus (1j49, 1j4a, boxypeptidase-like acyltransferase family (Milkowski and Strack, Razeto et al., 2002), HPR from Hyphomicrobium methylovorum 2004). The A. thaliana and Oryza sativa genomes revealed 64 and (1gdh, Goldberg et al., 1994), human HPR (2gcg, Booth et al., 119 members of the BADH superfamily, respectively. Conserved 2006) and others. The crystal structure of HPPR from C. blumei is sequence motifs of his BAHD acyltransferase family are the solved as well and will be published soon (Janiak et al., submitted). HxxxD(G) motif directly involved in substrate binding and the DFGWG motif located more to the C-terminal end. D’Auria (2006) 3.1. Hydroxy(phenyl)pyruvate reductase from C. blumei has defined five different clades of BAHD acyltransferases: clade I consists mostly of anthocyanin-modifying acyltransferases, here In RA biosynthesis, hydroxyphenylpyruvate reductase (HPPR) a third typical motif (YFGNC) can be used for classification. Clade channels a primary metabolite, 4-hydroxyphenylpyruvate which II is not very well defined but includes members of epicuticular is also involved in the biosynthesis of tocopherols and/or plastoqui- wax biosynthesis. Clade III comprises alcohol acetyltransferases nones (Hess, 1993; Douce and Joyard, 1996), into secondary metab- and acyltransferases involved in alkaloid biosynthesis. Clade IV in- olism. The newly formed OH group is necessary for the following cludes agmatine N-hydroxycinnamoyltransferase. In clade V, sub- esterification reaction. Based on peptide sequences of the purified groups catalysing the formation of volatile compounds (e.g. protein from suspension cultures of C. blumei a cDNA was cloned benzylbenzoate), alkaloids and a subgroup comprising hydroxycin- and the protein heterologously expressed. The protein catalysed namoyl/benzoyltransferases can be defined. In this last subgroup, the NAD(P)H-dependent reduction of pHPP and 3,4-dihydroxyphe- hydroxycinnamoyltransferases involved in the biosynthesis of nylpyruvate (DHPP) to the corresponding lactates (Fig. 1; Kim et al., hydroxycinnamoyl esters such as 4-coumaroylshikimate or -qui- 2004). Further biochemical studies, however, showed that the nate or CA are found. According to St. Pierre and De Luca (2000) heterologously expressed protein could additionally reduce other the evolutionary origin of the BAHD acyltransferase superfamily aromatic substrates (4-hydroxy-3-methoxyphenylpyruvate, phe- might lie in the CAT (chloramphenicol acetyltransferase) gene fam- nylpyruvate) as well as small substrates such as hydroxypyruvate, ily. The known sequences from plants indicate a monophyletic ori- pyruvate and glyoxylate. The highest affinity was shown for gin of all plant genes of this family. hydroxypyruvate which is an intermediate of photorespiration in Crystal structures of members of the BAHD superfamily have plants. The photorespiratory hydroxypyruvate reductases (HPRs) been solved for vinorine synthase from Rauvolfia serpentina (pdb- exist as NADH-dependent peroxisomal and as NADPH-dependent code: 2bgh; Ma et al., 2005), anthocyanin malonyltransferase from cytosolic forms. From C. blumei the sequences of the peroxisomal Dendranthema morifolium (pdb-codes: 2e1t, 2e1u, 2e1v; Unno HPR and the cytosolic HPPR show only 30% identity on amino acid et al., 2007) and trichothecene 3-O-acetyltransferase from Fusar- level. Both proteins, however, belong to the family of D-isomer-spe- ium sporotrichioides and Fusarium graminearum (pdb-codes: 2rkv, cific 2-hydroxyacid dehydrogenases. The amino acid sequence of 2rkt, 3b2s, 3b30, 2zba; Garvey et al., 2008). the peroxisomal HPR shows the typical carboxyterminal peroxi- Different hydroxycinnamoyltransferases of the BAHD superfam- some targeting sequence (own unpublished results). The function ily are involved in the biosynthesis of phenolic compounds. of the cytosolic HPR was unclear for a long time since the steps of N-Hydroxycinnamoyltransferases such as agmatine N-hydroxycin- photorespiration take place in chloroplasts, peroxisomes and mito- namoyltransferase (Burhenne et al., 2003) or (hydroxy)anthranilate chondria. Recently it was shown that the cytosolic HPR can replace N-hydroxycinnamoyltransferase (Yang et al., 1997, 2004) and flavo- the peroxisomal enzyme and thus was considered a bypass enzyme noid glycoside/anthocyanin hydroxycinnamoyltransferases (as in photorespiration (Timm et al., 2008). reviewed by Nakayama et al. (2003)) will not be discussed here. The HPPR-cDNA from C. blumei (EMBL accession number The hydroxycinnamoyltransferases discussed here show a moder- AJ507733) encodes a protein of 313 amino acid residues. Very sim- ate specificity for their hydroxycinnamoyl donors accepting both ilar cDNAs (EMBL accession numbers DQ099741, EF458148, 4-coumaroyl- and caffeoyl-CoA and often also other (hydroxy)cin- DQ266514) have been cloned from S. miltiorrhiza, a Lamiaceae spe- namic acid CoA-thioesters but sometimes have more distinct spec- cies also accumulating RA, (see Table 3) but the catalytic activities ificities for their acceptor substrates (Table 4). Recent investigations of the encoded proteins have not yet been shown. A cDNA encod- suggested that predominantly CS and to a lesser extent CA (at least ing a protein with 87% similarity on amino acid level has been in some plants) are the precursors for caffeic acid and/or caffeoyl- cloned from A. thaliana (accession number Q9CA90), which is not CoA which will be incorporated into phenolic compounds or trans- known for RA accumulation. formed to lignin monomers with more elaborated substitution pat- It remains to be shown whether the NADPH-dependent cyto- terns at the aromatic ring (3-methoxy-4-hydroxy, 3,5-dimethoxy- solic HPR/HPPR is an enzyme involved in two different pathways, 4-hydroxy). This renders hydroxycinnamoyl-CoA:quinate/shikim- a primary one like photorespiration and a secondary metabolic ate hydroxycinnamoyltransferases (HCS/QT) and/or hydroxycinna- pathway, namely RA biosynthesis. Alternatively a more specific moyl-CoA:shikimate hydroxycinnamoyltransferases (HST) central HPPR has to be detected in RA-synthesising plants. Experiments enzymes of phenolic metabolism (Fig. 1; Schoch et al., 2001; Hoff- to clarify the role of H(P)PR in RA biosynthesis using the RNAi-ap- mann et al., 2003). The enzymes forming caffeoyl-CoA by transfering proach are currently done in our laboratory. the 4-coumaric acid moiety from 4-coumaroyl-CoA to shikimate and/or quinate (HCS/QT, HST, HQT) and the 3-hydroxylases of the CYP98A family introducing the 3-OH group into the aromatic ring 4. CoA-ester-dependent BAHD hydroxycinnamoyltransferases (see below) thus should be essential for the formation of e.g. caffeic acid derivatives and lignin monomers. Consequently, silencing of 4.1. Hydroxycinnamoyltransferases in phenolic metabolism HCS/QT in Nicotiana benthamiana and A. thaliana affected lignin for- mation with respect to amount and composition (Hoffmann et al., Many acyltransferases transfering the acyl moiety from a coen- 2004, 2005). Similarly, lignin formation in Pinus taeda or Medicago zyme A thioester to an acceptor molecule in phenolic metabolism sativa was affected by silencing HST (Wagner et al., 2007; Shadle belong to the superfamily of BAHD acyltransferases, which was et al., 2007). named after the four first known enzymes of this family (St. Pierre Hydroxycinnamoyltransferases only or preferably using quinate and De Luca, 2000; D’Auria, 2006). The transfer of acyl moieties as acceptor substrate (HQT) are essential for the biosynthesis of CA, 1674 M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679 the most ubiquitously occurring phenolic ester in the plant king- patterns of HCS/QT and HQT in Coffea canephora were correlated dom. Down-regulation or silencing of HQT in tomato affected the to lignin and CA formation, respectively (Lepelley et al., 2007). levels of CA while lignin formation was not affected. Up-regulation The number of HCS/QTs and the relative use of quinic or shiki- resulted in enhanced CA levels and increased antioxidative capacity mic acid as substrate (Table 4) differ in plant species. While in A. and pathogen resistance (Niggeweg et al., 2004). Furthermore, the thaliana the absence of a CA-forming enzyme is consistent with plant’s UV-protection was dependent on HQT expression and on the absence of hydroxycinnamoylquinates, six hydroxycinnamoyl- the accumulation of CA (Clé et al., 2008). The differing expression transferase sequences were detected in Populus tremuloides which
Fig. 4. Phylogenetic tree from 36 amino acid sequences of members of the CYP98A family; CYP73A5 was used as outgroup. The neighbor joining and bootstrapping features (500 replicates) of the MEGA 4.0 program package (Tamura et al., 2007) were used. The accession numbers of the used sequences are: CYP98A1: AF029856, CYP98A2: AF022458, CYP98A3: O22203, CYP98A4: Q65X81, CYP98A5: AY963109, CYP98A6: AB017418, CYP98A7: AY107051, CYP98A8: Q9CA61, CYP98A9: Q9CA60, CYP98A10: AJ583530, CYP98A11: AJ583531, CYP98A12: AJ583532, CYP98A13v1: AY082611, CYP98A13v2: AY082611, CYP98A14: AJ427452, CYP98A18: Oryza sativa genome project, CYP98A19: AY064170, CYP98A20: AY065995, CYP98A21: AY532371, CYP98A23/24/25v1/27: Populus trichocarpa genome project, CYP98A28: AY466856, CYP98A29: constructed from Zea mays ESTs, CYP98A34: constructed from Physcomitrella patens ESTs, CYP98A35: DQ269126, CYP98A36: DQ269127, CYP98A37: Q2MJ10, CYP98A38: DN838382 (cDNA), CYP98A39v1: AJ585988, CYP98A39v2: AJ585990, CYP98A39v3: AJ585991, CYP98A40: AJ585989, CYP98A43: AM435080 (gDNA), CYP98A46: A9ZT63, Ginkgo biloba C3H: B1WAN6, CYP73A5: AAC99993. M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679 1675 accumulates an abundance of hydroxycinnamoyl esters (Tsai et al., to accept hydroxyphenyllactates are extremely specific for these 2006). substrates. RAS and HCS/QT from C. blumei, which preferentially The third type of hydroxycinnamoyltransferase in this context accepts shikimate as acceptor molecule, have identities/similarities is hydroxycinnamoyl-CoA:hydroxyphenyllactate hydroxycinna- of 56/73% on amino acid level and 66% on nucleic acid level. Inter- moyltransferase (rosmarinic acid synthase, RAS) which uses estingly, especially the region adjoining the conserved amino acids hydroxyphenyllactic acids but not quinate or shikimate as acceptor HxxxDG shows differing amino acids for RAS and for HCS/QT. A substrates. The first cDNA for RAS was cloned from C. blumei (syn. similar specificity with respect to the acceptor molecules shikimic Solenostemon scutellarioides), a RA-accumulating Lamiaceae species acid and pHPL acid has been reported for two partially purified 4- (Berger et al., 2006). The properties of this enzyme will be pre- coumaroyltransferases from Ocimum basilicum (Lamiaceae; Gang sented below. et al., 2002). The enzyme accepting shikimate as substrate was highly expressed in peltate glandular trichomes synthesising euge- 4.2. Properties of hydroxycinnamoyl-CoA:hydroxyphenyllactate nol but not in those accumulating (methyl)chavicol without a hydroxycinnamoyltransferase (rosmarinic acid synthase; RAS) meta-hydroxy group. This can be taken as an indication of the importance of the formation of 4-coumaroyl esters for the estab- The specific enzyme of RA biosynthesis is the hydroxycinna- lishment of the 3,4-dihydroxy substitution pattern also for com- moyltransferase that transfers the hydroxycinnamic acid moiety pounds other than monolignols. from hydroxycinnamoyl-CoA to the aliphatic hydroxyl group of a A phylogenetic tree (neighbor joining and bootstrapping fea- hydroxyphenyllactate thus forming an ester. This enzyme has been tures (500 replicates) of the MEGA 4.0 program package; Tamura described from suspension cultures of C. blumei as rosmarinic acid et al., 2007) constructed from 27 sequences of BAHD hydroxy- synthase (RAS; Petersen and Alfermann, 1988; Petersen, 1991; Pet- cinnamoyltransferases with assigned catalytic affinities showed ersen et al., 1993). The substrate affinities of RAS indicated the distinct groups (Fig. 3). Hydroxycinnamoyltransferases using preferential acceptance of monohydroxylated substrates, 4-cou- anthocyanins as acceptor substrates group together, another group maroyl-CoA and pHPL. The finalisation of the rosmarinic acid sub- is formed by hydroxycinnamoyl/benzoyltransferases (HCBTs). En- stitution pattern thus would be the final steps of RA biosynthesis, zymes using shikimate and/or quinate are clearly separated from catalysed by 3- and 30-hydroxylases (Petersen, 1997), as described hydroxycinnamoyltransferases with hydroxyphenyllactates as below. Caffeoyl-CoA and 3,4-dihydroxyphenyllactate are accepted substrate. Currently several more hydroxycinnamoyltransferase as RAS substrates as well. sequences putatively involved in RA biosynthesis are being inves- The cDNA for RAS (EMBL accession number AM283092) was tigated and will complete our view in near future. Modelling cloned using peptide information from the purified RAS protein and/or crystallisation studies, which are currently done in our lab- isolated from suspension cells of C. blumei (Berger et al., 2006). oratory, will show which differences in the architecture of the ac- The cDNA has an open reading frame of 1290 base pairs encoding tive centers of 4-coumaroyl-CoA:4-hydroxyphenyllactate and a protein of 430 amino acid residues with a calculated molecular shikimate/quinate hydroxycinnamoyltransferases explain the dif- mass of 47.9 kDa with a theoretical isoelectric point of 5.89. The ferent substrate acceptances. genomic sequence revealed a single phase 0 intron of 914 base pairs after 405 nucleotides. According to St. Pierre and De Luca 5. Cytochrome P450 CYP98A (2000) this is a typical ‘‘Q-intron” (inserted after the conserved amino acid Q = glutamine) 17 amino acid residues forward of the 5.1. CYP98A in phenylpropanoid metabolism conserved motif HxxxDG. This intron is highly conserved in the BADH superfamily of acyltransferases and this was seen as consis- Three families of cytochrome P450s have been described to be tent with the hypothesis that the plant sequences are derived from active in basic phenylpropanoid metabolism, namely CYP73 with one common ancestor. cinnamic acid 4-hydroxylase (C4H), CYP84 with coniferaldehyde The His-tagged RAS protein was expressed in E. coli and purified 5-hydroxylase (CA5H) and CYP98 whose members with known by metal chelate chromatography. The enzyme accepted 4-couma- activities are aromatic meta-hydroxylases (Ehlting et al., 2006). royl-CoA and caffeoyl-CoA as hydroxycinnamoyl donors with very The CYP73 and CYP98 families may share a common ancestor high affinities. 4-Hydroxyphenyllactate and 3,4-dihydroxyphenyl- (Schoch et al., 2001). Generally, the CYP98A family is to date lactate served as acceptors while shikimate and quinate were no known to introduce the 3-OH group into the 4-coumaroyl moieties acceptor substrates. Despite the high sequence similarities (see be- of hydroxycinnamic acid esters or amides such as 4-coumaroylqu- low) between RAS and HCS/QTs these enzymes have evolved diver- inate or 4-coumaroylshikimate or to a lesser extent 4-coumaroyl- gently with respect to their substrate binding centres. The tyramine (Ehlting et al., 2006; Morant et al., 2007). The substrate substrate specificities of hydroxycinnamoyltransferases differ con- preference usually is 4-coumaroylshikimate over 4-coumaroylqui- siderably (Table 4). While some hydroxycinnamoyltransferases nate while 4-coumaroyltyramine is mostly not accepted with a prefer quinic over shikimic acid, others strongly prefer shikimic high affinity (Ehlting et al., 2006). One of the major known acid or only use this acceptor. The enzymes characterised to date functions of CYP98A monooxygenases in cooperation with
Fig. 5. 3D structures of the acceptor substrates of hydroxycinnamoyltransferases. The OH group that accepts the 4-coumaric acid moiety is indicated by an arrow. 1676 M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679 hydroxy-cinnamoyltransferases – is the establishment of the caf- amino acid level to CYP98A13v2 from O. basilicum (EMBL acces- feic acid substitution pattern of phenylpropanoid moieties, puta- sion number AY082612; Gang et al., 2002) while the identities tively via 4-coumaroylshikimic acid (Schoch et al., 2001; Anterola to CYP98A6 from L. erythrorhizon (EMBL accession number et al., 2002; Franke et al., 2002; Nair et al., 2002), and the biosyn- AB017418; Matsuno et al., 2002) ranged at 68% and 65%, respec- thesis of CA via 4-coumaroylquinic acid (Niggeweg et al., 2004). tively (Table 5). The cDNA comprised an open reading frame of More than 46 partial or complete CYP98A sequences are known 1521 bp encoding a protein of 507 amino acid residues with a cal- (cytochrome P450 database by Dr. David Nelson), but most of them culated molecular mass of 57.6 kDa. The genomic DNA sequence have not been expressed and tested for their catalytic activities. of CYP98A14 from C. blumei revealed two introns: the first one Since the involvement in the formation of lignin precursors of is a phase 1 intron starting after 487 nucleotides with a length CYP98A3 is known and is anticipated for others, CYP98 sequences of 81 bp, the second phase 0 intron of 95 base pairs starts after have to be present in virtually all higher plant (tracheophyte) gen- 876 nucleotides of the coding sequence (Wolters and Petersen, omes. In wheat, duplication events resulted in eight CYP98A se- unpublished). With this respect the genomic structure is similar quences three of which showed meta-hydroxylation activity of 4- to CYP98A35 from C. canephora which also has two introns, a coumaroyl moieties after heterologous expression (Morant et al., phase 1 intron (116 bp) after 484 nucleotides and a phase 0 2007). More than one sequence have also been deposited for e.g. (106 bp) intron after 882 nucleotides (Mahesh et al., 2007). The Populus trichocarpa (CYP98A23, CYP98A24, CYP98A25, CYP98A26, genomic sequence of a ‘‘p-coumarate 3-hydroxylase” from Ginkgo CYP98A27), C. canephora (CYP98A35, CYP98A36), O. sativa biloba, an ancient gymnosperm, also had two introns after 487 (CYP98A4, CYP98A18) and A. thaliana (CYP98A3, CYP98A8, and 883 nucleotides of the cDNA sequence with lengths of 693 CYP98A9). and 383 base pairs (Liu et al., 2008). The second intron was re- ported to be conserved in CYP genes of the A-clade (Paquette 5.2. Properties of 4-coumaroyl-4’-hydroxyphenyllactate 3- and 3’- et al., 2000), while the first intron is not always present. hydroxylase from C. blumei (CYP98A14) A phylogenetic tree (neighbor joining and bootstrapping fea- tures (500 replicates) of the MEGA 4.0 program package; Tamura In RA biosynthesis in C. blumei, cytochrome P450-dependent et al., 2007) was constructed on the basis of 36 full-length amino monooxygenases are involved in the formation of 4-coumaric acid acid sequences of members of the CYP98A family (Fig. 4); C4H from from t-cinnamic acid (C4H) and in the 3- and 30-hydroxylation of A. thaliana (CYP73A5) was used as outgroup. The phylogram clearly 4-coumaroyl-30,40-dihydroxyphenyllactate (4C-DHPL) and caf- shows groupings of CYP98As from lower plants (Selaginella moel- feoyl-40-hydroxyphenyllactate (Caf-pHPL), respectively, or 4-cou- lendorffii, Physcomitrella patens), gymnosperms (P. taeda, G. biloba) maroyl-4’-hydroxyphenyllactate (4C-pHPL) finalising the RA and monocotyledonous angiosperms. Three sequences of CYP98As molecule (Petersen, 1997). Experiments with microsomal prepara- from two species (O. basilicum, C. blumei) accepting precursors of tions from suspension-cultured cells of C. blumei suggested the RA are grouped together while CYP98A6 from L. erythrorhizon involvement of two different cytochrome P450s in the introduc- which was reported to accept 4C-pHPL (other substrates have tion of the 3- and 30-hydroxyl groups (Petersen, 1997). We re- not been tested) groups with a 4-coumaroyl-CoA:shikimate/qui- cently isolated the cDNA and genomic DNA of a cytochrome nate 3-hydroxylase from C. canephora suggesting that a further elu- P450 from this species which was assigned the number CYP98A14 cidation of the substrate specificities of CYP98A6 should be (Nelson, personal communication). The cDNA was expressed in performed. Saccharomyces cerevisiae and characterised with respect to its The high sequence similarities between CYP98As acting in RA catalytic activity (Eberle et al., 2009). The main activity is the 3- biosynthesis and in CA/CS biosynthesis as well as the substrate hydroxylation of 4C-DHPL and to a lesser extent the 3’-hydroxyl- promiscuity of some of the CYP98As accepting both, substrates ation of Caf-pHPL while 4-coumaroylshikimate or -quinate were for CA/CS and RA biosynthesis, makes an evolutionary relationship not hydroxylated. CYP98A6 from L. erythrorhizon (Matsuno et al., probable. Our current knowledge with DNA sequences only avail- 2002) and CYP98A13 from O. basilicum (Gang et al., 2002) – both able from members of two higher plant families, Lamiaceae and plant species that are known for their accumulation of RA – were Boraginaceae, makes it impossible to know whether the recruit- reported to accept 4C-pHPL as substrate and to hydroxylate in po- ment of CYP98A from lignin monomer or CA biosynthesis for RA sition 3 of the 4-coumaroyl moiety, although to a low extent biosynthesis has taken place once or several times during (CYP98A13) compared to 4-coumaroylshikimate as substrate. evolution. Most members of the CYP98A family have not yet been tested with respect to their catalytic activities. CYP98A14 from C. blumei differs from the other characterised CYP98As since it does not ac- 6. Possible evolutionary relationship of caffeoylshikimic/ cept 4-coumaroylquinate or -shikimate as substrate and it is addi- chlorogenic acid and rosmarinic acid biosynthesis tionally able to hydroxylate both aromatic rings of 4C-DHPL and Caf-pHPL, respectively, thus acting as 3-hydroxylase as well as With respect to their biosynthetic enzymes, rosmarinic acid 0 as 3 -hydroxylase (Eberle et al., 2009). The apparent Km-values, and CA/CS biosynthesis seem to be rather similar and evolution- however, differ with 5 lM for 4C-DHPL and 40 lM for Caf-pHPL, arily related. In both cases 4-coumaroyl-CoA coming from the showing that the 3-hydroxylation is the preferred reaction. This general phenylpropanoid pathway is used to transfer the 4-cou- leaves the possibility open that a yet unknown CYP gene might maroyl moiety to the OH group of an acceptor molecule: shiki- encode a specific 30-hydroxylase in RA biosynthesis. A similar sit- mic, quinic or hydroxyphenyllactic acid. The acceptor OH uation has recently been described for Sesamum indicum, where groups differ considerably: the hydroxyl group in hydroxyphe- experiments with microsomal preparations suggested that two nyllactic acid is in the side chain which should be rather flexible, cytochrome P450s are involved in the formation of the two meth- while in shikimic and quinic acid it is attached to closed rings. ylenedioxy bridges of the sesamin molecule from pinoresinol (Jiao The distances between the carboxyl groups of the acceptor acids et al., 1998), while the heterologously expressed protein encoded and the OH groups that are esterified also differ between quinic by the CYP81Q cDNA was able to form both methylenedioxy and shikimic acid on the one side and 4-hydroxyphenyllactic bridges (Ono et al., 2006). CYP98A14 from C. blumei (EMBL acces- acid on the other (Fig. 5). Thus the active centers should have sion number AJ427452; Eberle et al., 2009) showed highest se- different architectures which is currently under investigation in quence identities with 74% on nucleotide level and 80% on our laboratory. M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679 1677
Given that the formation of 4-coumaroylshikimate and its ferent plant groups still remains open and will be the focus of our hydroxylation to CS are inherent steps of monolignol formation future investigations. as proposed by Schoch et al. (2001), the enzymes catalysing these steps must have evolved at the latest in early land plants. The Acknowledgement occurrence of monolignol-derived lignans and caffeic acid esters has been shown in ‘‘mosses”: a number of caffeic acid-derived lign- The financial support by the Deutsche Forschungsgemeinschaft ans have been isolated e.g. from the liverworts Jamesoniella (DFG) in parts of this project is gratefully acknowledged. autumnalis, Scapania undulata, Pellia epiphylla and Bazzania trilobata (Tazaki et al., 1995 and cited literature; Martini et al., 1998; gen- eral review: Asakawa, 2004). Anthocerotonic, megacerotonic and References rosmarinic acids have been detected in members of the hornworts (Takeda et al., 1990). Liverworts and hornworts are considered the Abdullah, Y., Schneider, B., Petersen, M., 2008. Occurrence of rosmarinic acid, chlorogenic acid and rutin in Marantaceae species. Phytochem. Lett. 1, 199–203. first groups of land plants following ancestors from the Charophy- Achamlale, S., Rezzonico, B., Grignon-Dubois, M., 2009. Rosmarinic acid from beach ceae green algae family. While lignin has not yet been reported waste: isolation and HPLC quantification in Zostera detritus from Arcachon from these groups of land plants it appears in tracheophytes lagoon. Food Chem. 113, 878–883. Amzad Hossain, M., Salehuddin, S.M., Kabir, M.J., Rahman, S.M.M., Vasantha (Waters, 2003). Nevertheless, the capacity to synthesise cinnamic Rupasinghe, H.P., 2009. Sinensetin, 30-hydroxy-5,6,7,40-tetramethoxyflavone acid derivatives with a higher substituted aromatic ring (e.g. caffeic and rosmarinic acid contents and antioxidative effect of the skin of apple fruit. acid) is already present in the earliest land plant groups. Recent Food Chem. 113, 185–190. Anterola, A.M., Jeon, J.H., Davin, L.B., Lewis, N.G., 2002. Transcriptional control of findings demonstrate the presence of lignified cell walls with 4- monolignol biosynthesis in Pinus taeda – factors affecting monolignol ratios and coumaryl, coniferyl and sinapyl moieties from red algae (Martone carbon allocation in phenylpropanoid metabolism. J. Biol. Chem. 277, 18272– et al., 2009) and thus opens up the discussion about the timepoint 18280. of the evolution of lignin biosynthesis and a mono- or polyphyletic Aquino, R., Ciavatta, M.L., De Simone, F., Pizza, C., 1990. A flavanone glycoside from Hamelia patens. Phytochemistry 29, 2358–2360. origin. Aquino, R., Morelli, S., Lauro, M.R., Abdo, S., Saija, A., Tomaino, A., 2001. Phenolic Peter and Neale (2004) postulated that gymnosperms and constituents and antioxidant activity of an extract of Anthurium versicolor angiosperms share a common ancient and conserved pathway for leaves. J. Nat. Prod. 64, 1019–1023. Asakawa, Y., 2004. Chemosystematics of the Hepaticae. Phytochemistry 65, 623– the formation of guiacyl lignin while the formation of syringyl lig- 669. nin is a more recent achievement of angiosperms. The ancient Berger, A., Meinhard, J., Petersen, M., 2006. Rosmarinic acid synthase is a new pathway comprises the enzymes of the general phenylpropanoid member of the superfamily of BAHD acyltransferases. Planta 224, 1503–1510. Bernard, N., Delcour, J., Alvarez, A., Cortes, A., Willis, C., Holbrook, J.J., 1995. pathway (PAL, C4H and 4CL), 4-coumaroyl-CoA:shikimate Dehydrogenases engineering to correct substrate inhibition in a commercial hydroxycinnamoyltransferase, 4-coumaroylshikimate 3-hydroxy- dehydrogenase. pdb database 2dld. lase as well as caffeoyl-CoA 3-O-methyltransferase, (hydroxy)cin- Bohm, B.A., 1968. Phenolic compounds in ferns – III. An examination of some ferns for caffeic acid derivatives. Phytochemistry 7, 1825–1830. namyl alcohol reductase (CCR) and (hydroxy)cinnamyl alcohol Booth, M.P.S., Conners, R., Rumsby, G., Brady, R.L., 2006. Structural basis of substrate dehydrogenase (CAD) and leads to the formation of 4-coumaryl specificity in human glyoxylate reductase/hydroxypyruvate reductase. J. Mol. alcohol and coniferyl alcohol as monolignols. Lignin formed from Biol. 360, 178–189. Bresinsky, A., Körner, C., Kadereit, J.W., Neuhaus, G., Sonnewald, U., 2008. these monolignols is primarily found in water-conducting ele- Strasburger – Lehrbuch der Botanik. Spektrum Akademischer Verlag, ments. In angiosperms syringyl lignin contains a further monolig- Heidelberg. nol, sinapyl alcohol, which needs further enzymes for its Burhenne, K., Kristensen, B.K., Rasmussen, S.K., 2003. A new class of N- biosynthesis, namely coniferaldehyde 5-hydroxylase, caffeic acid/ hydroxycinnamoyltransferases. Purification, cloning and expression of a agmatine coumaroyltransferase (EC 2.3.1.64). J. Biol. Chem. 278, 13919–13927. 5-hydroxyconiferaldehyde 3/5-O-methyltransferase and a specific Clé, C., Hill, L.M., Niggeweg, R., Martin, C.R., Guisez, Y., Prinsen, E., Jansen, M.A.K., sinapyl alcohol dehydrogenase (SAD). Syringyl lignin is predomi- 2008. Modulation of chlorogenic acid biosynthesis in Solanum lycopersicon: nantly formed in fiber cell walls and seems to be a more recent consequences for phenolic accumulation and UV-tolerance. Phytochemistry 69, 2149–2156. evolutionary achievement. This shows again that hydroxy- Comino, C., Lanteri, S., Portis, E., Acquadro, A., Romani, A., Hehn, A., Larbat, R., cinnamoyltransferases and hydroxycinnamoyl meta-hydroxylases Bourgaud, F., 2007. Isolation and functional characterization of a cDNA coding a seem to be evolutionarily old enzymes. Alternatively the first land hydroxycinnamoyltransferase involved in phenylpropanoid biosynthesis in Cynara cardunculus L. BMC Plant Biol. 4, 14. plants could have developed a differing set of enzymes to synthe- D’Auria, J.C., 2006. Acyltransferases in plants: a good time to be BAHD. Curr. Opin. sise the caffeic acid and further derived substitution patterns in Plant Biol. 9, 331–340. phenolic metabolites. De Tommasi, N., De Simone, F., De Feo, V., Pizza, C., 1991. Phenylpropanoid glycosides and rosmarinic acid from Momordica balsamina. Planta Med. 57, 201. The biosynthesis of RA does not require many enzymes spe- De-Eknamkul, W., Ellis, B.E., 1987. Tyrosine aminotransferase: the entrypoint cific for this biosynthetic pathway. As indicated above, the forma- enzyme of the tyrosine-derived pathway in rosmarinic acid biosynthesis. tion of 4-coumaroyl-CoA should be an inherent metabolic feature Phytochemistry 26, 1941–1946. Douce, R., Joyard, J., 1996. Biosynthesis of thylakoid membrane lipids. In: Ort, D.R., of all land plants. Furthermore, the formation of pHPP is neces- Yocum, C.F. (Eds.), Advances in Photosynthesis, vol. 4. Kluwer, Dordrecht, pp. sary for all photosynthetically active organisms since it is a pre- 69–101. cursor for tocopherols and/or plastoquinones. The Eberle, D., Ullmann, P., Werck-Reichhart, D., Petersen, M., 2009. cDNA cloning and transformation of pHPP to pHPL could possibly be catalysed by functional characterisation of CYP98A14 and NADPH:cytochrome P450 reductase from Coleus blumei involved in rosmarinic acid biosynthesis. Plant an enzyme of photorespiration, the cytosolic HPR, or by an HPPR Mol. Biol. 69, 239–253. enzyme very closely related to HPR. There are high similarities Ehlting, J., Hamberger, B., Million-Rousseau, R., Werck-Reichhart, D., 2006. between cytosolic HPRs and the putative HPPR from C. blumei. Cytochromes P450 in phenolic metabolism. Phytochem. Rev. 5, 239–270. Fernandez, L., Martin, T., Villaescusa, L., Bartolome, C., Rubio, B., Diaz, A.M., 1995. The transfer of the 4-coumaroyl moiety to pHPL and the introduc- Rosmarinic acid and iridoids of Scrophularia scorodonia L. Colloques – Institut tion of the 3,4-dihydroxy substitution patterns of both aromatic National de la Recherche Agronomique 69, 307–308. rings can be mediated by a hydroxycinnamoyltransferase and a Franke, R., Humphreys, J.M., Hemm, M.R., Denault, J.W., Ruegger, M.O., Cusumano, J.C., Chapple, C., 2002. The Arabidopsis REF8 gene encodes the 3-hydroxylase of aromatic meta-hydroxylase (CYP98A), which are very closely re- phenylpropanoid metabolism. Plant J. 30, 33–45. lated to enzymes in monolignol formation. Thus the achievement Gang, D.R., Beuerle, T., Ullmann, P., Werck-Reichhart, D., Pichersky, E., 2002. to synthesise RA could be very old which would be supported by Differential production of meta hydroxylated phenylpropanoids in Sweet Basil peltate glandular trichomes and leaves is controlled by the activities of specific the fact that RA was already found in hornworts. Whether the en- acyltransferases and hydroxylases. Plant Physiol. 130, 1536–1544. zymes of hydroxycinnamoyl transfer and meta-hydroxylation in Garvey, G.S., McCormick, S.P., Rayment, I., 2008. Structural and functional RA biosynthesis have evolved several times independently in dif- characterization of the TRI101 trichothecene 3-O-acetyltransferase from 1678 M. Petersen et al. / Phytochemistry 70 (2009) 1663–1679
Fusarium sporotrichioides and Fusarium graminearum: kinetic insights to Liu, X., Deng, Z., Gao, S., Sun, X., Tang, K., 2008. A new gene coding for p-coumarate combating Fusarium head blight. J. Biol. Chem. 283, 1660–1669. 3-hydroxylase from Ginkgo biloba. Russ. J. Plant Physiol. 55, 82–92. Goldberg, J.D., Yoshida, T., Brick, P., 1994. Crystal structure of a NAD-dependent D- Ly, T.N., Shimoyamada, M., Yamauchi, R., 2006. Isolation and characterization of glycerate dehydrogenase at 2.4 Å resolution. J. Mol. Biol. 236, 1123–1140. rosmarinic acid oligomers in Celastrus hindsii Benth. leaves and their Grant, G.A., 1989. A new family of 2-hydroxyacid dehydrogenases. Biochem. antioxidative activity. J. Agric. Food Chem. 54, 3786–3793. Biophys. Res. Commun. 165, 1371–1374. Ma, X., Koepke, J., Panjikar, S., Fritzsch, G., Stöckigt, J., 2005. Crystal structure of Grayer, R.J., Eckert, M.R., Veitch, N.C., Kite, G.C., Marin, P.D., Kokubun, T., Simmonds, vinorine synthase, the first representative of the BAHD superfamily. J. Biol. M.S.J., Paton, A.J., 2003. The chemotaxonomic significance of two bioactive Chem. 280, 13576–13583. caffeic acid esters, nepetoidins A and B, in the Lamiaceae. Phytochemistry 64, Mahesh, V., Million-Rousseau, R., Ullmann, P., Chabrillange, N., Bustamante, J., 519–528. Mondolot, L., Morant, M., Noirot, M., Hamon, S., de Kochko, A., Werck-Reichhart, Harborne, J.B., 1966. Caffeic acid ester distribution in higher plants. Z. Naturforsch. D., Campa, C., 2007. Functional characterization of two p-coumaroyl ester 30- 21b, 604–605. hydroxylase genes from coffee tree: evidence of a candidate for chlorogenic acid Häusler, E., Petersen, M., Alfermann, A.W., 1992. Rosmarinsäure in Blechnum- biosynthesis. Plant Mol. Biol. 64, 145–159. spezies. In: Haschke, H.P., Schnarrenberger, C. (Eds.), Botanikertagung 1992 Martini, U., Zapp, J., Becker, H., 1998. Lignans from the liverwort Bazzania trilobata. Berlin. Akademie-Verlag, Berlin, p. 507. Phytochemistry 49, 1139–1146. Heller, W., Kühnl, T., 1985. Elicitor induction of a microsomal 5-O-(4- Martone, P.T., Estevez, J.M., Lu, F., Ruel, K., Denny, M.W., Somerville, C., Ralph, J., coumaroyl)shikimate 30hydroxylase in parsley cell suspension cultures. Arch. 2009. Discovery of lignin in seaweed reveals convergent evolution of cell-wall Biochem. Biophys. 241, 453–460. architecture. Curr. Biol. 19, 169–175. Hess, J.L., 1993. Vitamin E, a-tocopherol. In: Alscher, R.G., Hess, J.L. (Eds.), Matsuno, M., Nagatsu, A., Ogihara, Y., Ellis, B.E., Mizukami, H., 2002. CYP98A6 from Antioxidants in Higher Plants. CRC Press, Boca Raton, pp. 111–134. Lithospermum erythrorhizon encodes 4-coumaroyl-40-hydroxyphenyllactic acid Hiller, K., 1965. Zur Kenntnis der Inhaltsstoffe einiger Saniculoidae. 1. Mitteilung: 3-hydroxylase involved in rosmarinic acid biosynthesis. FEBS Lett. 514, 219– Sanicula europaea L. – Isolierung und quantitative Erfassung von Chlorogen- und 224. Rosmarinsäure. Pharmazie 20, 574–579. Milkowski, C., Strack, D., 2004. Serine carboxypeptidase-like acyltransferases. Hiller, K., Kothe, N., 1967. Chlorogen- und Rosmarinsäure – Vorkommen und Phytochemistry 65, 517–524. quantitative Verteilung in Pflanzen der Saniculoideae. Pharmazie 22, 220–221. Morant, M., Schoch, G.A., Ullmann, P., Ertunc, T., Little, D., Olsen, C.E., Petersen, M., Ho, L.K., Chang, C.R., Chang, Y.S., 1995. Chemical components from Triumfetta Negrel, J., Werck-Reichhart, D., 2007. Catalytic activity, duplication and bartramia. J. Chin. Chem. Soc. (Taipei) 42, 93–95. evolution of the CYP98 cytochrome P450 family in wheat. Plant Mol. Biol. 63, Hoffmann, L., Maury, S., Martz, F., Geoffroy, P., Legrand, M., 2003. Purification, 1–19. cloning, and properties of an acyltransferase controlling shikimate and quinate Nair, R.B., Xia, Q., Kartha, C.J., Kurylo, E., Hirji, R.N., Datla, R., Selvaraj, G., 2002. ester intermediates in phenylpropanoid metabolism. J. Biol. Chem. 278, 95– Arabidopsis CYP98A3 mediating aromatic 3-hydroxylation. Developmental 103. regulation of the gene, and expression in yeast. Plant Physiol. 130, 210–220. Hoffmann, L., Besseau, S., Geoffroy, P., Ritzenthaler, C., Meyer, D., Lapierre, C., Pollet, Nakayama, T., Suzuki, H., Nishino, T., 2003. Anthocyanin acyltransferases: B., Legrand, M., 2004. Silencing of hydroxycinnamoyl-coenzyme A shikimate/ specificities, mechanism, phylogenetics, and applications. J. Mol. Catal. B 23, quinate hydroxycinnamoyltransferase affects phenylpropanoid biosynthesis. 117–132. Plant Cell 16, 1446–1465. Niggeweg, R., Michael, A., Martin, C., 2004. Engineering plants with increased levels Hoffmann, L., Besseau, S., Geoffroy, P., Ritzenthaler, C., Meyer, D., Lapierre, C., Pollet, of the antioxidant chlorogenic acid. Nat. Biotechnol. 22, 746–754. B., Legrand, M., 2005. Acyltransferase-catalysed p-coumarate ester formation is Olivier, D.K., van Wyk, B.E., van Heerden, F.R., 2008. The chemotaxonomic and a committed step of lignin biosynthesis. Plant Biosyst. 139, 50–53. medicinal significance of phenolic acids in Arctopus and Alepidea (Apiaceae Holzmannová, V., 1995. Kyselina rosmarinová a její biologická aktivita. Chem. Listy subfamily Saniculoideae). Biochem. Syst. Ecol. 36, 724–729. 90, 486–496. Olmstead, R., 2005. A synoptical classification of the Lamiales.
phenolic esters, a missing link in the phenylpropanoid pathway. J. Biol. Chem. Waters, E.R., 2003. Molecular adaptation and the origin of land plants. Mol. 276, 36566–36574. Phylogen. Evol. 29, 456–463.
Schuller, D.J., Grant, G.A., Banaszak, L.J., 1995. The allosteric ligand site in the Vmax- Yamamura, Y., Ogihara, Y., Mizukami, H., 2001. Cinnamic acid 4-hydroxylase from type cooperative enzyme phosphoglycerate dehydrogenase. Nat. Struct. Biol. 2, Lithospermum erythrorhizon: cDNA cloning and gene expression. Plant Cell Rep. 69–76. 20, 655–662. Shadle, G., Chen, F., Reddy, M.S.S., Jackson, L., Nakashima, J., Dixon, R.A., 2007. Yan, Q., Shi, M., Ng, J., Wu, J.Y., 2006. Elicitor-induced rosmarinic acid accumulation Down-regulation of hydroxycinnamoyl CoA:shikimate hydroxycinnamoyl and secondary metabolism enzyme activities in Salvia miltiorrhiza hairy roots. transferase in transgenic alfalfa affects lignification, development and forage Plant Sci. 170, 853–858. quality. Phytochemistry 68, 1521–1529. Yang, Q., Reinhard, K., Schiltz, E., Matern, U., 1997. Characterization and Sondheimer, E., 1964. Chlorogenic acid and related depsides. Bot. Rev. 30, 667–712. heterologous expression of hydroxycinnamoyl/benzoyl-CoA:anthranilate N- St. Pierre, B., De Luca, V., 2000. Evolution of acyltransferase genes: origin and hydroxycinnamoyl/benzoyltransferase from elicited cell cultures of carnation, diversification of the BAHD superfamily of acyltransferases involved in Dianthus caryophyllus L. Plant Mol. Biol. 35, 777–789. secondary metabolism. Rec. Adv. Phytochem. 34, 285–316. Yang, Q., Trinh, H.X., Imai, S., Ishihara, A., Zhang, L.Q., Nakayashiki, H., Stöckigt, J., Zenk, M.H., 1974. Enzymatic synthesis of chlorogenic acid from caffeoyl Tosa, Y., Mayama, S., 2004. Analysis of the involvement of coenzyme A and quinic acid. FEBS Lett. 42, 131–134. hydroxyanthranilate hydroxycinnamoyltransferase and caffeoyl-CoA 3- Takeda, R., Hasegawa, J., Sinozaki, K., 1990. The first isolation of lignans, O-methyltransferase in phytoalexin biosynthesis in oat. Mol. Plant megacerotonic acid and anthocerotonic acid, from non-vascular plants, Microb. Interact. 17, 81–89. Anthocerotae (hornworts). Tetrahedron Lett. 31, 4159–4162. Yoshida, M., Fuchigami, M., Nagao, T., Okabe, H., Matsunaga, K., Takata, J., Karube, Y., Tamura, K., Dudley, J., Nei, M., Kumar, S., 2007. MEGA4: Molecular Evolutionary Tsuchihashi, R., Kinjio, J., Mihashi, K., Fujioka, T., 2005. Antiproliferative Genetics Analysis (MEGA) software version 4.0. Mol. Biol. Evol. 24, 1596–1599. constituents from Umbelliferae plants VII. Active triterpenes and rosmarinic Tazaki, H., Adam, K.P., Becker, H., 1995. Five lignan derivatives from in vitro cultures acid from Centella asiatica. Biol. Pharm. Bull. 28, 173–175. of the liverwort Jamesoniella autumnalis. Phytochemistry 40, 1671–1675. Yun, Y.S., Satake, M., Katsuki, S., Kunugi, A., 2004. Phenylpropanoid derivatives from Timm, S., Nunes-Nesi, A., Pärnik, T., Morgenthal, K., Wienkoop, S., Keerberg, O., edible canna, Canna edulis. Phytochemistry 65, 2167–2171. Weckwerth, W., Kleczkowski, L.A., Fernie, A.R., Bauwe, H., 2008. A cytosolic Zhu, L., Li, Y., Yang, J., Zuo, L., Zhang, D., 2008. Studies on chemical constituents of pathway for the conversion of hydroxypyruvate to glycerate during Sarcandra glabra. Zhongguo Zhongyao Zazhi 33, 155–157. photorespiration in Arabidopsis. Plant Cell 20, 2848–2859. Trute, A., Nahrstedt, A., 1996. Separation of rosmarinic acid enantiomers by three different chromatographic methods (HPLC, CE, GC) and the determination of rosmarinic acid in Hedera helix L. Phytochem. Anal. 7, 204–208. Dr. Maike Petersen obtained her Diploma in biology Tsai, C.J., Harding, S.A., Tschaplinski, T.J., Lindroth, R.L., Yuan, Y., 2006. Genome-wide (1983) specialising in plant biology and her Dr. rer. nat. analysis of the structural genes regulating defense phenylpropanoid (1986) from the Eberhard-Karls-Universität Tübingen, metabolism in Populus. New Phytol. 172, 47–62. Germany. From 1986 to 1997, she worked as a Scientific Ulbrich, B., Zenk, M.H., 1979. Partial purification and properties of Assistant at the Heinrich-Heine-Universität Düsseldorf, hydroxycinnamoyl-CoA:quinate hydroxycinnamoyl transferase from higher Germany. In 1993, she got her ‘‘Habilitation”. From 1990 plants. Phytochemistry 18, 929–933. to 1991 she visited as a Postdoctoral Researcher the Ulbrich, B., Zenk, M.H., 1980. Partial purification and properties of p- University of Ghent (Belgium) and in 1995 she worked as hydroxycinnamoyl-CoA:shikimate-p-hydroxycinnamoyl transferase from a Professor for Pharmaceutical Biology at the University higher plants. Phytochemistry 19, 1625–1629. of Halle-Wittenberg, Germany. In 1997, she got a full Unno, H., Ichimaida, F., Suzuki, H., Takahashi, S., Tanaka, Y., Saito, A., Nishino, T., professorship in Pharmaceutical Biology at the Philipps- Kusunoki, M., Nakayama, T., 2007. Structural and mutational studies of Universität Marburg, Germany. anthocyanin malonyltransferases establish the features of BAHD enzyme In her research, Maike Petersen is interested in biochemistry and molecular biology catalysis. J. Biol. Chem. 282, 15812–15822. of plant secondary metabolism and in the use of plant in vitro-techniques for the Velazquez Fiz, M.P., Diaz Lanza, A.M., Fernandez Matellano, L., 2000. Polyphenolic compounds from Plantago lagopus L. Z. Naturforsch. 55c, 877–880. production of useful natural compounds. Main research topics are phenolic natural Vogelsang, K., Schneider, B., Petersen, M., 2005. Production of rosmarinic acid and a compounds, especially rosmarinic acid and lignans. In 1990, she was rewarded the new rosmarinic acid 30-O-b-D-glucoside in suspension cultures of the hornwort Research-Prize of Northrhine-Westfalia and in 1995 the Rhône-Poulenc Rorer Anthoceros agrestis Paton. Planta 223, 369–373. Award of the Phytochemical Society of Europe (PSE). Currently, she is a member of Wagner, A., Ralph, J., Akiyama, T., Flint, H., Phillips, L., Torr, K., Nanayakkara, B., Te the editorial boards of ‘‘Phytochemistry Reviews”, ‘‘Phytochemistry Letters” and Kiri, L., 2007. Exploring lignification in conifers by silencing hydroxycinnamoyl- ‘‘Plant Cell Reports”. CoA:shikimate hydroxycinnamoyltransferase in Pinus radiata. Proc. Natl. Acad. Sci. USA 104, 11856–11861.