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Phytochemistry Reviews 2: 371–390, 2003.© 2004 Kluwer Academic Publishers. Printed in the Netherlands.
371
Diversity in lignan biosynthesis
Toshiaki UmezawaWood Research Institute, Kyoto University, Uji, Kyoto 611-0011, Japan (E-mail, [email protected])
Key words: biosynthesis, evolution, lignans, phylogenetic distribution, stereochemistry, structural diversity
Abstract
Lignans are phenylpropanoid dimers, where the phenylpropane units are linked by the central carbon (C8) oftheir side chains. Ligans vary substantially in oxidation level, substitution pattern, and the chemical structure oftheir basic carbon framework. In addition to structural diversity, lignans show considerable diversity in terms ofenantiomeric composition, biosynthesis, and phylogenetic distribution. In this review, these diversities are outlinedand the phylogenetic distribution of plants producing 66 typical lignans is listed. The distribution is correlated withthe putative biosynthetic pathways of the lignans and discussed from evolutionary aspects.
Abbreviations: SIRD – Secoisolariciresinol dehydrogenase; PLR – pinoresinol lariciresinol reductase; DP –dirigent protein
Introduction
Lignans, constituting an abundant class of phenylpro-panoids, have been receiving widespread interest inmany fields. This is mainly because these compoundshave a number of medically important biological activ-ities, e.g. antitumor, antimitotic, and antiviral prop-erties (MacRae and Towers, 1984; Ayres and Loike,1990; Umezawa, 1996), as well as unique stereochem-ical properties (Umezawa, 1997; Lewis and Davin,1999; Umezawa, 2001). During the last decade, sig-nificant advances have been made in the chemistryand biosynthesis of lignans (Umezawa, 1997; Lewisand Davin, 1999; Umezawa, 2001). Additionally, thestructural, enantiomeric, and biosynthetic diversityexhibited by lignans, as well as their diverse phylogen-etic distribution have been noticed (Umezawa, 2001).Lignan biosynthesis has been found to be closelyrelated to but distinct from those of other phenyl-propanoids, such as norlignans, lignins, and neolig-nans (Umezawa, 2001; Suzuki et al., 2001; Suzukiet al., 2002a). The diversity exhibited by lignans andthe similarity of their biosynthesis to those of otherphenylpropanoids piqued our scientific interest in theorigination and evolution of phenylpropanoid biosyn-thesis in vascular plants, a central theme in plant
science. Lignans are distributed widely in vascularplants. But, unlike lignins, they are not ubiquitous.Hence, lignans may be a good subject for studying theevolution of plant secondary metabolism. Herein theauthor outlines the various diversities of lignans andcorrelates them with a phylogenetic classification oflignan producing plants.
Nomenclature
The term, lignan, was introduced by Haworth (1936)to describe a group of phenylpropanoid dimers, wherethe phenylpropane units were linked by the centralcarbon (C8) of their propyl side chains (Figure 1).McCredie et al. (1969) proposed to extend the termto cover all natural products of low molecular weightthat arise primarily from the oxidative coupling of p-hydroxyphenylpropene units, while Gottlieb (1972)coined the term neolignan for compounds composedof two phenylpropane units linked in a manner otherthan C8-C8′. However, later neolignans were re-defined as the dimers of allyl- and/or propenylphenylmonomers, while lignans were regarded as the dimersof cinnamyl alcohols and/or cinnamic acids (Gottlieb,1978). In spite of these redefinitions, Haworth’s defin-ition of lignans (Haworth, 1936) and Gottlieb’s former
372
definition of neolignans (Gottlieb, 1972) have beenused widely, and recently were adopted by the IUPACrecommendations 2000 (Moss, 2000). Analogs of lig-nans composed of three and four phenylpropane unitshave been commonly called sesquilignans and dilig-nans, respectively (Umezawa, 2000). However, themost recent IUPAC recommendations named thesecompounds sesquineolignans and dineolignans, re-spectively. The new terms are logical, because thesetri- and tetramers involve inherently neolignan typelinkages. This review follows the IUPAC recommend-ations (Moss, 2000).
Structural diversity of lignans
Lignans are classified into the following eight sub-groups based upon the way in which oxygen is in-corporated into the skeleton and the cyclization pat-tern: furofuran, furan, dibenzylbutane, dibenzylbu-tyrolactone, aryltetralin, arylnaphthalene, dibenzocyc-looctadiene (Whiting, 1985) and dibenzylbutyrolactol(Figure 1). Lignans of each subgroup vary substan-tially in oxidation levels of both the aromatic rings andpropyl side chains. Some lignans of furan, dibenzyl-butane, and dibenzocyclooctadiene have no oxygen atC9 (C9′) (Figures 1 and 2), while some lignans haveextra hydroxyl groups at C7 (C7′) or C8 (C8′) (e.g.podophyllotoxin 40 with C7′OH and wikstromol 33with C8OH, Figure 2). 3-Methoxy-4-hydroxyphenyl(guaiacyl), 3,4-dimethoxyphenyl (veratryl), 3,4-methylenedioxyphenyl (piperonyl), 3,5-dimethoxy-4-hydroxyphenyl (syringyl), and 3,4,5-trimethoxyphenyl(Figure 1) are the most frequently occurring aro-matic rings found in lignans. 4-Hydroxyphenyl and3,4-dihydroxyphenyl lignans have also been identified(Ayres and Loike, 1990), though they are rare.
Enantiomeric diversity of lignans
In addition to the structural diversity, lignans varysubstantially with respect to enantiomeric composition(Umezawa et al., 1997a).
First of all, it is important to compare the ab-solute configurations of typical lignans. The follow-ing lignans have the same absolute configurationsat C8 and C8′ with respect to the carbon skeleton(Figures 2 and 3) (Umezawa et al., 1997a; Umez-awa, 2001): (+)-pinoresinol (+)-1 and syringaresi-nol (+)-3 (furofuran); (+)-lariciresinol (+)-18 (furan);
(-)-secoisolariciresinol (-)-23 (dibenzylbutane); (-)-matairesinol (-)-27, (-)-arctigenin (-)-28, (-)-hinokinin(-)-29, (-)-pluviatolide (-)-30, (-)-kusunokinin (-)-67, (-)-haplomyrfolin (-)-68, thujaplicatin methylether (-)-70, and (-)-4-demethylyatein (-)-71 (Charltonand Chee, 1997) (dibenzylbutyrolactone); and (-)-wikstromol (= nortrachelogenin) (-)-33 and (-)-methyltrachelogenin (-)-69 (Khamlach et al., 1989)(8-hydroxydibenzylbutyrolactone).
Naturally occurring lignans have been found to ex-ist exclusively as one enantiomer or as enantiomericmixtures with various enantiomeric compositions (%e.e. values) (Table 1). Sometimes even racemic lignanshave been found to occur (Umezawa et al., 1997a).There is no example of furofuran and furan lignansproven to be optically pure by chiral HPLC analysis(Umezawa et al., 1997a). For instance, pinoresinol1 isolated from Wikstroemia sikokiana was found tobe a mixture of both enantiomers with 74% e.e. [(-)>(+)] (Umezawa and Shimada, 1996a), and that fromLarix leptolepis was dextrorotatory (92% e.e.) (Nabetaet al., 1991). In contrast, all dibenzylbutyrolactonelignans which have so far been analyzed by chiralHPLC have been found to be optically pure (>99%e.e.) regardless of the sign of optical rotation (Table 1)(Umezawa et al., 1997a). As for dibenzylbutane lig-nans, secoisolariciresinol 23 from Forsythia plants isoptically pure and levorotatory (Umezawa et al., 1991;Umezawa et al., 1992) and that from Phyllanthus sp.is almost optically pure (98% e.e.) in favor of the (+)-enantiomer (Umezawa et al., 1997b). On the otherhand, this lignan isolated from W. sikokiana and Arc-tium lappa (petiole) is not optically pure, with 45%e.e. [(-)>(+)] (Okunishi et al., 2000) and 81% e.e.,(+)>(-) (Umezawa and Shimada, 1996b; Suzuki et al.,1998; Suzuki et al., 2002a), respectively (Table 1).
Umezawa et al. (1997a) also pointed out thatthe predominant enantiomers (or the signs of op-tical rotation) of furofuran, furan, and dibenzylbu-tane lignans vary with plant species (Table 1). Forexample, (-)-secoisolariciresinol (-)-23 was isolatedfrom many plants, e.g. W. sikokiana (45% e.e.) (Ok-unishi et al., 2000), Forsythia spp. (optically pure)(Umezawa et al., 1991; Umezawa et al., 1992),Xanthoxylum ailanthoides (Ishii et al., 1983), andAraucaria angustifolia (Fonseca et al., 1978),while(+)-secoisolariciresinol (+)-23 was obtained fromPhyllanthus sp. (98% e.e.) (Umezawa et al., 1997b)and Daphne spp. (>99–97% e.e.) (Okunishi et al.,2001) (Table 1). Similarly, as shown in Table 1the predominant enantiomers of pinoresinol and lar-
373
Tabl
e1.
Ena
ntio
mer
icco
mpo
sitio
nsof
ligna
nsis
olat
edfr
omva
riou
spl
ants
peci
es
Pla
ntcl
assi
ficat
ion
rank
Lig
nans
∗ and
thei
ren
anti
omer
icco
mpo
siti
ons
(%e.
e.)
Fam
ilySp
ecie
sF
urof
uran
Fur
anD
iben
zylb
utan
eD
iben
zylb
utyr
olac
tone
Ref
eren
ce
Ast
erac
eae
Arc
tium
lapp
a(s
eed)
(-)-
SIR
(65%
e.e.
)(-
)-M
R(>
99%
e.e.
)(-
)-A
R(>
99%
e.e.
)U
mez
awa
and
Shim
ada,
1996
bSu
zuki
etal
.,19
98Su
zuki
etal
.,20
02a
Arc
tium
lapp
a(p
etio
le)
(+)-
SIR
(81%
e.e.
)
Ole
acea
eFo
rsyt
hia
kore
ana
(+)-
PR(8
2%e.
e.)
(+)-
LR
(35%
e.e.
)(-
)-SI
R(>
99%
e.e.
)(-
)-M
R(>
99%
e.e.
)(-
)-A
R(>
99%
e.e.
)U
mez
awa
etal
.,19
92U
mez
awa
etal
.,19
94U
mez
awa
etal
.,U
npub
lishe
d
Fors
ythi
ain
term
edia
(-)-
SIR
(>99
%e.
e.)
(-)-
MR
(>99
%e.
e.)
(-)-
AR
(>99
%e.
e.)
Um
ezaw
aet
al.,
1991
Oza
wa
etal
.,19
93
Lin
acea
eL
inum
flavu
mva
r.co
mpa
ctum
(+)-
PR(6
5%e.
e.)
(+)-
LR
(70%
e.e.
)(-
)-SI
R(>
99%
e.e.
)M
ikam
eet
al.,
2002
Eup
horb
iace
aeP
hylla
nthu
ssp
.(+
)-SI
R(9
8%e.
e.)
Um
ezaw
aet
al.,
1997
b
374
Tabl
e1.
Con
tinue
d
Pla
ntcl
assi
ficat
ion
rank
Lig
nans
∗ and
thei
ren
anti
omer
icco
mpo
siti
ons
(%e.
e.)
Fam
ilySp
ecie
sF
urof
uran
Fur
anD
iben
zylb
utan
eD
iben
zylb
utyr
olac
tone
Ref
eren
ce
Thy
mel
aeac
eae
Wik
stro
emia
siko
kian
a(-
)-PR
(74%
e.e.
)(-
)-L
R(3
9%e.
e.)
(-)-
SIR
(45%
e.e.
)(+
)-M
R(>
99%
e.e.
)(+
)-K
U(>
99%
e.e.
)(+
)-W
I(>
99%
e.e.
)(+
)-M
eTR
(>99
%e.
e.)
Um
ezaw
aan
dSh
imad
a,19
96a
Oku
nish
ieta
l.,20
00
Dap
hne
odor
a(-
)-PR
(95%
e.e.
)(-
)-L
R(8
9%e.
e.)
(+)-
SIR
(>99
%e.
e.)
(+)-
MR
(>99
%e.
e.)
Oku
nish
ieta
l.,20
01
Dap
hne
genk
wa
(-)-
PR(8
8%e.
e.)
(-)-
LR
(88%
e.e.
)(+
)-SI
R(9
7%e.
e.)
(+)-
MR
(>99
%e.
e.)
Oku
nish
ieta
l.,20
01
Pina
ceae
Lar
ixle
ptol
epis
(+)-
PR(9
2%e.
e.)
Nab
eta
etal
.,19
91
Cup
ress
acea
eC
ham
aecy
pari
sob
tusa
(cv.
Bre
vira
mea
)
(-)-
MR
(>99
%e.
e.)
(-)-
HI
(>99
%e.
e.)
(-)-
HA
(>99
%e.
e.)
(-)-
PL(>
99%
e.e.
)
Taka
kuet
al.,
2001
Thu
jaoc
cide
ntal
is(-
)-M
R(>
99%
e.e.
)(-
)-T
JM(>
99%
e.e.
)(-
)-D
MY
A(>
99%
e.e.
)(-
)-W
I(>
99%
e.e.
)
Kaw
aiet
al.,
1999
∗ PR
,pin
ores
inol
1;L
R,l
aric
ires
inol
18;S
IR,s
ecoi
sola
rici
resi
nol
23;M
R,m
atai
resi
nol
27;A
R,a
rctig
enin
28;
HI,
hino
kini
n29
;PL
,plu
viat
olid
e30
;WI,
wik
stro
mol
33;
KU
,kus
unok
inin
67;H
A,h
aplo
myr
folin
68;M
eTR
,met
hyltr
ache
loge
nin
69;T
JM,t
huja
plic
atin
met
hyle
ther
70;D
MY
A,4
-dem
ethy
lyat
ein
71
375
Figure 1. Basic skeletons of lignans.
iciresinol differ among various plant species (Umez-awa et al., 1997a). In contrast, most dibenzylbutyr-olactone lignans are levorotatory (Umezawa et al.,1997a), except that the lignans of this subgroup isol-ated from Thymelaeaceae plants such as Wikstroemiaspp., Daphne spp., and Stellera chamaejasme (Umez-awa and Shimada, 1996a; Umezawa et al., 1997a;Okunishi et al., 2000, 2001; Chen et al., 2001; Xuet al., 2001) (Table 1) and Selaginella doederleinii(Selaginellaceae) (Lin et al., 1994) are dextrorotatory.
Furthermore, within a single plant species theabsolute configurations of predominant lignan enan-tiomers may vary (Table 1) (Umezawa et al., 1997a).For instance, (+)-arctigenin (+)-28 (Suzuki et al.,1982) and (+)-pinoresinol (+)-1 (Tandon and Rastogi,1976) isolated from Wikstroemia indica (= W. viridi-flora) have opposite absolute configurations to eachother at C8 and C8′. Similarly, W . sikokiana pro-duces (+)-matairesinol (+)-27 (optically pure) (Umez-awa and Shimada, 1996a) and (-)-secoisolariciresinol(-)-23 (45% e.e.) (Okunishi et al., 2000), and thepredominant enantiomers of the lignans have oppos-ite absolute configurations (Table 1). In addition, itis noteworthy that the predominant enantiomer ofsecoisolariciresinol 23 isolated from A. lappa seeds isopposite to that from A. lappa petioles; (-)-23 (65%e.e.) was obtained from the seeds and (+)-23 (81%e.e.) was from the petioles (Umezawa and Shimada,
1996b; Suzuki et al., 1998, 2002a) (Table 1). Incontrast, the following lignans from Forsythia spp.have the same absolute configurations at C8 and C8′:(+)-pinoresinol (+)-1 (Kitagawa et al., 1988; Umez-awa et al., 1990b, 1992), (+)-lariciresinol (+)-18(Umezawa et al., 1994), (-)-secoisolariciresinol (-)-23(Umezawa et al., 1991, 1992), (-)-matairesinol (-)-27(Nishibe et al., 1988; Kitagawa et al., 1988; Rahmanet al., 1990; Umezawa et al., 1991, 1992) and (-)-arctigenin (-)-28 (Nishibe et al., 1988; Kitagawa et al.,1988; Rahman et al., 1990; Umezawa et al., 1992;Ozawa et al., 1993).
The enantiomeric properties of lignans can bedescribed with four statements. First, dibenzylbu-tyrolactone lignans are optically pure (>99% e.e.),while furofuran and furan lignans are mixtures of bothenantiomers and exhibit various enantiomeric com-positions. Second, dibenzylbutyrolactone lignans arefor the most part levorotatory except that the lig-nans from Thymelaeaceae plants and S. doederleiniiare dextrorotatory. Third, predominant enantiomersof furofuran, furan, and dibenzylbutane lignans varyamong plant species, and even within different organsin a single plant species (A. lappa). Fourth, the abso-lute configurations of the predominant enantiomers ofvarious lignans isolated from a single plant species aresometimes different.
376
Figure 2. Lignans obtained in the CAPLUS database search. Note that only one enantiomer of each lignan is shown.
377
Figure 2. Continued
378
Figure 2. Continued
Biosynthetic pathways of lignans
The biosynthetic pathway of several of the typical lig-nans listed in Figure 2 have been well established.However, the biosynthetic pathway for many otherlignans still remains unknown (Scheme 1).
Erdtman (1933) first suggested that the basic lig-nan structure was formed by the coupling of twophenylpropanoid monomer units. Later, this assump-tion was substantiated by isotope tracer experiments.These investigations were outlined in a number of re-views, for example, by Dewick (1989), Ayres andLoike (1990), and Umezawa (1997).
In 1990 the first example of in vitro formation ofoptically pure (-)-secoisolariciresinol (-)-23 from anachiral phenylpropanoid monomer, coniferyl alcohol,was reported using Forsythia intermedia as an enzymesource (Umezawa et al., 1990a). At the same time,selective oxidation of (-)-secoisolariciresinol (-)-23 to(-)-matairesinol (-)-27 by an enzyme preparation fromF. intermedia was reported (Umezawa et al., 1990b,1991). Later, this enzyme, secoisolariciresinol de-hydrogenase (SIRD), was purified and its cDNA wascloned (Xia et al., 2001). The selective reduction of(+)-enantiomer of pinoresinol (+)-1 to give rise to (-)-
secoisolariciresinol (-)-23 via (+)-lariciresinol (+)-18by Forsythia enzyme was also detected (Katayamaet al., 1992, 1993; Umezawa et al., 1994). This en-zyme, pinoresinol/lariciresinol reductase (PLR), waspurified and its cDNA was cloned (Chu et al., 1993;Dinkova-Kostova et al., 1996). Davin et al. (1997)isolated a unique protein from Forsythia sp. that ledto enantioselective formation of (+)-pinoresinol (+)-1 by coupling of coniferyl alcohol in the presenceof laccase/O2. The function of the unique protein[dirigent protein (DP)] as an asymmetric inducer isvery important and interesting from a stereochemicalaspect. These studies demonstrated that lignan syn-thesis mediated by Forsythia DP and enzymes is wellcontrolled in terms of stereochemistry.
Studies in a wide range of gymnosperms and an-giosperms showed the existence of a common lignanbiosynthetic pathway. PLR and SIRD have been de-tected from several plant species (Xia et al., 2000;Umezawa and Shimada, 1996b; Katayama et al.,1997; Suzuki et al., 1998, 2002b, 2002c; Okunishiet al., 2001). In addition, administration of [2H] or[14C]coniferyl alcohol to a variety of plant speciesresulted in the incorporation of 2H or 14C into pinores-
379
Sche
me
1.Po
ssib
lebi
osyn
thet
icpa
thw
ays
forv
ario
usty
pes
oflig
nans
.Sol
idan
dbr
oken
arro
ws
repr
esen
tpat
hway
ssu
bsta
ntia
ted
byex
peri
men
tsan
das
sum
edba
sed
onco
mpa
riso
nof
chem
ical
stru
ctur
es,r
espe
ctiv
ely.
380
inol 1, lariciresinol 18, secoisolariciresinol 23, and/ormatairesinol 27 (Umezawa et al., 1997b, 1998; Miyau-chi and Ozawa, 1998; Kato et al., 1998; Kawai et al.,1999; Takaku et al., 2001). These plants represent awide range of angiosperms and gymnosperms. There-fore the conversion, coniferyl alcohol → pinoresinol1 (furofuran) → lariciresinol 18 (furan) → secoisol-ariciresinol 23 (dibenzylbutane) → matairesinol 27(dibenzylbutyrolactone) (Scheme 1), appears to be acommon lignan biosynthetic pathway.
On the other hand, in terms of stereochemistry,the conversion from coniferyl alcohol to matairesinol27 involves great diversity. Thus, as mentioned, thefarthest upstream lignans in the biosynthetic pathway,pinoresinol 1, lariciresinol 18, and secoisolariciresinol23, isolated from various plant species, were com-posed of both enantiomers (with various enantiomericcompositions), and were not optically pure (Table 1)(Umezawa et al., 1997a; Umezawa, 2001). In sharpcontrast, all dibenzylbutyrolactone lignans, includingmatairesinol 27, for which enantiomeric compositionshave been determined using chiral HPLC, were op-tically pure regardless of the sign of optical rotation(Table 1) (Umezawa et al., 1997a; Umezawa, 2001).
These facts unequivocally indicated that not onlywas the entrance step mediated by DP involved, butsubsequent metabolic steps catalyzed by PLR andSIRD were also involved in determining the enan-tiomeric composition of lignans or the productionof optically pure lignans (Umezawa, 2001). It wasalso suggested that the variation of enantiomeric com-positions of the upstream lignans (lariciresinol 18,secoisolariciresinol 23, and matairesinol 27) amongdifferent plant species may be ascribed, at least inpart, to the characteristics of the reactions catalyzed byPLRs and SIRDs as well as their expression patterns(Umezawa, 2001). This view was supported at least inpart by enzymatic experiments as follows.
As mentioned (Table 1), different enantiomers ofsecoisolariciresinol 23 occur predominantly in differ-ent organs of Arctium lappa; (-)-secoisolariciresinol(-)-23 (65% e.e.) was isolated from the seeds, while(+)-enantiomer (+)-23 (81% e.e.) was isolated fromthe petioles. The enantiomeric segregation was alsodemonstrated by in vitro experiments with enzymepreparations from A. lappa seeds and petioles. Thepetiole enzyme preparation catalyzed the formationof (+)-secoisolariciresinol (+)-23 (20% e.e.) fromachiral coniferyl alcohol in the presence of NADPHand H2O2, whereas that from ripening seeds cata-lyzed the formation of (-)-secoisolariciresinol (-)-23
(38% e.e.) under the same conditions. Because theassay with only H2O2 as a cofactor exhibited signi-ficant pinoresinol formation, PLR-catalyzed reductionof once-formed pinoresinol 1 probably resulted insecoisolariciresinol formation. In addition, incuba-tion of (±)-pinoresinols (±)-1 and (±)-lariciresinols(±)-18 with a PRL preparation from the seeds gave(-)-secoisolariciresinol (-)-23 with high enantiomerexcess (99 and 91% e.e., respectively), whereas(-)-secoisolariciresinol (-)-23 with rather low enan-tiomer excess (44 and 37% e.e.) was obtained fol-lowing incubation of (±)-pinoresinols (±)-1 and (±)-lariciresinols (±)-18, respectively, with a PRL pre-paration from the petioles (Umezawa and Shimada,1996b; Suzuki et al., 1998; Suzuki et al., 1998,2002b). The stereochemical results were accountedfor by postulating that A. lappa has PLR isoformsshowing different selectivity in terms of enantiomersof the substrates and that the isoforms are expresseddifferentially in A. lappa organs (Suzuki et al., 2002b).Although final conclusions await further experiments,this view is in line with recent findings on PLRfrom various plant species. PLRs from F . interme-dia (Chu et al., 1993; Dinkova-Kostova et al., 1996)and Zanthoxylum ailanthoides (Katayama et al., 1997)catalyzed the selective formation of (+)-lariciresinol(+)-18 and (-)-secoisolariciresinol (-)-23 from (±)-pinoresinols (±)-1, whereas that from Daphne genkwacatalyzed the selective formation of (-)-lariciresinol(-)-18 from (±)-pinoresinols (±)-1 (Okunishi et al.,2001). Furthermore, the presence of cDNAs corres-ponding to the two stereochemically distinct PLRs wasdemonstrated in a single plant species (Thuja plicata)(Fujita et al., 1999).
As for SIRD, several papers dealing with the ste-reochemistry of SIRD-catalyzed reactions have beenpublished. SIRDs of F . intermedia (Umezawa et al.,1990b, 1991; Xia et al., 2001) and A. lappa (Su-zuki et al., 2002b) catalyzed the selective formation of(-)-matairesinol (-)-27 from (±)-secoisolariciresinols(±)-23. Considering the consistency of the enan-tiomers between the naturally occurring and in vitroformed matairesinols 27 in the cases of Forsythiaand Arctium, it seemed likely that (+)-matairesinolforming SIRD would be detected in (+)-matairesinolproducing Thymelaeaceae plants. However, it hasbeen found that this is not the case; D. genkwa andDaphne odora SIRDs catalyzed selective formation of(-)-matairesinol (-)-27 from (±)-secoisolariciresinols(±)-23 (Okunishi et al., 2004). Thus, mechanisms forthe (+)-matairesinol formation remain unclear and the
381
Figure 3. Some of the dibenzylbutyrolactone lignans which appear in Table 1. The other dibenzylbutyrolactone lignans are shown in Figure 2.
results present a new question about the stereochem-istry of lignan biosynthesis.
It was established that the conversion of secoisol-ariciresinol 23 to matairesinol 27 proceeded via theintermediary dibenzylbutyrolactollignan 79 using re-combinant F . intermedia and Podophyllum peltatumSIRDs. This result provides insight into the biosyn-thesis of dibenzylbutyrolactols. For example, diben-zylbutyrolactollignan 79 occurring in Abies pinsapo(Barrero et al., 1994) and Cedrus deodara (Tiwariet al., 2001) may be formed from secoisolariciresi-nol 23 by SIRD or dehydrogenases similar to SIRDs(Scheme 1).
Biosynthetic pathways for many other lignans canbe regarded as starting from the upstream lignans,pinoresinol 1, lariciresinol 18, secoisolariciresinol 23,and matairesinol 27 (Scheme 1). Among them, thepathway toward an important antitumor lignan, podo-phyllotoxin 40, has been substantiated by tracer andenzymatic experiments. In the 1980s Dewick and hiscolleagues conducted a series of detailed feeding ex-periments with radio-labelled precursors and revealedthe pathways from yatein 31 to podophyllotoxin40 via deoxypodophyllotoxin (= desoxypodophyllo-toxin, anthricin) 45 (Jackson and Dewick, 1984a, b;Kamil and Dewick, 1986a, b; Dewick, 1989). Next,they showed that matairesinol 27 was metabolizedto podophyllotoxin 40 and proposed yatein 31 as apossible intermediate between matairesinol 27 andpodophyllotoxin 40 (Broomhead et al., 1991).
The transformation of matairesinol 27 to yatein 31involves four steps: 5-hydroxylation, dual methyla-tion at C4OH and C5OH, and methylenedioxy bridgeformation at C3’ and C4’. Many possible sequences ofthese four steps can be envisaged. Recently based onmetabolic profiling and a series of stable isotope tracerexperiments using Anthriscus sylvestris (Scheme 2),Sakakibara et al. (2003) demonstrated a direct path-way and not a metabolic grid from matairesinol 27
to yatein 31 via thujaplicatin 80. It was also demon-strated that the pathway was accompanied by a branchfrom matairesinol 27 to bursehernin 83 which did notlead to yatein 31 (Scheme 2) (Sakakibara et al., 2003).
The transformation of yatein 31 to deoxypodo-phyllotoxin 45 has not yet been detected. But, sev-eral enzymes involved in the further transformationof deoxypodophyllotoxin 45 to podophyllotoxin 40(Scheme 1), β-peltatin 42, and methoxypodophyllo-toxin have been reported (Petersen and Alfermann,2001; Molog et al., 2001; Kuhlmann et al., 2002).Taken together, these data provide an outline of thebiosynthetic pathways which may exist for severalaryltetralin lactone lignans.
Enzymes involved in the formation of the3,4-dimethoxyphenyl and 3,4-methylenedioxyphenylgroups which are present in lignans (Figure 2)have been reported. Ozawa et al. detected O-methyltransferase activities converting pinoresinol 1and matairesinol 27 to eudesmin 4 and arctigenin28, respectively (Ozawa et al., 1993; Miyauchi andOzawa, 1998). A P-450 monooxygenase obtainedfrom the microsomal fraction of Sesamun indicumseeds catalyzed the conversion of pinoresinol 1 topiperitol (mono 3,4-methylenedioxyphenyl analogueof pinoresinol) (Jiao et al., 1998).
Some lignans have hydroxyl groups at C7 (C7′)or C8 (C8′) of their side chain [e.g. wikstromol 33,trachelogenin 34, olivil 21, and podophyllotoxin 40(Figure 2)]. The 7 (7′)- or 8 (8′)-hydroxylated lignansare probably formed from the corresponding deoxyanalogs. Recently, 7′-hydroxylation of matairesinol27 (Xia et al., 2000) and deoxypodophyllotoxin 45(Petersen and Alfermann, 2001; Kuhlmann et al.,2002) were reported.
As for biosynthesis of arylnaphthalenes, Broom-head et al. (1991) administered 14C-labeled matairesi-nol 27 to Diphylleia cymosa, but no incorporationof 14C into an arylnaphthalene lignan diphyllin 52
382
Scheme 2. Biosynthetic pathways for yatein and bursehernin in Anthriscus sylvestris.
was detected. Hence, only speculative discussionbased on a comparison of their chemical structureswith lignans whose biosynthetic pathways are knownis possible. Considering the structural similarity ofarylnaphthalenes to aryltetralins, it seems likely thatarylnaphthalenes are formed by dehydrogenation ofthe corresponding aryltetralins or by hydroxylation ofaryltetralins followed by dehydration (Scheme 1).
Some aryltetralin lignans have two OH groups atC9 and C9′ (Figure 2). The 9,9′-dihydroxyaryltetralinlignans (e.g. isolariciresinol 36 and lyoniresinol 37)may be formed by a rearrangement of the corres-ponding furan lignans (lariciresinol 18 and 5,5’-dimethoxylaricirsinol, respectively) or by oxidation ofthe corresponding dibenzylbutane lignans followed bycyclization (Scheme 1).
Dibenzocyclooctadiene lignans can be dividedinto two categories based on their oxidation statesat C9 and C9′. One category includes dibenzocyc-looctadiene lignans absent oxygen at C9 (C9′) (e.g.gomisin A 62 and wuweizisu C 66, Figure 2). Theother category is butyrolactone, steganacin 54 (Fig-ure 2). They might be formed from the corresponding‘seco’ analogs without the biphenyl bond (Scheme 1).
Plants producing dibenzocyclooctadiene lignanswithout 9(9′)-oxygen are restricted to Illiciales(Magnoliidae) (Table 2), while many dibenzylbutaneand furan lignans without oxygen at C9 and C9′were isolated especially from Magnoliidae plants. It isnoteworthy that some plants of Magnoliidae are alsogood sources of allyl- and propenylphenols such aseugenol, safrole, and anethole which have no oxy-gen at C9 (Gibbs, 1974). This suggests that lignanswithout 9(9′)-oxygen may be formed by a couplingof propenylphenols such as isoeugenol (Scheme1), asproposed by Gottlieb (1972). Recently, Moinuddinet al. (2003) proposed coupling of p-anol (demeth-
oxyisoeugenol) to give several furan lignans without9(9′)-oxygen in Larrea tridentata (Zygophyllaceae).
During the last decade, lignans of another typehave been isolated from liverworts (Hepaticopsida).An optically active dicarboxylic acid lignan, epiphyl-lic acid 72 (a caffeic acid dimer, Figure 4), and itsderivatives, that do not belong to the 12 subgroups oftypical lignans shown in Figure 2, were isolated fromseveral liverworts (Cullmann et al., 1993, 1996, 1999;Martini et al., 1998; Cullmann and Becker, 1999;Tazaki, 2000; Tazaki et al., 2002; Scher et al., 2003).Dicarboxylic acid lignans (p-hydroxycinnamate di-mers) and their esters and amides also occur in somevascular plants: thomasidioic acid 73 (Figure 4) isol-ated from Ulmus thomasii (Ulmaceae) (Hostettler andSeikel, 1969), rabdosiin 74 (a rosmarinic acid di-mer, Figure 4) from Rabdosia japonica (Lamiaceae)(Agata et al., 1988) and Lithospermum erythrorhizon(Boraginaceae) (Yamamoto et al., 2000), arillatose A(a sucrose ester of thomasidioic acid 73) from Poly-gala arillata (Polygalaceae) (Kobayashi et al., 2000),chilianthin A (= rhoipteleic acid A, an triterpene es-ter of epiphyllic acid 72) from Rhoiptelea chiliantha(Rhoipteleaceae) (Jiang et al., 1996), and cannabisinsB, C, and D 75, 76, and 77 (Figure 4) from Cannabissativa (Cannabaceae) (Sakakibara et al., 1992). Tazakiet al. (1999) demonstrated that caffeic acid was con-verted to epiphyllic acid 72 in a liverwort Lophocoleaheterophylla (Geocalycaceae) (Scheme 1), while noth-ing is known about the biosynthesis of this type oflignans in vascular plants.
Phylogenetic distribution of lignans
Recent developments in molecular biology provideuseful tools for analyzing the molecular evolution ofproteins. However, he numbers of cloned cDNAs
383
Figure 4. Examples of dicarboxylic acid lignans (p-hydroxycinnamate dimers).
involved in lignan biosynthesis are still too limitedto conduct a comprehensive and systematic analysisof the molecular evolution of lignan biosynthesis.Additionally, fossil records do not provide inform-ation about the appearance of phenylpropanoid bio-synthesis. Consequently, in this review the authorcorrelates the accumulation of lignans to extant plantspecies.
First, 308 typical lignans listed by Ayres andLoike (1990) were subjected to a database searchirregardless of their signs of optical rotation [Sci-Finder Search; database, Chemical Abstracts Plus(CAPLUS); keywords, ‘the name of each lignan(e.g. pinoresinol)’ and ‘isolation’. Lignans which ap-peared in more than 10 papers were chosen. Thisgave the 66 lignans, shown in Figure 2. Lig-nan glycosides (e.g. arctiin) and acylated lignans(e.g. acetoxypinoresinol) were treated as the corres-ponding aglycones (e.g. arctigenin 28) and deacyl-ated lignans (e.g. hydroxypinoresinol 9), respect-ively, except for steganacin 54 and gomisin B 64.As shown in Figure 2, the selected lignans wereclassified into 12 subgroups based upon their pos-sible biosynthetic pathways (Scheme 1): furofuran;furan with 9(9′)-oxygen; furan without 9(9′)-oxygen;9,9′-dihydoxydibenzylbutane; dibenzylbutane without9(9′)-oxygen; dibenzylbutyrolactol; dibenzylbutyro-lactone; 9,9′-dihydroxyaryltetralin; aryltetralin lac-tone; arylnaphthalene; dibenzocyclooctadiene lactone;and dibenzocyclooctadiene without 9(9′)-oxygen.Next, plant species producing at least one of the66 lignans were arranged phylogenetically (Table 2).The plant classification for Magnoliophyta is due toCronquist (1981) and Kato (1997) and for Gymno-spermophyta and Pteridophyta it is Kramer and Green(1990) and Kato (1997). Due to the limited length ofthis paper, only plant families of the lignan-producingplant species versus the lignan subgroups are listed.The detailed phylogenetic list of lignan producingplant species in relation to the 66 lignans which com-
plements Table 2 is available elsewhere (Umezawa,2003).
As mentioned, the dicarboxylic acid lignans (p-hydroxycinnamate dimers) isolated recently from liv-erworts and some Magnoliopsida plants. They werenot obtained in the present database search, but this ismainly because many of them have been isolated afterthe publication of the book by Ayres and Loike (1990).Hence, the dicarboxylic acid lignans are also includedin Table 2. The classification of Bryophyta is due toFuruki and Mizutani (1994).
Table 2 shows that Coniferopsida are especiallywell represented. Lignan producing plants are distrib-uted throughout the six subclasses of Magnoliopsida(Table 2). In contrast, Liliopsida plants are rather poorlignan sources; only eight families of the class con-tained lignan producing plant species (Table 2). Mostof them are furofuran lignans which are upstreammetabolites in the biosynthetic pathways (Scheme 1).Three examples of other subgroups [secoisolariciresi-nol 23 (dibenzylbutane) from Hymenocallis littoralis(Liliaceae) (Lin et al., 1995), lariciresinol 18 andits glucosides (furan) from Arum italicum (Araceae)(Della Greca et al., 1993), and grandisin 58 (furan)from Rhaphidophora decursiva (Araceae) (Zhanget al., 2001)] were obtained in the present databasesearch (Table 2). There were 108 families of lig-nan producing plants in the division Magnoliophyta(Table 2), which was twice that (51 families) reportedby MacRae and Towers about 20 years ago (MacRaeand Towers, 1984). The increase is probably due tothe accumulation of phytochemical data during thelast two decades. It is noteworthy that Table 2 isin line with that presented by MacRae and Towers(1984), i.e. Magnoliidae, Rosidae, and Asteridae in-clude many lignan producing families compared withthe total family numbers of each subclass.
The phylogenetic distribution of lignan producingplant species obtained in the present data base search(Table 2) shows several important characteristics in
384
Tabl
e2.
Dis
trib
utio
nof
ligna
nsin
plan
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gdom
.
385
Tabl
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(Con
tinue
d.)
386
Tabl
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tinue
d.)
Solid
box
repr
esen
tsth
eoc
curr
ence
oflig
nans
ofea
chsu
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resp
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es.
387
relation to lignan biosynthesis. First, the occurrenceof lignans without 9(9′)-oxygen (furan, dibenzylbu-tane, and dibenzocyclooctadiene) is rather restricted.They are found in one order (Sapindales) of Rosidae,six orders of Magnoliidae, and one order (Arales)of Arecidae. Interestingly, this coincides with thefact that some Magnoliidae plants are good sourcesof phenylpropanoid monomers with propenyl or allylside chains (e.g., isoeugenol, safrole, and anethole)(Gibbs, 1974), suggesting that the evolution of the bio-synthesis of lignans without 9(9′)-oxygen is closely re-lated to that of other phenylpropanoids without oxygenat C9.
Second, furofurans are the most widely dis-tributed lignans (Table 2). In Coniferales plants,whose lignins are predominantly the guaiacyl type,pinoresinol 1 with two guaiacyl aromatic rings oc-curs widely, whereas neither medioresinol 2 nor syr-ingaresinol 3, both having at least one 3,5-dimethoxy-4-hydroxyphenyl (syringyl) group), were detected(Umezawa, 2003). In contrast, there are many ex-amples of the simultaneous occurrence of pinoresinol1 (or furofuran lignans with two 3,4-dialkoxyphenylgroups) and syringaresinol 3 (or furofuran lignans withone or two 3,4,5-trialkoxyphenyl groups) in a singlespecies of angiosperm (Magnoliopsida) which pro-duce both guaiacyl and syringyl lignins (Umezawa,2003). These facts, together with the above-mentionedcase of lignans without 9(9′)-oxygen, suggest a closerelationship between the evolution of lignan biosyn-thesis and that of other phenylpropanoid compoundsincluding lignins and phenylpropanoid monomers.
Third, in contrast, there is evidence to suggestthat a lignan biosynthetic system was acquired priorto that of a lignin biosynthetic system. In additionto the dicarboxylic acid lignans (p-hydroxycinnamatedimers) (Table 2), liverworts produce other phenyl-propanoid compounds such as flavonoids (Zinsmeisteret al., 1991). Lignins, however, have not been detectedin liverworts (Erickson and Miksche, 1974; Mikscheand Yasuda, 1978), indicating that the emergence ofepiphyllic acid biosynthesis occurred prior to that oflignin biosynthesis. In addition, the typical lignansderived from coniferyl alcohol, such as pinoresinol 1,lariciresinol 18, secoisolariciresinol 23, and matairesi-nol 27, have not yet been isolated from liverworts(Table 2). These facts strongly suggest that liverwortslack the reduction pathway from p-hydroxycinnamicacids to p-hydroxycinnamyl alcohols, and, thereforelack the biosynthetic systems for lignans and ligninsinvolving p-hydroxycinnamyl alcohols as intermedi-
ates. The point of emergence and evolution of thebiosynthetic systems for p-hydroxycinnamyl alcoholsand the compounds derived thereof are of special in-terest in connection with the evolution of vascularplants. Also, it is of interest to elucidate the evolution-ary relationship between the biosynthesis of epiphyllicacid 72 in liverworts and that of the dicarboxylic acidlignans in vascular plants.
Fourth, distribution of dextrorotatory dibenzylbu-tyrolactone lignans is also of special interest. As men-tioned, most dibenzylbutyrolactone lignans are levoro-tatory and have the same absolute configuration at C8and C8′ in terms of the carbon skeleton, whereas thelignans occurring in Thymelaeaceae plants (Table 1)(Umezawa et al., 1997a; Umezawa, 2001) and Sela-ginella doederleinii (Lin et al., 1994) are dextroro-tatory. Thymelaeaceae and Selaginella plants belongto the divisions Magnoliophyta and Pteridophyta, re-spectively, and both divisions are phylogenetically farapart. This spotty distribution of dextrorotatory diben-zylbutyrolactone lignans suggests a parallel evolutionof some lignan biosynthetic systems in phylogenetic-ally distant taxa.
Conclusions
Lignans show considerable diversity in terms of basicstructure. Typical lignans can be classified into 12 sub-groups based on their basic structures and oxidationlevels at C9 (C9′).
Lignans exist in diverse enantiomeric composi-tions. Dibenzylbutyrolactone lignans, which occurlate in the biosynthetic pathway, are optically pure.On the other hand, the most biosynthetically up-stream lignans, furofuran and furan, are mixturesof both enantiomers and exhibit various enantio-meric compositions. This indicates that lignan enan-tiomeric compositions are determined through severalupstream reaction steps mediated by dirigent pro-tein (DP), pinoresinol/lariciresinol reductase (PLR),and secoisolariciresinol dehydrogenase (SIRD). In ad-dition, most dibenzylbutyrolactone lignans are le-vorotatory, whereas those from Thymelaeaceae plantsand Selaginella doederleinii (Selaginellaceae) are dex-trorotatory. The spotty distribution of dextrorotatorydibenzylbutyrolactone lignans among vascular plantssuggests a parallel evolution of the biosynthetic sys-tems for the dextrorotatory dibenzylbutyrolactone lig-nans.
388
It was also suggested that the acquisition and evol-ution of the biosynthesis of a variety of lignans in vas-cular plants may occur in relation to those of ligninsand other related phenylpropanoid monomers, whilethe lignan biosynthetic system in liverworts probablyappeared prior to lignin biosynthesis.
Acknowledgements
The author thanks Dr Hiroyuki Kuroda, Wood Re-search Institute, Kyoto University, for his suggestionon chemotaxonomy. Thanks are also due to Dr Tat-suwo Furuki, Natural History Museum & Institute,Chiba, for his suggestion on the classification of liv-erworts, and Dr Hiroyuki Tazaki, Obihiro Universityof Agriculture and Veterinary Medicine, for the in-formation on liverwort lignans. The author is indebtedto Jacqueline Leshkevich for valuable comments onEnglish writing.
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