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Journal of Integrative Plant Biology 2012, 54 (10): 703–712

Invited Expert Review

Transcriptional Regulation of Plant Secondary
Metabolism F

Chang-Qing Yang1 , Xin Fang1 , Xiu-Ming Wu1 , Ying-Bo Mao1 , Ling-Jian Wang1
∗
and Xiao-Ya Chen1,2
1 National Key Laboratory of Plant Molecular Genetics, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological
Sciences, the Chinese Academy of Sciences, Shanghai 200032, China
2 Plant Science Research Center, Shanghai Chenshan Botanical Garden, Shanghai 201602, China
∗
Corresponding author
Tel: +86 21 5492 4033; Fax: +86 21 5492 4015; E-mail: xychen@sibs.ac.cn
F Articles can be viewed online without a subscription.

Available online on 4 September 2012 www.jipb.net and www.wileyonlinelibrary.com/journal/jipb

doi: 10.1111/j.1744-7909.2012.01161.x

Abstract

Plant secondary metabolites play critical roles in plant-environment

interactions. They are synthesized in different organs or tissues
at particular developmental stages, and in response to various
environmental stimuli, both biotic and abiotic. Accordingly, corre-
sponding genes are regulated at the transcriptional level by multiple
transcription factors. Several families of transcription factors have
been identified to participate in controlling the biosynthesis and
accumulation of secondary metabolites. These regulators integrate
internal (often developmental) and external signals, bind to corre-
sponding cis-elements — which are often in the promoter regions
Xiao-Ya Chen
— to activate or repress the expression of enzyme-coding genes,
(Corresponding author)
and some of them interact with other transcription factors to form
a complex. In this review, we summarize recent research in these
areas, with an emphasis on newly-identified transcription factors
and their functions in metabolism regulation.

Keywords: Alkaloid; phenylpropanoid; secondary metabolism; terpenoid; transcription factor.

Yang CQ, Fang X, Wu XM, Mao YB, Wang LJ, Chen XY (2012) Transcriptional regulation of plant secondary metabolism. J. Integr. Plant Biol.
54(10), 703–712.

protect plants from abiotic stresses such as ultraviolet (UV)

Introduction
Plant secondary metabolites, which for a long time were
thought to be not directly involved in energy production, growth,
reproduction, or other primary functions, are fascinating and
important players in mediating plant responses to biotic and
abiotic environmental factors. For example, they contribute to
the flavor and taste of fruits and the colors of flowers, and serve
as attractors for pollinators and seed dispersers. In addition,
secondary metabolites also function as defensive compounds
or toxins which guard against pathogens and herbivores, and
light (Vogt 2010; Vranova et al. 2012). Furthermore, secondary
metabolites have been widely utilized by humans as a source
of natural fragrances and pharmaceutical medicines (He and
Giusti 2010; Kroymann 2011; Duan et al. 2012).
Plant secondary metabolites are highly diverse in their
chemical structures. Structurally and biosynthetically, they
are classified into three major groups: terpenoids, phenolic
compounds, and nitrogen-containing compounds. Terpenoids
contain one or more C5 units, which are synthesized ei-
ther via the cytosolic mevalonate pathway or the plastidial


C 2012 Institute of Botany, Chinese Academy of Sciences

704 Journal of Integrative Plant Biology Vol. 54
methylerythritol phosphate pathway. Phenolic compounds are
highly diverse, and include phenylpropanoids, coumarins, stil-
benes, and flavonoids. Phenylpropanoids contain at least one
aromatic ring with one or more hydroxyl groups, and are syn-
thesized via the shikimate pathway alone or in combination with
the melonate pathway. The nitrogen-containing compounds are
also highly diverse, and include alkaloids, non-protein amino
acids, and amines. Their biosynthetic pathways usually have
multiple routes, frequently starting from amino acids. To this
point, more than 36,000 terpenoids, 12,000 alkaloids, and
10,000 flavonoids have been found, although this represents
only a fraction of what exists in nature (Chen et al. 2007; Fang
2011).
Spatial and Temporal Patterns of
Secondary Metabolism
The biosynthesis and accumulation of secondary metabolites
are usually tissue- and developmental stage-specific. For ex-
ample, in cotton, the phytoalexin gossypol accumulates largely
in pigmented glands of aerial organs and in epidermal and
subepidermal layers of roots (Xu et al. 2004). During em-
bryo (seed) development, transcripts of genes encoding (+)-
δ-cadinene synthase (cad1-C), the first enzyme committed to
gossypol biosynthesis, and CYP706B1, a P450 monooxyge-
nase that catalyzes the second step, are undetectable until 20 d
post-anthesis. Pigmented glands, which accumulate gossypol,
consistently appear shortly afterwards (Tan et al. 2000; Luo
et al. 2001). Artemisinin, a sesquiterpene lactone found solely
in Artemisia annua, is a highly-effective drug used in the
treatment of malaria. Both the accumulation of artemisinin
and the expression of its biosynthetic pathway genes, includ-
ing amorpha-4,11-diene synthase (ADS), CYP71AV1, double
bond reductase 2 (DBR2), and aldehyde dehydrogenase 1
(ALDH1), are highly active in the particular glandular trichomes
distributed on leaves, stems, and inflorescences of Artemisia
annua (Olsson et al. 2009). In Arabidopsis, root or aerial
tissue-specific expression of terpene synthases determines the
distribution of terpenoids. In flowers, where most terpenoids
are detected, with (E)-β-caryophyllene being predominant, two
sesquiterpene synthases of TPS21 and TPS11 are responsible
for the formation of the sesquiterpenes, but with different tissue-
specific expression patterns. TPS21 is expressed mainly in
the stigma of open flowers and not much in sepals, whereas
TPS11 is expressed in intrafloral nectaries and oveles. In
roots, the volatile 1,8-cineole is produced by the specifically
root-expressed monoterpene synthase AtTPS-Cin (Chen et al.
2004; Tholl et al. 2005; Tholl and Lee 2011). All of the above
cases show secondary metabolites being biosynthesized and
accumulated at the same place. Interestingly, the tobacco
(Nicotiana tabacum) alkaloid nicotine is mainly accumulated
in the leaf vacuoles, but its biosynthesis occurs in root tissues.
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No. 10 2012
This root-produced nicotine is then transported to the aerial
parts of the tobacco plant and is finally stored in the central
vacuoles of leaves (Hashimoto and Yamada 2003). Recently,
the MATE-type transporter Nt-JAT1 was shown to be respon-
sible for nicotine translocation in aerial parts of the plant, and
its deposition in vacuoles (Shitan et al. 2009).
The biosynthesis of secondary metabolites is often in re-
sponse to environmental factors, and the formation of defensive
phytoalexins can be stimulated by herbivoral damage and mi-
crobial infection. The treatment of cotton plants or suspension-
cultured cells with a fungal elicitor induced the expression of
gossypol pathway genes and increased the accumulation of
gossypol (Luo et al. 2001; Xu et al. 2004). Similar induction
was also observed in ginkgo (Ginkgo biloba), with treatments
of fungal elicitors resulting in the formation of greater amounts
of bilobalide, ginkgolide A, and ginkgolide B (Kang et al.
2009). In rice (Oryza sativa), 13 sesquiterpenes were detected
upon elicitor treatment, in comparison to trace amounts of
sesquiterpenes under normal conditions (Cheng et al. 2007).
The recently-discovered maize sesquiterpenoid phytoalexins,
zealexins, also showed increased accumulation by a wide
range of elicitors (Huffaker et al. 2011).
Transcription Factors Involved in
Secondary Metabolism
The spatial, temporal, and inducible formation of secondary
metabolites and the transcripts of corresponding biosynthetic
genes are under tight regulation at different levels, in which
transcriptional regulation via transcription factors has been
investigated intensively. Transcription factors are sequence-
specific DNA-binding proteins that interact with the regulatory
(often promoter) regions of the target genes, and modulate the
rate of transcriptional initiation by RNA polymerase (Vom Endt
et al. 2002). They can integrate internal (often developmen-
tal) and external (environmental) signals to regulate enzyme
gene expression, thus controlling the specific accumulation of
secondary metabolites. Some transcription factors of different
types form complexes to activate or suppress downstream
gene expression. Several families of transcription factors have
been described to be regulators of plant secondary metabolism
(Table 1).
MYB
MYB transcription factors are characterized by varying num-
bers of the MYB DNA-binding domain, which consists of up
to four imperfect repeats of 52 amino acids (Feller et al.
2011). The MYB family proteins can be divided into four
families, and several members of the R2R3 family have been
reported to be regulators of multiple biosynthetic pathways in
various plant species. In Arabidopsis, AtMYB113, AtMYB114,
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Secondary Metabolism Regulation 705

Table 1. Representative transcription factors involved in plant secondary metabolism regulation

TF Metabolism pathway Species Reference
MYB
AtMYB75 Anthocyanin Arabidopsis thaliana Teng et al. 2005
AtMYB90 Anthocyanin A. thaliana Gonzalez et al. 2008
AtMYB113 Anthocyanin A. thaliana Gonzalez et al. 2008
AtMYB114 Anthocyanin A. thaliana Gonzalez et al. 2008
LhMYB6 Anthocyanin Asiatic hybrid lily Yamagishi et al. 2010
LhMYB12 Anthocyanin Asiatic hybrid lily Yamagishi et al. 2010
Ruby Anthocyanin Camellia sinensis Butelli et al. 2012
MYB10 Anthocyanin Malus × domestica Takos et al. 2006
MYB1/MYBA Anthocyanin M. × domestica Takos et al. 2006
VvMYBPA1 Anthocyanin Vitis vinifera Matus et al. 2009
VvMYB5 a&b Anthocyanin V. vinifera Matus et al. 2009
TT2 Proanthocyanidin A. thaliana Nesi et al. 2001
MtPAR Proanthocyanidin Medicago truncatula Verdier et al. 2012
AtMYB29 Glucosinolates A. thaliana Gigolashvili et al. 2008
AtMYB76 Glucosinolates A. thaliana Gigolashvili et al. 2008
AtMYB34 Glucosinolates A. thaliana Celenza et al. 2005
AtMYB51 Glucosinolates A. thaliana Gigolashvili et al. 2007
AtMYB122 Glucosinolates A. thaliana Gigolashvili et al. 2009
NtMYBJS1 Phenylpropanoids Nicotiana tabacum Galis et al. 2006
bHLH
GL3 Anthocyanin A. thaliana Feyissa et al. 2009
eGL3 Anthocyanin A. thaliana Feyissa et al. 2009
TT8 Anthocyanin A. thaliana Nesi et al. 2000
CrMYC2 TIAs Catharanthus roseus Zhang et al. 2011
MYC2 Terpene A. thaliana Hong et al. 2012
MYC2 a&b Nicotine N. tabacum Shoji et al. 2011
NbbHLH1 Nicotine N. benthamiana Todd et al. 2010
NbbHLH2 Nicotine N. benthamiana Todd et al. 2010
AP2/ERF
ORCA2 TIAs C. roseus Menke et al. 1999
ORCA3 TIAs C. roseus van der Fits, 2000
AaERF1 Artemisinin Artemisia annua Yu et al. 2012
AaERF2 Artemisinin A. annua Yu et al. 2012
WRKY
GaWRKY1 Gossypol Gossypium arboreum Xu et al. 2004
AaWRKY1 Artemisinin A. annua Ma et al. 2009
AtWRKY33 Camaleaxin A. thaliana Zheng et al. 2006
CrWRKY1 TIAs C. roseus Suttipanta et al. 2011
Zinc finger
ZCT1 TIAs C. roseus Pauw et al. 2004
ZCT2 TIAs C. roseus Pauw et al. 2004
ZCT3 TIAs C. roseus Pauw et al. 2004
DOF
OBP2 Glucosinolate A. thaliana Skirycz et al. 2006
AtDOF4;2 Flavonoid A. thaliana Skirycz et al. 2007
NAC
ANAC042 Camaleaxin A. thaliana Saga et al. 2012
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706 Journal of Integrative Plant Biology Vol. 54 No. 10 2012

Table 1. Continued
TF Metabolism pathway Species Reference
SPL
SPL9 Anthocyanin A. thaliana Gou et al. 2011
bZIP
DkbZIP5 Proanthocyanidin Diospyros kaki Akagi et al. 2011
TF, transcription factors; TIAs, terpenoid indole alkaloids.

AtMYB75, and AtMYB90 are involved in controlling antho-
cyanin content in vegetative tissues by activating the entire
phenylpropanoid pathway (Borevitz et al. 2000; Stracke et al.
2001; Tohge et al. 2005; Gonzalez et al. 2008), whereas
TT2 affects proanthocyanidins in the seed coat by regulating
BANYULS (BAN) expression, which encodes nicotinamide
adenine dinucleotide phosphate-dependent leucoanthocyani-
din reductase (Nesi et al. 2001). Members of this family also
regulate glucosinolate biosynthesis, with AtMYB29 and At-
MYB76 regulating aliphatic glucosinolate biosynthesis in aerial
issues (Gigolashvili et al. 2008), and AtMYB34, AtMYB51, and
AtMYB122 controlling indolic glucosinolate production in roots
and late-stage rosette leaves through regulation of tryptophan
(Trp) metabolizing P450 genes of CYP79B2, CYP79B3, and
CYP83B1 (Celenza et al. 2005; Gigolashvili et al. 2007; Dubos
et al. 2010). In other plants, for example, tobacco (N. tabacum),
MYBJS1 was found to be involved in phenylpropanoid regula-
tion (Galis et al. 2006); and in the Asiatic hybrid lily (Lilium spp.),
MYB6, and MYB12 are positive regulators of biosynthesis
and determine the organ- and tissue-specific accumulation of
anthocyanin (Yamagishi et al. 2010).
et al. 2011). A similar pattern was also observed in common
tobacco (N. tabacum): the NbMYC2a/b proteins enhanced
nicotine biosynthesis by upregulating the ORCA-related NIC2
locus, which encodes an AP2/ERF family transcription factor
(Shoji and Hashimoto 2011). Furthermore, three more bHLH
transcription factors (NbbHLH1, NbbHLH2, and NbbHLH3) are
correlated to nicotine accumulation according to expressed se-
quence tag screening via virus-induced gene silencing, of which
NbbHLH1 and NbbHLH2 are positive regulators by their binding
to G-box elements in the putrescine N-methyltransferase pro-
moter, whereas BbbHLH3 is a negative regulator (Todd et al.
2010).
AP2/ERF
The APETALA2/ethylene response factor (AP2/ERF) family
transcription factors are characterized by their DNA-binding
AP2 domain, which consists of approximately 60 conserved
amino acid residues (Mizoi et al. 2012). The ORCA proteins
of C. roseus are the AP2/ERF transcription factors involved
in secondary metabolism. ORCA3 controls the expression of

bHLH

bHLH transcription factors often interact with MYB family

proteins to form a complex, and then regulate the down-
stream expression of target genes (Feller et al. 2011). A
well-characterized example is the transcriptional regulation of
anthocyanin, which is mostly studied in genes of the antho-
cyanin pathway in Arabidopsis. The bHLH proteins GL3, eGL3,
and TT8 interact with MYB proteins in the presence of a
WD40 repeat containing protein TTG1, forming a transcriptional
regulation complex which activates anthocyanin biosynthetic
genes (Gonzalez et al. 2008; Dubos et al. 2010).
Figure 1. The role of bHLH transcription factor MYC2 in jas-
Another important bHLH regulator is MYC2. MYC2 has
monate (JA)- and gibberellin (GA)-regulation of sesquiterpene
widely been found to directly or indirectly participate in sec-
biosynthesis.
ondary metabolism in multiple plant species. In Arabidopsis,
it interacts with DELLA proteins to integrate gibberellin (GA) MYC2 positively regulates the production of sesquiterpenes by
and jasmonate (JA) signaling pathways to upregulate the ex- binding to cis-elements in corresponding sesquiterpene synthase
pression of sesquiterpene synthase genes in flowers (Figure 1, gene promoter regions. It also interacts with JAZ and DELLA
Hong et al. 2012). In Catharanthus roseus, CrMYC2 binds proteins, which are negative regulators of JA and GA signaling
directly to cis-elements in the ORCA3 gene promoter, thereby pathways, respectively. Other signaling pathways are also involved
controlling the expression of several terpenoid indole alka- in regulation of the expression of sesquiterpene synthase genes
loid (TIA) biosynthesis genes, and TIA accumulation (Zhang (modified from Hong et al. 2012).

multiple genes involved in the TIA biosynthesis pathway, in-
cluding both the primary plastidial isopentenyl pyrophosphate
pathway and the secondary TIA pathways (van der Fits and
Memelink 2000). It activates strictosidine synthase (Str) gene
expression by directly binding to the JA- and elicitor-responsive
element (JERE) in its promoter region (van der Fits and
Memelink 2001). Overexpression of this transcription factor has
been found to promote accumulation of TIAs in suspension
cells (van der Fits and Memelink 2000).
Recently, AP2/ERF proteins were reported to participate in
secondary metabolism regulation in other plant species, too. In
A. annua, two JA-responsive AP2/ERF proteins, AaERF1 and
AaERF2, were shown to bind to the CRTDREHVCBF2 (CBF2)
and RAV1AAT (RAA) motifs in promoters of genes encoding
amorpha-4,11-diene synthase (ADS) and CYP71AV1, and to
activate expression of both genes. Overexpression of AaERF1
or AaERF2 led to increased accumulation of artemisinin and
artemisinic acids (Yu et al. 2012). In tobacco, a locus con-
taining at least seven AP2/ERF genes is related to nicotine
biosynthesis, of which ERF189 and ERF221 are most efficient
(Shoji et al. 2010).
WRKY
Many WRKY family transcription factors play important roles in
mediating plant responses to stress factors, and the inducible
expression patterns of WRKY genes supports their involvement
in the regulation of biosynthesis of defense-related secondary
metabolites. In cotton, GaWRKY1 is a positive regulator of
gossypol biosynthesis, and it binds to the promoter of one
of the (+)-δ-cadinene synthase genes (Xu et al. 2004). In
A. annua, AaWRKY1 is also a positive regulator of artemisinin
biosynthesis by binding to and activating the corresponding
sesquiterpene synthase gene promoter (Ma et al. 2009). In
tobacco, two transcription factors, WRKY3 and WRKY6, were
found to be related to volatile terpene production (Skibbe
et al. 2008). Aside from functioning in terpenoid biosynthesis
pathways, the WRKY family proteins also participate in the
regulation of other pathways. For example, WRKY33 regulates
the biosynthesis of camalexin, the most important phytoalexin
of Arabidopsis (Qiu et al. 2008).
NAC
The plant-specific NAC (for NAM, ATAF1/2, and CUC2)
domain-containing proteins represent one of the largest tran-
scription factor families in plants. They are known to control
multiple processes in plants, including developmental pro-
grams and abiotic/biotic stress responses (Olsen et al. 2005).
Recently, an Arabidopsis NAC family protein ANAC042 was
reported to be a regulator of camalexin, which represents the
first NAC family transcription factor involved in plant secondary
metabolism regulation. The anac042 mutant, which upon elic-
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Secondary Metabolism Regulation 707
itation failed to accumulate as much camalexin as the wild
type, was highly susceptible to Alternaria brassicicola infection,
possibly due to deficient expression of camalexin biosynthetic
genes CYP71A12, CYP71A13, and CYP71B15 (Saga et al.
2012).
SPL
The SQUAMOSA Promoter Binding Protein-Like (SPL) family
transcription factors, targeted by microRNA 156 (miR156),
participate in a broad range of developmental processes in
Arabidopsis (Wang et al. 2009). A recent investigation showed
that SPL9 is a negative regulator of anthocyanin accumula-
tion. By interfering with the MYB-bHLH-WD40 transcriptional–
activation complex and then DFR gene expression, SPL9 and
its regulator miR156 control anthocyanin metabolism in an age-
dependent manner (Gou et al. 2011).
Transcriptional Regulation of
Representative Secondary Metabolite
Groups
Anthocyanin
Anthocyanin accumulation in plants is modulated by the WD-
repeat/bHLH/MYB complex. In Arabidopsis, the WD-repeat
protein TTG1 recruits bHLH transcription factors of GL3, TT8,
or EGL3, as well as MYB transcriptional factors of MYB75,
MYB90, MYB113, and MYB114 to form a complex to upreg-
ulate dihydroflavonol 4-reductase, anthocyanin synthase, and
glucosyltransferase gene expression as well as anthocyanin
accumulation (Dubos et al. 2010). Interestingly, through tissue-
or developmental stage-specific expression of the complex
component homologues, accumulation of anthocyanin can be
specified, leading to colorful leaves, flowers, and fruits. For ex-
ample, in apple (Malus domestica), anthocyanin accumulation
in fruit flesh is determined by the MYB family transcription factor
MYB10, whereas in fruit skin, it is controlled by another skin-
specific transcription factor MYB1 (or MYBA), although both of
these are in the same family and share high sequence identity
(Takos et al. 2006; Ban et al. 2007; Lin-Wang et al. 2010). In
lily, the accumulation of anthocyanin pigmentation in tepals,
filaments, and styles is determined by tissue-specific expres-
sion of LhMYB12, whereas expression of LhMYB6 correlates
with anthocyanin spots in tepals and light-induced pigmentation
in leaves (Yamagishi et al. 2010). In grape (Vitis vinifera),
seasonal expression of three MYB transcription factors of
VvMYBPA1, VvMYB5a, and VvMYB5b in response to light
conditions is correlated to anthocyanin accumulation in the skin
and seeds (Matus et al. 2009). Furthermore, insertion of a
Copia-like retrotransposon adjacent to the MYB transcrip-
tion activator Ruby was shown to result in cold-dependent

708 Journal of Integrative Plant Biology Vol. 54
accumulation of anthocyanins in blood oranges (Butelli et al.
2012).
Terpenoid indole alkaloids
Catharanthus roseus is well known for its production of TIAs
including ajmalicine, catharanthine, serpentine, and vindoline,
which are efficient inhibitors of microtubule polymerization and
are used to treat certain cancers. Tryptamine is catalyzed by
Trp decarboxylase (TDC) hybrid with the MEP pathway product
secologanin by strictosidine synthase to form strictosidine,
which is then transformed to the monomeric and dimeric TIAs
(Suttipanta et al. 2011).
Production of TIAs and of known biosynthetic genes is
inducible by JA treatment. Two cis-elements, BA and JERE
(JA and ethylene-responsive element), were identified near
the TATA box, of which the JERE region is absolutely re-
quired for JA induction whereas the BA region enhances
induction. An elicitor-inducible but JA-independent MYB-like
factor CrBPF1 binds to this BA region (van der Fits and
Memelink 2000), whereas the JA-dependent AP2/ERF domain-
containing ORCA transcription factors (ORCA2, ORCA3) can
bind to the JERE region of the strictosidine synthase gene
promoter (van der Fits and Memelink 2001). Recently, the
bHLH family protein CrMYC2 was found to bind to the JA-
responsive element in the ORCA3 promoter and activate gene
expression, in turn regulating a subset of alkaloid biosynthesis
genes (Zhang et al. 2011).
By yeast one-hybrid screening with the elicitor responsive
part of the TDC promoter, three members of the Cys2/His2 type
(transcription factor IIIA-type) zinc finger proteins, ZCT1, ZCT2,
and ZCT3, were isolated. They were shown to exhibit binding
activity to the TDC and STR promoters in a sequence-specific
manner, and repress their activity. In addition, they have also
been shown to repress the activating activity of ORCAs on
the STR promoter (Pauw et al. 2004). Furthermore, the root-
specific and phytohormone responsive WRKY transcription
factor CrWRKY1 is also able to bind to the W-box in the
TDC promoter and activate its expression. Interestingly, over-
expression of CrWRKY1 in C. roseus hairy roots upregulated
several key TIA pathway genes and the transcriptional repres-
sors ZCT1, ZCT2, and ZCT3, but repressed the activators
ORCA2, ORCA3, and CrMYC2, thus increasing the level of
serpentine accumulation threefold but significantly decreasing
catharanthine and tabersonine. This suggests that CrWRKY1
plays a key role in determining the root-specific accumulation
of serpentine in C. roseus plants (Suttipanta et al. 2011).
Glucosinolates and camalexin
The indolic secondary metabolite camalexin is the major
phytoalexin of Arabidopsis. It shares indole-3-acetaldoxime
(IAOx) as a precursor with indolic glucosinolates and auxin
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No. 10 2012
biosynthesis, which is produced from Trp by cytochrome P450
CYP79B2 and CYP79B3 (Glawischnig et al. 2004). IAOx is
further converted to indole-3-acetonitrile (IAN) by CYP71A13
(Nafisi et al. 2007) and CYP71A12 (Millet et al. 2010), and then
conjugated to glutathione by glutathione S-transferases (Chen
et al. 2012). The subsequent hydroxylation and final conversion
to camalexin via dihydrocamalexic acid are catalyzed by P450
CYP71B15/PAD3 (Bottcher et al. 2009).
Biosynthesis of camalexin can be induced by infection with
bacterial pathogens such as Pseudomonas syringae and
Erwinia carotovora, and fungi such as Alternaria brassicicola
and Botrytis cinerea, as well as through exogenous factors
like herbicides, heavy metal ions, and UV-B irradiation.
The DNA-binding-with-one-finger (DOF) transcription factor
OBP2 is expressed in Arabidopsis organs, leaves, roots,
flowers, and petals, and its expression is responsive
to herbivores, pathogens, and the phytohormone JA.
Overexpression of OBP2 was shown to activate expression
of CYP83B1, whereas silencing OBP2 led to suppression
of the expression of CYP83B1, suggesting that OBP2 is
part of a regulatory network that regulates glucosinolate
biosynthesis in Arabidopsis (Skirycz et al. 2006). MYB
transcription factor ATR1 (AtMYB34), identified in a screen for
altered Trp metabolism, controls production of glucosinolates
in Arabidopsis. Its dominant overexpression allele atr1D
confers elevated expression of genes encoding CYP79B2,
CYP79B3, and CYP83B1. Overexpression of ATR1 increased
indolyl glucosinolate and IAA accumulation but not aliphatic
glucosinolates, whereas the recessive atr1–2 mutant showed
reduced gene expression and a lower accumulation of indolyl
glucosinolates (Celenza et al. 2005).
The WRKY transcription factor WRKY33 was found to bind
to the promoter regions of CYP71B15/PAD3 in response to P.
syringae infection (Qiu et al. 2008). The wrky33 mutant was
found to be highly susceptible to B. cinerea and A. brassici-
cola infection, and its overexpression increased resistance to
these pathogens (Zheng et al. 2006). The mitogen-activated
protein (MAP) kinase cascade plays a critical role in WRKY33
regulation. In response to P. syringae infection, MPK4 is
activated to phosphorylate MKS1, releasing WRKY33 from the
MKS1/WRKY33 complex, which targets the CYP71B15 pro-
moter and stimulates camalexin biosynthesis (Qiu et al. 2008).
Moreover, WRKY33 is also phosphorylated by MPK3/MPK6 in
response to B. cinerea infection (Mao et al. 2011). It is likely
that different pathogen infection signals activate various MAP
cascades and converge to WRKY33 activation, leading to the
induction of camalexin biosynthesis.
Recently, the Arabidopsis NAC transcription factor ANAC042
was shown to participate in the regulation of camalexin biosyn-
thesis. The anac042 mutant failed to accumulate camalexin
at the level of wild-type plants, and was highly susceptible to
A. brassicicola infection. Expression of biosynthetic pathway

genes CYP71A12, CYP71A13, and CYP71B15/PAD3 were
reduced in the mutants, indicating that the camalexin defects
were at least partly a result of reduced expression of these
P450 genes. Although ANAC042 expression can be induced
by pathogen infection, kinase inhibitor treatment and mutant
analysis showed that ANAC042 might function independently
of the WRKY33-dependent signaling pathways (Saga et al.
2012).
Perspectives
Transcription factors play a paramount role in regulating
genes involved in likely all aspects of plant growth and
development, including secondary metabolism. In recent
years, an increasing number of transcription factors and
the underlying mechanisms of plant secondary metabolism
regulation have been elucidated. However, other mecha-
nisms regulating specific pathways do exist. For example,
the DnaJ Cys-rich domain containing plastid protein OR
enhances the differentiation of non-colored plastids into
chromoplasts for carotenoid accumulation in cauliflower
(Brassica oleracea) (Lu et al. 2006); and in soybean (Glycine
max), the dominant inhibition of seed coat pigmentation is
due to inverted clusters of three chalcone synthase (CHS)
genes, which results in the silencing of the expression of all
CHS genes (Tuteja et al. 2009). Investigation of the network
controlling the biosynthesis, transportation, accumulation,
and release of secondary metabolites will further our under-
standing of plant adaptation to changing environments and
the interaction among plants and other organisms.
Many secondary metabolites are highly valuable to hu-
mans. However, due to their low concentrations in plant
tissues, direct extraction of these metabolites is usually ex-
pensive and inefficient. Engineering biosynthetic pathways
in microbes or other plant species via a synthetic approach
is a recent phenomenon that holds promise, but successful
examples of this approach are still limited, partially due to
the complexity of biosynthesis pathways and the frequent
toxicity of metabolic intermediates. Increasing metabolite
production by engineering transcription factors is a promis-
ing alternative. By ectopic expression or overexpression of
regulatory proteins, we can expect to upregulate the entire
pathway.
Acknowledgements
This work was supported by the State Key Basic Research
Program of China (No. 2007CB108800), the National Natural
Science Foundation of China (No. 30630008).
Received 17 Jul. 2012 Accepted 22 Aug. 2012
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Secondary Metabolism Regulation 709
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