Carotenoid Metabolism in Plants - Cell Press

Molecular Plant Review Article

Carotenoid Metabolism in Plants Nazia Nisar1, Li Li2, Shan Lu3, Nay Chi Khin1 and Barry J. Pogson1,* 1

Australian Research Council Centre of Excellence in Plant Energy Biology, The Australian National University, Canberra, ACT 0200, Australia

2

US Department of Agriculture-Agricultural Research Service, Robert W. Holley Centre for Agriculture and Health, Department of Plant Breeding and Genetics, Cornell University, Ithaca, NY 14853, USA

3

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 2100923, China

*Correspondence: Barry J. Pogson ([email protected]) http://dx.doi.org/10.1016/j.molp.2014.12.007

ABSTRACT Carotenoids are mostly C40 terpenoids, a class of hydrocarbons that participate in various biological processes in plants, such as photosynthesis, photomorphogenesis, photoprotection, and development. Carotenoids also serve as precursors for two plant hormones and a diverse set of apocarotenoids. They are colorants and critical components of the human diet as antioxidants and provitamin A. In this review, we summarize current knowledge of the genes and enzymes involved in carotenoid metabolism and describe recent progress in understanding the regulatory mechanisms underlying carotenoid accumulation. The importance of the specific location of carotenoid enzyme metabolons and plastid types as well as of carotenoid-derived signals is discussed. Key words: carotenoid biosynthesis, degradation, sequestration, plastids, signaling, development Nisar N., Li L., Lu S., Khin N.C., and Pogson B.J. (2015). Carotenoid Metabolism in Plants. Mol. Plant. 8, 68–82.

INTRODUCTION Carotenoids are the second most abundant naturally occurring pigments on earth, with more than 750 members. Carotenoid pigments are mainly C40 lipophilic isoprenoids and synthesized in all photosynthetic organisms (bacteria, algae, and plants), as well as in some non-photosynthetic bacteria and fungi. Carotenoids range from colorless to yellow, orange, and red, with variations reflected in many fruits, flowers, and vegetables, which contribute to their economic value as well. Several eyecatching examples include b-carotene from carrots and sweet potatoes, lycopene from tomatoes and watermelon, capsanthin and capsorubin from red peppers, and lutein from marigold flowers. Carotenoids and their oxidative and enzymatic cleavage products called apocarotenoids are crucial for various biological processes in plants, such as assembly of photosystems and light harvesting antenna complexes for photosynthesis and photoprotection, and regulation of growth and development (Cazzonelli and Pogson, 2010b; Ruiz-Sola and Rodrı´guez-Concepciońa, 2012; Havaux, 2014). Apocarotenoids are also proposed to serve as signaling molecules and have been implicated in the interactions of plants with their environment (Walter and Strack, 2011; Cazzonelli, 2011). While carotenoids are necessary to maintain normal health and behavior of animals, nearly all animals do not synthesize carotenoids and therefore rely on their diet to obtain these compounds. Dietary uptake of carotenoids such as astaxanthin can provide pigmentation to the tissues of some marine animals (e.g. salmon, trout, shrimp, and lobster) and birds (e.g. flamingo and quail), improving their immune system and in many cases 68

Molecular Plant 8, 68–82, January 2015 ª The Author 2015.

providing a sexual selective advantage (McGraw et al., 2006; Baron et al., 2008). Moreover, provitamin A carotenoids play essential roles in animals as precursors for the synthesis of retinoid, retinol (vitamin A), retinal (main visual pigment), and retinoic acid (which controls morphogenesis) (Fraser and Bramley, 2004; Krinsky and Johnson, 2005). In humans, carotenoids also serve as antioxidants and reduce age-related macular degeneration of the eye, the leading cause of blindness in the elderly worldwide (Johnson and Krinsky, 2009; Fiedor and Burda, 2014). Carotenoid enzymes are labile in vitro, making their study difficult using the classic biochemical approaches. It was only in the 1990s that carotenoid biosynthesis at the molecular level was elucidated. Carotenoid metabolism and regulation in plants have since been described in previous review articles (Cunningham and Gantt, 1998; Hirschberg, 2001; Fraser and Bramley, 2004; DellaPenna and Pogson, 2006; Lu and Li, 2008; Cazzonelli and Pogson, 2010b; Zhu et al., 2010; Walter and Strack, 2011; Ruiz-Sola and Rodrı´guez-Concepciońa, 2012; Li and Yuan, 2013; Moise et al., 2013; Giuliano, 2014). Due to the pivotal role of carotenoids in nature, the understanding of how plant cells regulate the accumulation and flux of various carotenoids and their metabolites advances rapidly. This review covers recent progress in various aspects of carotenoids research, along with the knowledge on carotenoid metabolism and regulation in plants.

Published by the Molecular Plant Shanghai Editorial Office in association with Cell Press, an imprint of Elsevier Inc., on behalf of CSPB and IPPE, SIBS, CAS.

Carotenoid Metabolism and Regulation

Molecular Plant Figure 1. Schematic Carotenoid Biosynthetic Pathway. The pathway shows the primary steps found in nearly all plant species. The C40 carotenoid phytoene is derived by condensation of two molecules of the C20 GGPP, produced from IPP and DMAPP. Phytoene is converted into lycopene via a series of desaturation and isomerization. Lycopene is cyclized by b-LCY and ε-LCY or b-LCY to produce a-carotene or b-carotene. These carotenes are further hydroxylated to produce xanthophylls (e.g. lutein and zeaxanthin). The cleavage of b-carotene branch by CCDs and NCEDs produces various volatiles (e.g. b-citraurin, etc.) and phytohormones (strigolactones and abscisic acid). Arabidopsis mutants defective in carotenogenesis (cla1; altered chloroplast 1, clb5; chloroplast biogenesis 5, ccr1, and ccr2; carotenoid and chloroplast regulation-1 and 2, lut1, lut2, and lut5; lutein deficient-1, 2, and 5) are shown in red. b-LCY, b-cyclase; b-OHase, b-carotene hydroxylase; CCD, carotenoid cleavage dioxygenase; CRTISO, carotenoid isomerase; ; ε-LCY, ε-cyclase; ε-OHase, ε-carotene hydroxylase; GA3P, glyceraldehyde-3-phosphate; GGPPs, GGPP synthase; NCED, 9-cis-epoxycarotenoid dioxygenase; NXS, neoxanthin synthase; PDS, phytoene desaturase; PSY, phytoene synthase; SDG8, SET2 histone methyltransferase; VDE, violaxanthin de-epoxidase; ZDS, z-carotene desaturase; ZEP, zeaxanthin epoxidase; Z-ISO, zcarotene isomerase. Adapted from Cazzonelli et al. (2010a).

SYNTHESIS OF CAROTENOID PRECURSORS: ISOPENTENYL DIPHOSPHATE/DIMETHYLALLYL DIPHOSPHATE Carotenoids are derived from two isoprene isomers, isopentenyl diphosphate (IPP) and its allylic isomer dimethylallyl diphosphate (DMAPP). A diverse range of compounds including tocopherols, chlorophylls, phylloquinone, gibberellins (GA), monoterpenes, and plastoquinone are also derived from these isoprenoid precursors (Rodriguez-Concepcion, 2010). Two pathways exist for IPP production in plants: the cytosolic mevalonic acid pathway (MVA) and the plastidic methylerythritol 4-phosphate (MEP) pathway (Rodriguez-Concepcion and Boronat, 2002; Eisenreich et al., 2004). The IPP and DMAPP used for carotenoid biosynthesis in plants are derived from the MEP pathway (Eisenreich et al., 2001; Rodriguez-Concepcion and Boronat, 2002). The MEP pathway uses glyceraldehyde 3-phosphate and pyruvate as initial substrates to form deoxy-D-xylulose 5-phosphate (DXP); this is catalyzed by DXP synthase (DXS). MEP is subsequently formed via an intramolecular rearrangement and reduction of DXP by the enzyme DXP reductoisomerase (DXR). Both DXS and DXR are important in carotenoid flux regulation. In Arabidopsis, both enzymes are encoded by single genes and appear to be rate-determining enzymes. Indeed, overexpression of DXS and

DXR in Arabidopsis seedlings increases carotenoid production (Este´vez et al., 2001; Carretero-Paulet et al., 2006). Recent work has also suggested the involvement of J-protein (J20) and heat shock protein 70 (Hsp70) chaperones in posttranscriptional regulation of DXS activity, as mutants defective in J20 activity exhibit reduced DXS enzyme activity but accumulate DXS protein in an inactive form (Pulido et al., 2013). Plastidial J20 protein appears to assist Hsp70 chaperone in the proper folding and assembly of DXS and participate in the regulation of MEP-derived isoprenoid biosynthesis (Pulido et al., 2013). In poplar, feedback inhibition of DXS by DMAPP reveals an important regulatory mechanism of the MEP pathway and thus carotenoid biosynthesis (Ghirardo et al., 2014). IPP and DMAPP are formed after a number of subsequent steps and consequently undergo a sequential series of condensation reactions to yield the precursor of carotenoid biosynthesis, geranylgeranyl diphosphate (GGPP), as shown in Figure 1.

SYNTHESIS OF CAROTENES AND XANTHOPHYLLS Carotenoid biosynthesis starts with the condensation of two GGPP molecules by phytoene synthase (PSY) to form phytoene as a 15-cis isomer. There is only one PSY gene in Arabidopsis, while three tissue-specific isoforms exist in tomato with PSY1, Molecular Plant 8, 68–82, January 2015 ª The Author 2015.

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Molecular Plant which contributes to carotenoid production in tomato fruit (Bramley, 2002; Giorio et al., 2008). There are three PSY genes reported in cereal crops such as maize, rice, and wheat (Li et al., 2008a, 2008b; Welsch et al., 2008; Dibari et al., 2012) and two in carrots (Just et al., 2007) and cassava (Arango et al., 2010). Four double bonds are introduced into phytoene via two phylogenetically related enzymes: phytoenede saturase (PDS) and z-carotene desaturase (ZDS). These enzymes catalyze two symmetric dehydrogenation reactions converting 15-cis phytoene to tetra-cis-lycopene. Both of these enzymes are encoded by single-copy genes in tomato, grape and Arabidopsis. The all-trans isomer of lycopene in higher plants demonstrates a requirement of specific isomerase enzymes. A carotenoid isomerase (CRTISO) that is capable of isomerizing cis bonds at 7, 9 and 70 , 90 positions has been demonstrated to convert tetra-cislycopene to all-trans-lycopene. Despite some protein identity to desaturases, CRTISO exhibits no desaturase or cyclase activity in an Escherichia coli expression system, instead using cis isomers as substrates to form all-trans products (Park et al., 2002; Isaacson et al., 2004). The isomerase activity of CRTISO depends upon the flavin adenine dinucleotide (FAD) binding motif, which bonds to the reduced form of cofactor (FADred) to catalyze a reaction without net redox changes (Yu et al., 2011). In contrast, the desaturases require a redox-active cofactor catalyzing net electron transfer. This is especially interesting as CRTISO depends on reduced flavin for its activity and seems to be more related to CrtY (bacterial lycopene cyclase) than its possible ancestor CrtI (Mialoundama et al., 2010; Yu et al., 2010, 2011). Recently, two distantly related CRTISO-like singlecopy genes (CrtISO-L1 and CrtISO-L2) have been discovered in tomato, Arabidopsis, and grape. These enzymes are suggested to initiate a competing metabolic pathway, metabolizing carotenes upstream of all-trans-lycopene (Fantini et al., 2013). CRTISO is not the sole carotenoid isomerase in plants. In vitro assays of CRTISO support the presence of a second isomerase because the C15-150 double bond in phytoene is not a substrate for isomerization by CRTISO (Isaacson et al., 2004). Furthermore, ZDS activity under in vitro conditions can be regained only after isomerizing this 15-cis double bond to trans; this was previously thought to be performed by light (Beyer, 1989). Y9 in maize or ZIC in Arabidopsis encodes the enzyme Z-ISO, which is essential for the cis-to-trans conversion of the 15-cis-bond in 9,15,90 -tri-cis-z-carotene (the product of PDS) to 9,90 -di-cis-zcarotene, the substrate of ZDS (Li et al., 2007; Chen et al., 2010). Interestingly, the Z-ISO enzyme has been found to be similar to NnrU, a bacterial gene (for nitrite and nitric oxide) required for denitrification, whereas CRTISO is thought to be evolved from bacterial-type desaturase (CrtI) (Isaacson et al., 2002; Park et al., 2002; Isaacson et al., 2004; Chen et al., 2010). Nonetheless, both CRTISO and Z-ISO have distinct roles in carotene isomerization, even although the activity of both of these enzymes can partially be compensated by photoisomerization of the upstream cis-carotenes to yield alltrans-lycopene in photosynthetic tissues. These isomerases may have functions beyond carotenoid biosynthesis in plants, as the Arabidopsis loss-of-function CRTISO mutant ccr2 exhibits some novel developmental phenotypes, as do analogous mutants in tomato and rice (Park et al., 2002; Fang et al., 2008; Kachanovsky et al., 2012). 70


Carotenoid Metabolism and Regulation In plants, all-trans-lycopene is the preferred substrate for the cyclases. The cyclization of lycopene is a crucial step in carotenoid metabolism and generates carotenoid diversity distinguished by different cyclic end groups: either the addition of beta (b-ring) and/or epsilon (ε-type ring). These rings are generated by lycopene b-cyclase (b-LCY) and lycopene ε-cyclase (ε-LCY), respectively (Cunningham et al., 1993; Cunningham et al., 1996; Pecker et al., 1996;Ronen et al., 1999). The formation of two b-rings forms the b,b branch of carotenoids, comprising b-carotene and its derivatives. The combination of b- and ε-rings defines the b,ε branch of carotenoids, comprising a-carotene and its derivate lutein (3,30 -dihydroxy-a-carotene), the major xanthophyll in green leaves (Goodwin, 1980). While b-LCY catalyzes cyclization of both ends of lycopene, ε-LCY typically cyclizes only one end, forming the monocyclic d-carotene (ε,ccarotene). Carotenoids with two ε-rings are uncommon in most plants and algae (Goodwin, 1980). The lettuce ε-LCY enzyme, a close homolog of Arabidopsis and tomato proteins, appears to be atypical in generating bicyclic ε,ε-carotene and its hydroxylated derivative lactucaxanthin (Phillip and Young, 1995; Cunningham and Gantt, 2001). Other cyclase activities include the production of k-cyclic carotenoids with an unusual cyclopentane ring, i.e. capsanthin and capsorubin, which are the signature pigments of the pepper family catalyzed by capsanthin-capsorubin synthase (CCS) (Lefebvre et al., 1998; Go´mez-Garcıá and Ochoa-Alejo, 2013). CCS is able to convert the epoxy-carotenoids antheraxanthin and violaxanthin into capsanthin and capsorubin (Bouvier et al., 1994). CCS shares sequence similarity with b- and ε-cyclase and belongs to the FAD-binding flavoproteins family. These proteins contain a non-covalently bound FAD, which functions as the reductant and catalyzes the reaction with no net redox change without transferring hydrogen from dinucleotide cofactors to b-carotene or capsanthin (Mialoundama et al., 2010). a-Carotene and b-carotene are further hydroxylated to produce xanthophylls (e.g. lutein and zeaxanthin), which are among the main carotenoid pigments in the photosystems of plants. b-OHase (b-hydroxylase) catalyzes two hydroxylation reactions, converting b-carotene to zeaxanthin via b-cryptoxanthin. a-Carotene is twice hydroxylated by two different enzymatic reactions catalyzed by ε- and b-OHases. Although most of the carotenoid pathway reactions are encoded by single genes, multiple carotenoid hydroxylase genes have been identified with distinct evolutionary backgrounds involved in xanthophyll biosynthesis in Arabidopsis and tomato. These comprise two ferredoxin-dependent, non-heme b-ring hydroxylases, a P450-type ε-ring hydroxylase (CYP97C1, encoded by the LUT1 locus) and a P450-type b-ring hydroxylase (CYP97A3, encoded by the LUT5 locus) (Pogson et al., 1996; Sun et al., 1996; Tian and DellaPenna, 2001). CYP97B subfamily members are also present in higher plants (represented by CYP97B3 in Arabidopsis), although their biosynthetic role is unclear (Kim et al., 2010; Yang et al., 2014). While the CYP97 subfamilies have ring-specificities in plants, red algal CYP97B29 can hydroxylate both b- and ε-rings, suggesting that CYP97 subfamilies originated before the divergence of higher plants and green algae lineages (Bak et al., 2011; Yang et al., 2014). Zeaxanthin epoxidase (ZEP) hydroxylates b-rings of zeaxanthin in two consecutive steps to yield antheraxanthin and then violaxanthin. Violaxanthin is converted to neoxanthin by

Molecular Plant

Carotenoid Metabolism and Regulation neoxanthin synthase, which represents the final step in the core carotenoid biosynthetic pathway.

REGULATION OF CAROTENOGENESIS Modulation of PSY Regulatory control of carotenoid biosynthesis has been subjected to extensive studies, and much remains to be elucidated (Cazzonelli, 2011; Hannoufa and Hossain, 2012). PSY is considered a rate-limiting enzyme in carotenoid biosynthesis, and varying its expression or activity alters flux through the pathway (Maass et al., 2009; Rodriguez-Villalon et al., 2009a; Meier et al., 2011). Constitutive PSY overexpression has enhanced total carotenoid contents and substantially increased synthesis of b-carotene in canola seeds, cassava roots, potato tubers, endosperms, and in seed derived callus and roots (Shewmaker et al., 1999; Ducreux et al., 2005; Paine et al., 2005; Maass et al., 2009; Naqvi et al., 2009; Welsch et al., 2010). Transcriptionally, PSY genes are induced in response to various factors, such as development, abscisic acid (ABA), high light, salt, drought, temperature, photoperiod and posttranscriptional feedback regulation (Cazzonelli and Pogson, 2010b). Furthermore, expression profiles of different PSY isoforms exhibit tissue specificity. Tomato PSY1 is expressed highly in fruits, with its expression being correlated with carotenoid content, whereas PSY2 is required for carotenoid synthesis in leaf tissues (Giuliano et al., 1993; Fraser et al., 1999). The third PSY in tomato (PSY3) is predicted to function in roots under stress conditions (Kachanovsky et al., 2012; Fantini et al., 2013). Maize and rice PSY3 have specialized roles in abiotic stress-induced ABA formation, and respond to ABA in a positive feedback loop in roots (Li et al., 2008a; Welsch et al., 2008). Under salt and drought stress, increased levels of PSY3 mRNA in maize roots results in the increased carotenoid flux and ABA (Li et al., 2008b). Additionally, salt stress also triggers the root specific up-regulation of Arabidopsis PSY gene expression, which results in enhanced carotenoid accumulation in the roots for the synthesis of ABA (Ruiz-Sola et al., 2014). Blocking of the Arabidopsis MEP pathway results in down-regulation of PSY, whereas increased activity of DXS induces PSY expression in potato and tomato (Rodriguez-Concepcion et al., 2001; Laule et al., 2003). In addition, PSY is negatively regulated by phytochrome-interacting factor 1 (PIF1) and other members of this transcription factor family in Arabidopsis during seedling de-etiolation (Toledo-Ortiz et al., 2010). In tomato fruit, PSY1 expression can be feedback regulated by cis-carotenoids (Kachanovsky et al., 2012). Recent studies identify new processes that influence PSY protein level or activity, such as the localization of PSY within the chloroplast. Maize PSY1 isozymes are localized to distinct chloroplast suborganellar sites (e.g. globular or fibrillar) based on their allelic variation, while other known PSYs are localized to plastoglobuli (Shumskaya et al., 2012; Shumskaya and Wurtzel, 2013), suggesting that PSY1 sequence variation can affect suborganellar localization of carotenoid storage and bioavailability. Carotenoid metabolites are also found to negatively regulate the PSY protein level and total carotenoid

content. Overexpression of AtCYP97A in carrots resulted in increased conversion of a-carotene to lutein but unexpectedly reduced PSY protein levels with a correlated decrease of total root carotenoids (Arango et al., 2014). This suggests that either reduced levels of a-carotene or increased levels of downstream metabolites modulate PSY protein levels in regulating carotenogenesis (Arango et al., 2014).

Influence of Desaturation Activity Carotenoid biosynthesis may also be redox regulated via the carotene desaturases, as PDS and ZDS are both membranebound electron acceptors that bind a redox-active cofactor at the flavin-binding motif (Nievelstein et al., 1995). Quinones act as electron acceptors for PDS and ZDS desaturation reactions, as demonstrated in daffodil and Arabidopsis, in which the impaired plastoquinone biosynthesis (Mayer et al., 1992; Norris et al., 1995) in pds1 and pds2 resulted in albino phenotypes and phytoene accumulation (Norris et al., 1995; Norris et al., 1998). The cloning of the IMMUTANS gene encoding PTOX (plastid targeted alternative oxidase) also revealed a link between phytoene desaturation and redox poise of the chloroplast (Carol et al., 1999; Wu et al., 1999; Aluru et al., 2001; Yu et al., 2007). The Arabidopsis immutans (im) and tomato white ‘‘ghost’’ leaves are variegated, comprising green and albino sectored leaves, the latter accumulating phytoene at the expense of photosynthetic carotenoids (Carol et al., 1999; Josse et al., 2000). In maize, the viviparous mutants, such as vp5 (viviparous5), vp2 (viviparous2) and w3 (white3), have defective copies of the PDS gene and exhibit increased accumulation of phytoene (Matthews et al., 2003). The vp2 mutant is similar to Arabidopsis pds1 and associated with plastoquinone biosynthesis, whereas w3 is a candidate for PTOX, and spc1 mutation of the ZDS gene results in the accumulation of z-carotene (Dong et al., 2007).

Modification of Isomerization Although most carotenoids found in nature are primarily in the more stable all-trans configurations (Britton, 1988), a small proportion of cis isomers are encountered. They have different biological potency than that of their trans counterparts (e.g. lower provitamin A activity); constituents of the light harvesting complex (LHC) (e.g. 9-cis-neoxanthin) (Liu et al., 2004; Snyder et al., 2004); and serve as substrates for the biogenesis of plant hormone, ABA (e.g. 9-cis-epoxyxanthophylls) (Schwartz et al., 1997a). The Arabidopsis, tomato, and melon mutants of CRTISO (ccr2, tangerine, and yolf, respectively) accumulate cis-carotenes in the etioplasts (dark-grown plastids) of seedlings or chromoplasts of fruit (Isaacson et al., 2002; Park et al., 2002; Galpaz et al., 2013). However, it is interesting to note that the CRTISO activity can partially be substituted by exposure to light in green tissues via photoisomerization (Isaacson et al., 2002; Park et al., 2002). Photoisomerization of the cis bonds facilitates carotene synthesis in the chloroplasts of the ccr2 mutant but delays greening and chlorophyll accumulation during photomorphogenesis. Similarly, loss of CRTISO causes partial inhibition of lutein biosynthesis in light-grown tissues and varying degrees of chlorosis in newly developed leaves of tomato and rice (Isaacson et al., 2002; Masamoto et al., 2004; Fang et al., 2008; Molecular Plant 8, 68–82, January 2015 ª The Author 2015.

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Molecular Plant Wei et al., 2010; Chai et al., 2011). In contrast to green tissues, CRTISO activity cannot be substituted by light in nonphotosynthetic tissues. The etiolated tissues of ccr2, tangerine, and yolf fruits exhibit an orange color due to the accumulation of cis-lycopene (Isaacson et al., 2002; Park et al., 2002; Galpaz et al., 2013). Such accumulation is associated with a metabolitedependent feedback regulation of early carotenoid synthesis genes. The feedback regulation of early tomato carotenoid genes (PSY1, PDS, and ZDS) observed in tangerine elucidates the recently discovered epistasis effect of tangerine over the r mutation in PSY, which partially restores PSY1 expression by cis-carotene accumulation in tangerine (Kachanovsky et al., 2012). An epigenetic mechanism also contributes to the regulation of carotenoid isomerization (Cazzonelli et al., 2009, 2010c). The SET2 histone methyltransferase (SDG8) is a chromatinmodifying enzyme that is required to maintain permissive histone methylation surrounding the CRTISO promoter. Accordingly, the Arabidopsis ccr1 mutation of SDG8 results in reduced CRTISO expression (Cazzonelli et al., 2009).

Control of Cyclase Expression

Carotenoid Metabolism and Regulation b-carotene/a-carotene ratio and thus controlling pathway flux to carotenes with high provitamin A value (Harjes et al., 2008).

Regulation of Xanthophyll Biosynthesis Many regulatory mechanisms control the biosynthesis of lutein, which represents the most abundant carotenoid found in leaf tissues of plants and is the product of the b,ε branch. The characterization of lutein biosynthetic mutants, like lut1 (Tian et al., 2004), lut2 (Cunningham et al., 1996; Pogson et al., 1996), ccr2 (Isaacson et al., 2002; Park et al., 2002), and lut5 (Kim and DellaPenna, 2006) have provided insights into regulation of plant lutein biosynthesis, as described above. Furthermore, the Arabidopsis lut5 mutant, defective in CYP97A3 hydroxylase overaccumulates a-carotene (Kim and DellaPenna, 2006). Similar to Arabidopsis lut5, orange carrot defective in CYP97A3 accumulates constitutively high levels of a-carotene (Arango et al., 2014). In addition, the dihydroxylation of a-carotene to drive lutein biosynthesis requires co-expression and perhaps physical interaction of CYP97 enzymes (e.g. CYP97A and CYP97C) and thus can regulate flux (Quinlan et al., 2012).

The two lycopene cyclases, b-LCY and ε-LCY, are also important in determining carotenoid content and composition in different plants. Some plants fine-tune carotenoid content using tissuespecific isoforms of lycopene cyclases. In contrast to the single-copy b-LCY genes in Arabidopsis and rice, chromoplastspecific b-LCY genes are expressed in the fruits and flowers of tomato, watermelon, papaya, citrus, and saffron (Tadmor et al., 2005; Alque´zar et al., 2009; Ahrazem et al., 2010; Devitt et al., 2010; Zhang et al., 2013). The expression of chromoplastspecific b-LCY has been found to correlate with the accumulation of b-carotene and/or downstream xanthophylls in tomato and citrus (Ronen et al., 2000; Alque´zar et al., 2009).

Hydroxylation and epoxidation of xanthophylls are also coordinated in plants. The presence of the dominant b-OHase (Chy2) allele is associated with reduced ZEP expression, causing an orange flesh phenotype in potato due to high accumulation of zeaxanthin (Wolters et al., 2010). Loss of function of ZEP in the aba1 mutant of Arabidopsis and aba2 mutant in tobacco causes accumulation of high zeaxanthin levels in leaves and lower ABA (Rock and Zeevaart, 1991; Marinn et al., 1996). On the other hand, b-Ohase overexpression in transgenic tobacco enhances zeaxanthin levels and results in improved drought tolerance without a marked change in ABA content; the authors propose a role for zeaxanthin in this unexpected result (Zhao et al., 2014).

Flux can also be biased toward one or the other branch of the carotenoid pathway by manipulation of lycopene cyclase expression and enzyme activity (Yu and Beyer, 2012; Giorio et al., 2013). Transcript analysis of homo- and heterozygous Arabidopsis lut2 mutants demonstrates that lut2 is semi-dominant (Pogson et al., 1996) and ε-LCY mRNA levels can be rate limiting (Cuttriss et al., 2007). In maize endosperm tissues lacking b-LCY activity, ε-LCY functions as a dual mono- or bicyclic enzyme and causes the accumulation of ε,ε-carotene, dcarotene, and ε-carotene (Bai et al., 2009). Similarly, ε-LCY downregulation in canola results in the enhanced accumulation of b-carotene, zeaxanthin, violaxanthin, and lutein, although it should be noted that the ratio of b-carotene to lutein increased substantially (Yu et al., 2008). Suppression of ε-LCY in sweet potato and tobacco showed increased synthesis of a b-branch–specific pathway and enhanced tolerance to abiotic stress (Kim et al., 2013; Shi et al., 2014). Enhanced levels of b-carotene were also observed in ε-LCY tuber-specific silencing of potato (Diretto et al., 2006). Recent studies on the roles of ε-LCY and b-LCY in lutein synthesis in tomato, rice, and Arabidopsis have revealed that the relative cyclase activities as well as the synthesis of cyclic carotenoids appear to be affected by the expression levels of two cyclase genes (Giorio et al., 2013; Yu and Beyer, 2012). Thus, relative lycopene cyclase activities can play a critical role in determining the

Xanthophyll composition is regulated by light intensity and chloroplast redox status (Jahns and Holzwarth, 2012). Zeaxanthin aids thermal dissipation of excess light energy in the LHCs and thus plays a key role in protecting the photosynthetic apparatus from strong light (Niyogi et al., 1998; Li et al., 2002; Bonente et al., 2008; Pinnola et al., 2013). During light stress, zeaxanthin can be synthesized from antheraxanthin and violaxanthin via a process known as the xanthophyll cycle (Jahns and Holzwarth, 2012; Latowski et al., 2011). The enzymes responsible for the process, ZEP and VDE, are members of the lipocalin group of proteins, which bind and transport small hydrophobic molecules (Hieber et al., 2000). In vitro assay of pepper ZEP found that ferredoxin and ferrodoxin:NADP oxidoreductase are required for enzyme activity in addition to NADPH, implicating that reduced ferredoxin availability may limit zeaxanthin epoxidation (Bouvier et al., 1996). Conversely, VDE is activated by low pH generated in the chloroplast lumen under high light (Pfundel and Bilger, 1994).

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Xanthophyll esterification limits their degradation and increases their sequestration within the chromoplast by accumulating increased levels of esterified xanthophylls (Ariizumi et al., 2014). The tomato carotenoid-modifying gene PYP1 (Pale Yellow Petal 1) is involved in the production of xanthophyll esters from neoxanthin and violaxanthin. Disruption of this gene causes the loss of

Carotenoid Metabolism and Regulation xanthophyll esters, decreasing total carotenoid levels and disrupting chromoplast development (Ariizumi et al., 2014). The function of neoxanthin is critical to plant photosynthetic machinery, since it is present in the LHCs of essentially all higher plants. ABA4 is needed for neoxanthin synthesis in Arabidopsis and for subsequent ABA biosynthesis (North et al., 2007). The aba4 mutants are more sensitive to oxidative stress than wildtype and contain significantly reduced levels of ABA, demonstrating the requirement of neoxanthin in ABA biosynthesis (North et al., 2007). In addition to ABA4, a newly discovered NXD1 gene in tomato and Arabidopsis appears to be essential for neoxanthin synthesis in plants (Neuman et al., 2014). Both 9cis-neoxanthin and 9-cis-violaxanthin can be cleaved by 9-cisepoxycarotenoid dioxygenase (NCED) and further modified to produce plant hormone, ABA. In maize, Vp14 encodes NCED, which has been demonstrated to specifically cleave only the 9cis-geometric isomers of violaxanthin and neoxanthin to yield the ABA precursor, cis-xanthoxin (Schwartz et al., 1997a, 1997b).

CAROTENOID METABOLIC CHANNELING AND ENZYME ORGANIZATION The suborganellar location of carotenogenic enzymes, especially their membrane association, is a critical determinant for their activity. For example, PSY activity is low in etioplasts but increases significantly after integration into the chloroplast thylakoid membrane in the chloroplast during de-etiolation (Welsch et al., 2000; Rodriguez-Villalon et al., 2009a). Therefore, depending on the tissue and plastid type, a complex feedback mechanism coordinates carotenoid metabolism to ensure appropriate production of carotenoids (Beyer et al., 2002; Cuttriss et al., 2007; Qin et al., 2007; Bai et al., 2009; Rodriguez-Villalon et al., 2009b; Rodriguez-Villalon et al., 2009a; Cazzonelli and Pogson, 2010b). Despite our knowledge of the core carotenoid enzymes, the understanding of the regulation of locationspecific carotenogenesis is still limited, partially due to the lack of appropriate knowledge of the membrane-associated multienzyme complexes. Putative carotenoid enzyme ‘‘metabolons’’ likely consist of plastid-localized protein complexes, which contain sequential groups of enzymes, as proposed a decade ago (Cunningham and Gantt, 1998). In the plastid membrane, one such multiprotein complex could consist of desaturases and cyclases, which may mediate the channeling of phytoene to synthesize cyclic carotenes (Cunningham and Gantt, 1998) and determine the flux of lycopene toward either b- or ε-ring cyclization (Kim and DellaPenna, 2006). Moreover, the existence of these metabolons explains the rationale of metabolic channeling required to accumulate and transport various carotenoid intermediates and end products to thylakoid membranes, where most of them are integrated into PSI, PSII, and LHCs (Ruiz-Sola and Rodrı´guez-Concepciońa, 2012). So far, there are four hypothetical membrane-bound metabolons, comprising (1) IDI, GGDS, and PSY (to synthesize phytoene from IPP and DMAPP), (2) two catalytic units PDS with Z-ISO and ZDS with CRTISO (to synthesize lycopene from phytoene), (3) PDS, Z-ISO, ZDS, CRTISO, and b-LCY (to synthesize b-carotene from phytoene), and (4) b-LCY, ε-LCY, and the CYP97 hydroxy-

Molecular Plant lases (to mediate the synthesis of lutein from lycopene) (RuizSola and Rodrı´guez-Concepciońa, 2012). Protein–protein interaction between CYP97A and CYP97C suggests the formation of a multienzyme complex to synergistically convert a-carotene to lutein (Quinlan et al., 2012). A PDS-containing (350 kDa) protein complex has also been found on the plastid membrane (Lopez et al., 2008). Recent studies in tomato may support the existence of metabolons that control the levels of different intermediates that can feedback regulate the pathway (Kachanovsky et al., 2012). Mutation in fruit-specific PSY1 (yellow flesh; r2997) eliminates PSY1 transcription, and the PSY1 expression in yellow flesh/tangerine (r2997/t3002) double mutant is partially recovered (Kachanovsky et al., 2012). More research is needed to provide further insights on the site of carotenoid biosynthesis and how carotenogenic enzymes are recruited to assemble biologically active metabolons.

CAROTENOID SEQUESTRATION AND STORAGE IN PLASTIDS Plastids, most importantly, chloroplasts and chromoplasts, are the organelles that synthesize and store carotenoid metabolites (Lopez-Juez and Pyke, 2005). De novo carotenoid synthesis occurs in almost all types of differentiated plastids in leaves, fruits, flowers, roots, and seeds. The type and size of plastids have significant effects on carotenoid accumulation and stability: understanding of this topic owes much to findings from the metabolic engineering of plant carotenoid biosynthesis to enhance dietary provitamin A (Hannoufa and Hossain, 2012; Li and Yuan, 2013). Chromoplasts are carotenoid-enriched plastids in which various lipoprotein substructures (e.g. globules, crystals, membranes, fibrils, and tubules) sequester carotenoids (Vishnevetsky et al., 1999; Egea et al., 2010; Li and Yuan, 2013). Tomato high pigment (hp1, hp2, and hp3) mutants have particularly high carotenoid content due to increased chromoplast number and/or volume (Kolotilin et al., 2007; Galpaz et al., 2008; Azari et al., 2010; Enfissi et al., 2010). Or, a cauliflower mutant, over-accumulates b-carotene in chromoplasts of the pith and curd as sheet, ribbon, and crystal substructures, without significant changes in the expression of major carotenoid genes (Li et al., 2001; Lu et al., 2006). In chloroplasts, thylakoid membranes and plastoglobuli provide the plastids with high capacity to sequester and store the synthesized carotenoids, leading to high levels of carotenoid accumulation in green tissues. Other plastids store varying levels of carotenoids. In wheat seeds, starch-storing amyloplasts accumulate lutein (Hentschel et al., 2002; Howitt et al., 2009). Leucoplasts are colorless plastids characteristic of mature root cells, which accumulate trace levels of neoxanthin and violaxanthin (Parry and Horgan, 1992). The lack of appropriate lipoprotein substructures in these plastids limits their capacity to significantly accumulate and stably store carotenoids (Li et al., 2012). Similarly, etioplasts, the chloroplast precursor in dark-grown plants, have little capacity to biosynthesize and store carotenoids (Park et al., 2002; Toledo-Ortiz et al., 2010). Carotenoids are also present in the elaioplasts (specialized lipid-storing plastids). Proteomic studies of plastid proteins and thylakoid fractions further demonstrate the relationship between carotenoid Molecular Plant 8, 68–82, January 2015 ª The Author 2015.

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Molecular Plant composition and plastid biogenesis, morphology, and protein translocation (Tzvetkova-Chevolleau et al., 2007; Wang et al., 2013). Plastid morphology and development are also factors affecting carotenoid sequestration. Microscopic analyses reveal that a change in chromoplast architecture is associated with carotenoid composition in a variety of capsicum fruits (Kilcrease et al., 2013). Bai et al. postulate that Or increases the carotenoid levels by lowering the threshold of carotenoid content required to trigger chromoplast differentiation (Bai et al., 2014). Interestingly, the carotenoid pathway can also be regulated by physical partitioning of carotenoid metabolites away from downstream enzymes that influence carotenoid sequestration mechanism (Nogueira et al., 2013). For example, PSY1 is preferentially localized in stroma, with its active form perhaps loosely associated with the membrane, whereas its product, phytoene, is largely present in the membrane and plastoglobuli, which may not be completely accessible to PDS as a precursor for carotene formation unless it is reintegrated into the membrane enzyme complex (Fraser et al., 1994; Fraser and Bramley, 2004; Nogueira et al., 2013). Subplastidial organization of carotenoid synthesis and sequestration are two important aspects to better engineer carotenoid metabolism in plants. So far, limited numbers of genes are thought to be involved in the regulation of carotenoid sequestration in plants. CHCR (chromoplast-specific carotenoid-associated protein) enhances the carotenoid content in hp mutants (hp1, 2, and 3) by increasing the sequestration capacity and stabilization of carotenoids (Kilambi et al., 2013). Similarly, the plastid encoded acetyl coenzyme A carboxylase D, Hsp21 (heat shock protein 21), and OR are also involved in enhanced carotenoid accumulation, storage, and stability (Neta-Sharir et al., 2005; Barsan et al., 2012; Carvalho et al., 2012; Li et al., 2012; Kilambi et al., 2013). Thus, changes in carotenoid levels likely trigger different regulatory mechanisms and result in the activation of a signaling cascade to generate an adaptive response in the cell (Nogueira et al., 2013). However, further investigation is needed to understand how a plant cell triggers different regulatory mechanisms, including regulation of transcription and protein localization together with organelle and suborganelle structural organization in order to adapt the altered carotenoid content.

ROLE OF CAROTENOIDS IN PLANT DEVELOPMENT Carotenoids are important to plant physiology. Proteomic studies have advanced our understanding of the molecular mechanisms controlling specific types of plastidial isoprenoids, including carotenoids, chlorophylls, tocopherols, plastoquinone, and phylloquinone, as well as the dynamic connection among the varieties of these isoprenoids produced in the plant cells (Joyard et al., 2009). The specific functions of carotenoids and their coordination with different plastidial isoprenoid pigments (e.g. chlorophylls) in regulating plant growth and development are discussed here.

Role of Carotenoids in Photosynthesis and Photoprotection Photosynthesis inevitably generates highly reactive intermediates and by-products, causing oxidative damage to the photo74


Carotenoid Metabolism and Regulation synthetic apparatus and decreasing the efficiency of photosynthesis (Niyogi, 1999). Photosynthetic organisms have evolved various photoprotective mechanisms to cope with the damaging effects of light. Numerous antioxidant compounds, such as carotenoids, tocopherols, ascorbate, glutathione, and antioxidant enzymes (superoxide dismutase and ascorbate peroxidase) mitigate the generation of these reactive molecules, especially reactive oxygen species (ROS) (Niyogi, 1999). The importance of carotenoids as antioxidants is demonstrated by the mutants with bleached phenotypes in algae and plants that are unable to synthesize carotenoids (Avendanõ-Va´zquez et al., 2014; Baroli and Niyogi, 2000; Dong et al., 2007; Qin et al., 2007). In addition, comparison of Arabidopsis mutants with altered xanthophyll composition (e.g. szl1, chy1chy2, lut5, etc.) suggests that carotenoids are the major determinant of photoprotective efficiency in these plants (Niyogi et al., 2001; Dall’Osto et al., 2007; Kim et al., 2009; Cazzaniga et al., 2012). Besides the essential function as photoprotectants and antioxidants, carotenoids act as oxidative stress ‘‘sensor’’ and ‘‘signals’’ upon oxidation by ROS (Havaux, 2014; Ramel et al., 2012a, 2012b; Shumbe et al., 2014).

Carotenoids and Photomorphogenesis The biosynthesis and accumulation of carotenoids in the darkgrown etioplasts are essential for the assembly of the membrane structures and benefit the development of chloroplasts when seedlings emerge from light exposure (Rodrı´guez-Villaloń et al., 2009). During photomorphogenesis, the chlorophyll and carotenoid compounds are produced in a coordinated manner and in conjunction with other components that direct the formation of thylakoid membranes for functional photosynthetic apparatus (Burkhardt et al., 1997; Welsch et al., 2000). In chloroplasts, most carotenoid biosynthetic genes, including those in the MEP pathway, are activated during light-triggered de-etiolation (Cazzonelli and Pogson, 2010b; Giuliano et al., 2008; Rodriguez-Concepcion, 2010). In particular, a strong coordination with enhanced transcript abundance of flux controlling genes (e.g. PSY and DXS) is observed in response to light-activated de-etiolation (Welsch et al., 2000; Meier et al., 2011). In addition, phytochrome-mediated light signals are known to regulate carotenoid accumulation in Arabidopsis and tomato (von Lintig et al., 1997; Alba et al., 2000; Giovannoni, 2001; Hirschberg, 2001).The involvement of the PIF family, particularly PIF1, is shown to regulate Arabidopsis PSY expression and carotenoid accumulation in the leaves (ToledoOrtiz et al., 2010).

CAROTENOID CLEAVAGE The steady-state level of carotenoids is dependent on the metabolic equilibrium between biosynthesis and degradation of carotenoids along with storage (Hannoufa and Hossain, 2012; Li and Yuan, 2013). Thus, the catalytic activity of carotenoid cleavage dioxygenases (CCDs), which leads to the enzymatic turnover of C40 carotenoids into apocarotenoids, is critical in regulating carotenoid accumulation. In addition to CCDs, enzymatic oxidation via peroxidases/lipo-oxygenases or non-enzymatic photochemical oxidation in photosynthetic tissues under high light stress also mediates carotenoid homeostasis (Auldridge et al., 2006a; Vallabhaneni et al., 2010; Walter and Strack,

Molecular Plant

Carotenoid Metabolism and Regulation 2011). The purposes of enzymatic and non-enzymatic cleavage fall into two categories: turnover and production of hormones, signals, and volatile/flavor compounds. In Arabidopsis, the CCD gene family consists of nine members and can be divided into two groups: four CCDs and five NCEDs. These enzymes cleave different carotenoids and some exhibit unique substrate specificity (Auldridge et al., 2006b). The substrate specificity of CCD1 and CCD4 remains unclear, but their role in modulating carotenoid content is emerging. Carotenoid accumulation in various plant species and tissues, including Arabidopsis seed, chrysanthemum flowers, potato, and strawberry, is found to be negatively correlated with the expression of CCD1 or CCD4, suggesting their roles in carotenoid turnover (Auldridge et al., 2006a; Ohmiya et al., 2006; Garcia-Limones et al., 2008; Campbell et al., 2010; Zhou et al., 2011; Gonzalez-Jorge et al., 2013). CCD1 expression is in addition associated with the emission of volatile scent metabolites in tomato, crocus, petunia, grape, melon, and coffee (Bouvier et al., 2003b; Simkin et al., 2004a, 2004b; Mathieu et al., 2005; Ibdah et al., 2006; Kato et al., 2006; Ilg et al., 2014). Similarly, strong up-regulation of CCD1 transcripts in maize (white cap1 [wc1]) and white flower orchid mutants correlates with the loss of carotenoids (Chiou et al., 2010; Vallabhaneni et al., 2010). Enhanced expression of CCD4 in chrysanthemums results in white petal flowers and loss of yellow carotenoid pigments (Ohmiya et al., 2006). CCD4 has also been shown to control peach flesh pigmentation, with high CCD4 transcript abundance in white flesh peach, which is associated with the emission of carotenoid-derived volatiles (Brandi et al., 2011; Falchi et al., 2013). However, there are conflicting reports indicating that CCD1 and CCD4 expression is not correlated with carotenoid levels in morning glory (Yamamizo et al., 2010). Similarly, increased CCD1 expression does not alter violaxanthin accumulation in citrus (Kato et al., 2006), suggesting that other factors must regulate carotenoid turnover. Several products derived from oxidative carotenoid cleavage reactions in flowers and fruits are volatile (e.g. ionones and b-damascenone). Thus, some apocarotenoids have commercial value in the food and cosmetic industries as aromas, flavors, and pigments (Giuliano et al., 2003). Examples include b-ionone and all other cleavage products, which are vital components of many flavors. Zeaxanthin-derived apocarotenoids (e.g. crocin, cocetin glycosides, picocrocin, and saffaranal) contribute to the red color of saffron (Bouvier et al., 2003b; Frusciante et al., 2014). Likewise, bixin (annatto), a red apocarotenoid derived from Bixa orellana is a widely used flavoring and coloring agent in foods and cosmetics (Bouvier et al., 2003a; Botella-Pavıá and Rodrı´guezConcepcioń, 2006; Schwab et al., 2008; Cazzonelli, 2011). In citrus, cleavage of b-cryptoxanthin and zeaxanthin via CCD4 leads to the formation of b-citraurin, which is responsible for characteristic red pigmentation of citrus fruits (Ma et al., 2013). Similarly, cleavage of carotenoids in tomato fruits by CCD1 enzymes (SlCCD1A and SlCCD1B) produces various isoprenoid volatiles, including neral (cis-citral), geranial (trans-citral), and farnesyl acetone (Ilg et al., 2014). Carotenoid cleavage products have other biological roles. Some are root specific and apparently accumulate in response to inoculation with arbuscular mycorrhizal fungi, mycorradicin and blumenin (Klingner et al., 1995; Maier et al., 1995; Walla et al., 2000). A

role of b-ionone in plant–insect interaction is also known (Gruber et al., 2009), as Arabidopsis CCD1 overexpression results in increased emission of b-ionone, which prevents damages from insect attack (Wei et al., 2011). The NCED subfamily has been shown to cleave 9-cis-isomers of epoxy-carotenoid to yield the ABA precursor (Tan et al., 2003), while CCD7 and CCD8 are involved in the production of strigolactones (Gomez-Roldan et al., 2008; Umehara et al., 2008; Alder et al., 2012; Ruyter-Spira et al., 2013) via the synthesis of carlactone from b-carotene (Alder et al., 2012; Seto et al., 2014).

CAROTENOID-DERIVED SIGNALS Evidence is accumulating for additional carotenoid-derived signals. A mobile carotenoid-derived metabolite BPS1 is proposed to act as negative regulator for normal root and shoot development (Sieburth and Lee, 2010; Adhikari et al., 2013). Nonenzymatic carotenoid oxidation by ROS also plays a critical role in sensing and signaling the oxidative stress condition (Havaux, 2014; Ramel et al., 2012b). Arabidopsis leaves exposed to high light stress produce bioactive, volatile plant compounds, including b-cyclocitral and dihydroactinidiolide, which are derived from the oxidation of b-carotene and act as stress signals to reprogram gene expression and activate plant cellular defense mechanisms (Ramel et al., 2012b; Shumbe et al., 2014). In addition, it has been reported recently that the development and prepatterning of lateral roots as well as periodic root branching in Arabidopsis also require an uncharacterized apocarotenoid, which is distinct from ABA and strigolactones (Van Norman et al., 2014). Another interesting finding is the demonstration of novel z-carotene-derived molecules that act as signaling compounds in ZDS-deficient mutants (clb5 [chloroplast biogenesis 5]) to cause the impairment of normal leaf development and the repression of multiple nuclear and chloroplastic genes (Avendanõ-Va´zquez et al., 2014). Collectively, these reports suggest that carotenoid-derived compounds besides ABA and strigolactones are important for plant development.

CONCLUSION Carotenoid metabolism in plants has been extensively studied in the past two decades due to their importance to plants and human well-being. Our understanding of carotenoid metabolism, regulation, and roles of carotenoid derivatives is still developing. Future research will address the key questions related to the coordinated organization of different components of carotenoid pathway to assemble ‘‘metabolons’’ in a known suborganellar location. This will provide further insights into the mechanisms controlling the localized and context-specific carotenoid synthesis and degradation and lead to a better understanding of the spatial distribution and function of different carotenoids and their derivatives in response to environmental and developmental signals. The knowledge may facilitate further advancement in the field of carotenoid metabolic engineering to improve crop nutritional quality.

FUNDING We acknowledge the support of Australian Research Council Centre of Excellence in Plant Energy Biology grant CE140100008 (to B.J.P.).


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Molecular Plant AUTHOR CONTRIBUTIONS N.N. undertook the majority of manuscript writing and all co-authors have contributed to writing and reading of the manuscript as well as preparing the figure.

ACKNOWLEDGMENTS We would like to thank John Rivers (Australian National University) for critical reading. No conflict of interest declared. Received: August 29, 2014 Revised: November 30, 2014 Accepted: December 11, 2014 Published: December 17, 2014

Carotenoid Metabolism and Regulation expression of chloroplast and nuclear genes in Arabidopsis. Plant Cell 26:2524–2537. Azari, R., Reuveni, M., Evenor, D., Nahon, S., Shlomo, H., Chen, L., and Levin, I. (2010). Overexpression of UV-damaged DNA binding protein 1 links plant development and phytonutrient accumulation in high pigment-1 tomato. J. Exp. Bot. 61:3627–3637. Bai, L., Kim, E.H., DellaPenna, D., and Brutnell, T.P. (2009). Novel lycopene epsilon cyclase activities in maize revealed through perturbation of carotenoid biosynthesis. Plant J. 59:588–599.

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