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. 2013 Mar 27;4:62. doi: 10.3389/fpls.2013.00062

Shikimate and Phenylalanine Biosynthesis in the Green Lineage

Takayuki Tohge 1,*, Mutsumi Watanabe 1, Rainer Hoefgen 1, Alisdair R Fernie 1
PMCID: PMC3608921  PMID: 23543266

Abstract

The shikimate pathway provides carbon skeletons for the aromatic amino acids l-tryptophan, l-phenylalanine, and l-tyrosine. It is a high flux bearing pathway and it has been estimated that greater than 30% of all fixed carbon is directed through this pathway. These combined pathways have been subjected to considerable research attention due to the fact that mammals are unable to synthesize these amino acids and the fact that one of the enzymes of the shikimate pathway is a very effective herbicide target. However, in addition to these characteristics these pathways additionally provide important precursors for a wide range of important secondary metabolites including chlorogenic acid, alkaloids, glucosinolates, auxin, tannins, suberin, lignin and lignan, tocopherols, and betalains. Here we review the shikimate pathway of the green lineage and compare and contrast its evolution and ubiquity with that of the more specialized phenylpropanoid metabolism which this essential pathway fuels.

Keywords: shikimate pathway, aromatic amino biosynthesis, evolution, gene copy number, gene duplication, plant secondary phenolic metabolite

Introduction

The shikimate pathway is closely interlinked with those of the aromatic amino acids (L-tryptophan, l-phenylalanine, and L-tyrosine) and in land plants bears very high fluxes with estimates of the amount of fixed carbon passing through the pathway varying between 20 and 50% (Weiss, 1986; Corea et al., 2012; Maeda and Dudareva, 2012). Considerable research focus has been placed on this pathway since the aromatic amino acids are not produced by humans and monogastric livestock and are therefore an important dietary component (Tzin and Galili, 2010). Furthermore, one of the enzymes of the pathway – 5-enolpyruvalshikimate-3-phosphate synthase (EPSP) – is one of the most widely employed herbicide target sites (see, Duke and Powles, 2008). Moreover, as we have recently described, plant phenolic secondary metabolites and their precursors are synthesized via the pathway of shikimate biosynthesis and its numerous branchpoints (Tohge et al., 2013). The shikimate pathway is highly conserved being found in fungi, bacteria, and plant species wherein it operates in the biosynthesis of not just the three aromatic amino acids described above but also of innumerable aromatic secondary metabolites such as alkaloids, flavonoids, lignins, and aromatic antibiotics. Many of these compounds are bioactive as well as playing important roles in plant defense against biotic and abiotic stresses and environmental interactions (Hamberger et al., 2006; Maeda and Dudareva, 2012), and as such are highly physiologically important. It is estimated that under normal conditions as much as 20% of the total fixed carbon flows through to shikimate pathway (Ni et al., 1996), with greater carbon flow through the pathway under times of plant stress or rapid growth (Corea et al., 2012). Given its importance it is perhaps not surprising that all members of biosynthetic genes and corresponding enzymes involved in shikimate pathway have been characterized in model plants such as Arabidopsis. Cross-species comparison of the shikimate biosynthetic enzymes has revealed that they share sequence similarity, divergent evolution, and commonality in reaction mechanisms (Dosselaere and Vanderleyden, 2001). However, all other species vary considerably from fungi which has evolved a complex system with a single pentafunctional polypeptide known as the AroM complex which performs five consecutive reactions (Lumsden and Coggins, 1977; Duncan et al., 1987). In this review we will summarize current knowledge concerning the genetic nature of this pathway focusing on cross-species comparisons bridging a wide range of species including algae (Chlamydomonas reinhardtii, Volvox carteri, Micromonas sp., Ostreococcus tauri, Ostreococcus lucimarinus), moss (Selaginella moellendorffii, Physcomitrella patens), monocots (Sorghum bicolor, Zea mays, Brachypodium distachyon, Oryza sativa ssp. japonica and Oryza sativa ssp. indica), and dicots (Vitis vinifera, Theobroma cacao, Carica papaya, Arabidopsis thaliana, Arabidopsis lyrata, Populus trichocarpa, Ricinus communis, Manihot esculenta, Malus domestica, Fragaria vesca, Glycine max, Lotus japonicus, Medicago truncatula) species (Table 1). Finally, we compare and contrast the evolution of this pathway with that of the more specialized pathways of phenylpropanoid biosynthesis.

Table 1.

Summary of the species used in the study.

Species name ID Common name Classification Species
1 Chlamydomonas reinhardtii CR Green algae Chlorophyte Chlamydomonadaceae
2 Volvox carteri VC Algae Chlorophyte Volvoceae
3 Micromonas sp. RCC299 MRC Micromonas Chlorophyta Prasinophyceae
4 Ostreococcus tauri OT Microalgae Prasinophyte Prasinophyceae
5 Ostreococcus lucimarinus OL Microalgae Prasinophyte Prasinophyceae
6 Selaginella moellendorffii SM Spike moss Lycophytes Selaginellaceae
7 Physcomitrella patens PP Moss Lycophytes Funariaceae
8 Sorghum bicolor SB Sorghum Monocot Poaceae
9 Zea mays ZM Corn Monocot Poaceae
10 Brachypodium distachyon BD Purple false brome Monocot Poaceae
11 Oryza sativa ssp. japonica OS Japonica rice Monocot Poaceae
12 Oryza sativa ssp. indica OSI Indica rice Monocot Poaceae
13 Vitis vinifera VV Grapevine Dicot Vitaceae
14 Theobroma cacao TC Cacao Dicot Malvaceae
15 Carica papaya CP Papaya Dicot Caricaceae
16 Arabidopsis thaliana AT Arabidopsis Dicot Brassicaceae
17 Arabidopsis lyrata AL Lyrata Dicot Brassicaceae
18 Populus trichocarpa PT Poplar Dicot Salicaceae
19 Ricinus communis RC Castor oil plant Dicot Euphorbiaceae
20 Manihot esculenta ME Cassava Dicot Euphorbiaceae
21 Malus domestica MD Apple Dicot Rosaceae
22 Fragaria vesca FV Strawberry Dicot Rosaceae
23 Glycine max GM Soybean Dicot Fabaceae
24 Lotus japonicus LJ Lotus Dicot Fabaceae
25 Medicago truncatula MT Medicago Dicot Fabaceae
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Coding genes is estimated by Plaza (http://bioinformatics.psb.ugent.be/plaza/). Relationships among the species considered are presented on the Plaza website (http://bioinformatics.psb.ugent.be/plaza/).

Shikimate Biosynthesis and Phenylalanine Derived Secondary Metabolism in Plants

Given that phenolic secondary metabolites which are derived from phenylalanine via shikimate biosynthesis are widely distributed in plants and other eukaryotes, genes encoding shikimate biosynthetic enzymes are generally highly conserved in nature. Eight and two reactions are involved in shikimate and phenylalanine biosynthesis, respectively. Both members of all gene families and the corresponding biosynthetic enzymes involved in these pathways have been characterized in model plants such as Arabidopsis (Figure 1A). In contrast, phenolic secondary metabolites derived from phenylalanine display considerable species-specific distribution with the phenolic secondary metabolites have been found in plant kingdom such as coumarin derivatives, monolignal, lignin, spermidin derivatives, flavonoid, tannin being present in specific families within the green lineage (Figure 1B). This diversity has arisen by the action of diverse evolutionary strategies for example gene duplication and cis-regulatory evolution in order to adapt to prevailing environmental conditions. Given their species-specific distribution, the genes involved in plant phenolic secondary metabolism such as phenylammonia-lyase (PAL), polyketide synthase (PKS), 2-oxoglutarate-dependent deoxygenases (2ODDs), and UDP-glycosyltransferases (UGTs) are frequently used as case studies of plant evolution (Tohge et al., 2013). Despite the fact that shikimate-phenylalanine biosynthetic genes are well conserved in all species including algae species, phenolic secondary metabolism related orthologous genes were not detected in all algae species (Table 2, Tohge et al., 2013). This result suggests a considerably more ancient origin of the shikimate-phenylalanine pathways. In the next sections, we will discuss the evolution of shikimate-phenylalanine pathways focusing on cross-species comparisons for each gene encoding on of the constituent enzymes of either pathway.

Figure 1.

Figure 1

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The shikimate and phenylalanine derived secondary metabolite biosynthesis in plants. (A) Shikimate biosynthesis starting from phosphoenolpyruvate (PEP) and D-erythrose 4-phosphate is described with characterized genes and reported intermediate metabolites. (B) phenylalanine derived major phenolic secondary mebolite biosynthesis in the green lineage. Arrow indicates enzymatic reaction, circle indicates metabolite. Abbreviation: DAHPS, 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase; DQS, 3-dehydroquinate synthase; DHQD/SD, 3-dehydroquinate dehydratase; SK, shikimate kinase; ESPS, 3-phosphoshikimate 1-carboxyvinyltransferase; CS, chorismate synthase; CM, chorismate mutase; PAT, prephenate aminotransferase; ADT, arogenate dehydratase. PAL, phenylalanine ammonia-lyase; C4H, cinnamate-4-hydroxylase; 4CL, 4-coumarate CoA ligase; CAD, cinnamoyl-alcohol dehydrogenase; F5H, ferulate 5-hydroxylase; C3H, coumarate 3-hydroxylase; ALDH, aldehyde dehydrogenase; CCR, cinnamoyl-CoA reductase; HCT, hydroxycinnamoyl-Coenzyme A shikimate/quinate hydroxycinnamoyltransferase; CCoAOMT, caffeoyl/CoA-3-O-metheltransferase; CHS, chalcone synthese; CHI, chalcone isomerase; F3H, flavanone 3-hydroxylase; F3′H, flavonoid-3′-hydroxylase; F3GT, flavonoid-3-O-glycosyltransferase; FS, flavone synthase; FOMT, flavonoid O-methyltransferase; FCGT, flavone-C-glycosyltransferase; FLS, flavonol synthese; F3GT, flavonoid-3-O-glycosyltransferase; DFR, dihydroflavonol reductase; ANS, Anthocyanidin synthese; AGT, Flavonoid-O-glycosyltransferase; AAT, anthocyanin acyltransferase; BAN, oxidoreductase|dihydroflavonol reductase like; LAC, laccase.

Table 2.

Shikimate and phenylalanine biosynthetic genes and homologs in each species with/without tandem duplicated genes.

No. ID 1 CR 3 MRCC299 4 OT 8 SB 9 ZM 10 BD 11 OS 12 OSindica
DHS Cr17g06460 Mrcc02g07760 Ot06g03510 Sb01g028770 Zm02g39200 Bd1g21330 Os03g27230 Osi07g35030
Sb01G033590 Zm04g31550 Bd1g60750 Os07g42960 Osi08g36090
Sb02G039660 Zm05g06990 Bd3g33650 Os08g37790 Osi10g31830
Sb07G029080 Bd3g38670 Os10g41480
DQS Cr08g02240 Mrcc01g05190 Ot05g01830 Sb02G031240 Zm02g34320 Bd4g36507 Os09g36800 Osi09g29080
DHQD Cr08g04550 Mrcc01g03580 Ot12g02660 Sb08G016970 Zm03g17940 Bd4g05897 Os12g34874 Osi12g23310
Zm10g05140
SK Cr10g04010 Mrcc13g02500 Ot14g03180 Sb06G030260 Zm02g02970 Bd3g59237 Os04g54800 Osi02g49680
Zm04g27840 Bd5g23460
Zm05g40530
SKL1 Sb08G018630 Zm01g26660 Bd2g03680 Os01g01302
SKL2 Mrcc02g03490 Ot07g01450 Sb01G027930 Zm01g22640 Bd3g34245 Os10g42700
ESPS Cr03g06830 Mrcc13g01100 Ot14g02430 Sb10G002230 Zm09g05500 Bd1g51660 Os06g04280 Osi06g03190
CS Cr01g12390 Mrcc05g01430 Ot02g06020 Sb01G040790 Zm01g10020 Bd1g67790 Os03g14990 Osi03g13340
Zm09g24540
CM Cr03g01600 Mrcc08g05060 Ot08g02860 Sb03G035460 Zm03g31000 Bd2g50800 Os01g55870 Osi01g52850
Sb04G005480 Zm05g21270 Bd3g06050 Os02g08410 Osi02g08160
Zm08g34320 Os12g38900
Zm08g34330
PAT Cr02g15900 Mrcc06g00860 Ot16g00690 Sb03G041180 Zm03g25600 Bd2g24300 Os01g65090 Osi01g61700
Sb09G021360 Zm08g15210 Bd2g56330
ADT Cr06g02760 Mrcc01g05870 Ot01g01250 Sb01G038740 Zm01g12020 Bd5g09020 Os04g33390 Osi03g16350
Sb06G015310 Zm02g16320 Bd5g09030 Os03g17730 Osi04g25440
Zm10g16000 Bd1g16517 Os07g49390 Osi07g41390
Bd1g65800
No. ID 13 VV 14 TC 16 AT 17 AL 18 PT 21 MD 22 FV 23 GM 24 LJ 25 MT
DHS Vv00g09200 Tc01g008590 At1g22410 Al1g23930 Pt01g14860 Md00g000730 Fv0g22320 Gm02g37080 Lj1g002520 Mt2g009080
Vv00g17890 Tc01g012940 At4g33510 Al7g02250 Pt02g09760 Md00g361080 Fv5g19610 Gm06g10670 Mt5g064500
Vv18g03830 Tc02g011250 At4g39980 Al7g07720 Pt05g07260 Md01g001320 Gm14g35370
Tc03g024120 Pt05g16320 Md04g002280 Gm15g06020
Tc08g008780 Pt07g04970 Md05g021570
Md05g025390
Md10g003880
Md11g021260
DQS Vv04g00350 Tc01g001360 At5g66120 Al8g34560 Pt05g11110 Md00g089850 Fv1g13270 Gm01g36890 Lj2g022420 Mt5g022580
Gm11g08350
DHQD Vv05g03610 Tc04g027300 At3g06350 Al3g06450 Pt10g01690 Md00g196450 Fv1g19500 Gm01g20760 Lj4g005930 Mt4g090620
Vv14g04450 Tc05g024340 Pt13g02880 Md00g199470 Fv6g07230 Gm20g37400
Vv14g04460 Tc05g024370 Md00g208810 Fv6g07240
Md01g014110
Md01g014130
Md04g017400
Md15g026460
SK Vv00g22160 Tc01g010070 At2g21940 Al4g01190 Pt02g06000 Md00g396950 Fv6g01580 Gm04g39700 Lj1g014890
Vv07g06350 At4g39540 Al7g01530 Pt05g08460 Md02g009820 Gm04g39710
Pt07g06400 Gm05g31730
Gm08g14980
SKL1 Vv14g14000 Tc04g004710 At3g26900 Al5g05650 Pt17g08780 Fv6g51520 Gm02g08050 Lj1g008480
Gm16g27060
SKL2 Vv02g01940 Tc03g029930 At2g35500 Al4g20870 Pt03g08570 Md00g061570 Fv0g29740 Gm01g01890 Lj3g020970 Mt1g009450
Md00g432830 Fv2g18080 Lj3g020980 Mt5g029550
Md06g002680
ESPS Vv15g09330 Tc01g037810 At1g48860 Al1g42610 Pt02g14550 Md00g030870 Fv7g11420 Gm01g33660 Lj3g025840 Mt4g024620
Vv15g09350 At2g45300 Al4g33160 Pt14g06200 Md00g271560 Gm03g03190
CS Vv06g05280 Tc10g005370 At1g48850 Al1g42550 Pt08g03850 Md00g355380 Fv4g18660 Gm10g35560 Lj0g038950 Mt1g095160
Vv13g03240 Al3g19880 Pt10g21700 Md01g008950 Fv4g18670 Gm20g31980 Lj0g284550 Mt1g095240
Md08g005430 Fv7g23950 Mt1g095250
Fv7g24040
CM Vv01g02110 Tc02g032570 At1g69370 Al2g17620 Pt10g15830 Md00g250450 Fv0g04690 Gm13g05830 Lj5g005890 Mt1g013820
Vv04g13080 Tc04g009770 At3g29200 Al5g08750 Pt17g12090 Md00g329990 Fv2g52320 Gm14g11870 Lj5g005900 Mt5g043210
Vv14g02700 Tc09g001490 At5g10870 Al6g10610 Pt18g02330 Md01g020010 Fv6g43680 Gm17g33940
Md16g003330 Gm19g03290
Md17g004580
PAT Vv07g05790 Tc01g009420 At2g22250 Al4g01710 Pt05g07910 Md00g135490 Fv6g00440 Gm05g31490 Lj6g003720 Mt8g091280
Vv18g03130 Pt07g05690 Md00g246930 Gm08g14720
Md00g304630 Gm11g36190
Gm11g36200
ADT Vv06g04790 Tc02g034990 At1g08250 Al1g12100 Pt00g13690 Md00g099570 Fv3g01120 Gm11g15750 Lj3g029800 Mt2g088130
Vv10g00970 Tc06g019290 At1g11790 Al3g08080 Pt04g01150 Md00g099580 Fv3g16180 Gm11g19430 Lj4g001780 Mt4g055310
Vv12g10860 Tc09g026620 At2g27820 Al4g12300 Pt04g18820 Md00g456520 Fv3g29940 Gm12g07720 Mt4g061070
Tc09g028840 At3g07630 Al5g12520 Pt08g19820 Md05g001400 Gm12g09050 Mt4g132250
At3g44720 Al6g22310 Pt09g14910 Md15g019040 Gm12g30660
At5g22630 Gm12g31940
Gm17g01610
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Orthologous genes were estimated by BLAST search in Plaza website. Bold indicates tandem gene duplication.

3-Deoxy-D-Arabino-Heptulosonate 7-Phosphate Synthase

The first enzymatic step of the shikimate pathway, 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAHPS), catalyzes an aldol condensation of phosphoenolpyruvate (PEP), and D-erythrose 4-phosphate (E4P) to produce 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) (Figure 1). According to their protein structure, DAHPSs can be clustered into two distinct homology classes. The microbe derived class I DAHPS contain a bifunctional chorismate mutase (CM)-DAHPS domains, for that reason microbial DAHPSs, for example, E. coli (AroF, G, and H) and S. cerevisiae (Aro3 and 4), are classified as class I DAHPSs. By contrast, class II DAHPS were previously thought to be present only in plant species, but have subsequently been reported in certain microbes such as Streptomyces coelicolor, Streptomyces rimosus, and Neurospora crassa (Bentley, 1990; Maeda and Dudareva, 2012). The DAHPS (AroA) and CM (AroQ) activities of B. subtilis DAHPS are, however, separated by domain truncation. Detailed sequence structure analysis of the bacterial AroA and AroQ families, enzymatic studies with the full-length protein and the truncated domains of AroA and AroQ of B. subtilis, and comparison with fusion proteins of Porphyromonas gingivalis in which the AroQ domain was fused to the C terminus of AroA, suggest that “feedback regulation” may indeed be the evolutionary link between the two classes which are evolved from primitive unregulated member of class II DAHPS (Wu and Woodard, 2006). Class II plant DAHPSs have been reported from carrot roots (Suzich et al., 1985) and potato cell culture (Pinto et al., 1986; Herrmann and Weaver, 1999). DAHPS is encoded by three genes in the Arabidopsis genome (AtDAHPS1, AT4G39980; AtDAHPS2, At4g33510; AtDAHPS3, At1g22410). Orthologous gene search queries using the Arabidopsis DAHPSs, revealed a single gene in algae species (Chlamydomonas reinhardtii, Volvox carteri, Micromonas sp., and Ostreococcus tauri) and Lotus japonica but two to eight isoforms in other higher plant species (Table 2). AtDAHPS1-type and AtDAHPS2 type genes display differential expression in Arabidopsis thaliana, Solanum lycopersicum, and Solanum tuberosum (Maeda and Dudareva, 2012). AtDAHPS1-type genes, which are additionally subject to redox regulation by the ferredoxin-thioredoxin system, exhibit significant induction by wounding and pathogen infection (Keith et al., 1991; Gorlach et al., 1995; Maeda and Dudareva, 2012), whereas AtDAHPS2 type genes display constitutive expression (Gorlach et al., 1995). A phylogenetic analysis of DAHPS genes reveals four major clades, (i) a microphyte clade, (ii) a bryophyte duplication clade, (iii) monocot and dicot woody species clade, (iv) a AtDAHPSs clade (Figure 2Aa). Furthermore, major clade iv has four sub-groups, (iv-a) AtDAHPS2 group, (iv-b) monocot, (iv-c) AtDAHPS1 group and (iv-d) AtDAHP3 group. This result indicates that the constitutively expressed AtDAHPS1 and the stress responsive AtDAHPS 3 type genes display well conserved sequence between species (clade iv-c and iv-d), whereas the second constitutively expressed AtDAHPS2 type genes are clearly separated between monocot and dicot species (clade iv-a).

Figure 2.

Figure 2

Figure 2

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Phylogenetic tree analysis of shikimate and phenylalanine biosynthetic genes in 25 species. Amino acid sequence phylogenetic trees of (A) shikimate pathway: (a), DAHPS, (b) DHS, (c) DHQD/SD, (d) SK, (e) ESPS, and (f) CS, (B) phenylalanine related genes, (a) CM and (b) PAT. Amino acid sequences of shikimate biosynthetic genes are obtained from Plaza database (http://bioinformatics.psb.ugent.be/plaza/). Relationships among the species considered are presented on the Plaza website. The phylogenetic tree was constructed with the aligned protein sequences by MEGA (version 5.10; http://www.megasoftware.net/; Kumar et al., 2004) using the neighbor-joining method with the following parameters: Poisson correction, complete deletion, and bootstrap (1000 replicates, random seed). The protein sequences were aligned by Plaza. Values on the branches indicate bootstrap support in percentages.

3-Dehydroquinate Synthase

The second step of the shikimate pathway is catalyzed by 3-dehydroquinate synthase (DHQS), an enzyme which promotes the intramolecular exchange of the DAHP ring oxygen with carbon 7 to convert DAHP into 3-dehydroquinate. Unlike the fungal situation detailed above, the plant DHQS gene is monofunctional and only found as a single copy in all species with the exception Glycine max which harbors two genes in its genome (Figure 2Ab). Phylogenetic analysis of DHQS genes reveals three major clades consisting of (i) microphyte (ii) bryophyte, (iii) monocot, (iv) Brassicaceae, and (v) dicot species. Intriguingly, by contrast to other shikimate biosynthetic genes, gene expression of DHQS gene is not well correlated to phenylpropanoid production in Arabidopsis (Hamberger et al., 2006).

3-Dehydroquinate Dehydratase/Shikimate Dehydrogenase

3-Deoxy-d-arabino-heptulosonate 7-phosphate is converted to 3-dehydroquinate by the bifunctional enzyme 3-dehydroquinate dehydratase/shikimate dehydrogenase (DHQD/SD), which catalyzes firstly the dehydration of DAHP to 3-dehydroshikimate and consequently the reversible reduction of this intermediate to shikimate using NADPH as co-factor. DHQD/SD exists in three forms; bacterial specific class I shikimate dehydrogenases (AroE type), class II shikimate/quinate dehydrogenases (YdiB type), and class III of shikimate dehydrogenase-like (SHD-l type) (Michel et al., 2003; Singh et al., 2005). In plants class IV, enzymatic activity of DHQD is 10 times higher than SD activity indicating that the amount of 3-dehydroshikimate will be more than sufficient to support flux through the shikimate pathway (Fiedler and Schultz, 1985). This bifunctional enzyme plays an important role in regulating metabolism of several phenolic secondary metabolic pathways (Bentley, 1990; Ding et al., 2007). In general, seed plants contain a single DHQD/SD gene which contains a sequence encoding a plastic transit peptide in their genome (Maeda et al., 2011, Table 2). However, an exception to this statement is Nicotiana tabacum which contains two genes in its genome. Intriguingly, silencing of NtDHD/SHD-1 results strong growth inhibition and reduction of the level of aromatic amino acids, chlorogenic acid, and lignin contents (Ding et al., 2007), however, a second cytosolic isoform can compensate for the production of shikimate but not at the phenotypic level. On a more general basis phylogenetic analysis reveals that microphytes also contain a low number of DHQD/SD genes (between one and two), whilst clear separation between (i) the microphyte clade, (ii) bryophyte clade, (iii) monocot clade, (iv) woody species-specific tandem gene duplication clade, and (v) dicot clades could be observed (Figure 2Ac; Table 2). Interestingly, the observation of the woody species-specific tandem gene duplication clade suggests that these species evolved after DHQD/SD gene duplication. The cytosolic localization of NtDHD/SHD-2 is intriguing since the presence of DAHP synthase, ESPS synthase and CM isoforms lacking N-terminal plastid targeting sequences has been reported (d’Amato, 1984; Mousdale and Coggins, 1985; Ganson et al., 1986). Furthermore, the findings that both ESPS synthase and shikimate kinase (SK) are active even when they retain their target sequences (Dellacioppa et al., 1986; Schmid et al., 1992) suggests that they could also potentially be constituents of a cytosolic pathway. Finally, experiments in which isolated and highly pure mitochondria were supplied with 13C labeled glucose to investigate the binding of the cytosolic isoforms of glycolysis (Giege et al., 2003) also revealed 13C enrichment in shikimate (Sweetlove and Fernie, 2013), indicating that a full cytosolic pathway is likely also in this species.

Shikimate Kinase

The fifth reaction of the shikimate pathway is catalyzed by SK which catalyzes the ATP-dependent phosphorylation of shikimate to shikimate 3-phospate (S3P). E. coli has two SKs, one of class I (AroL type) and one of II (AroK type) which share only 30% sequence identity (Griffin and Gasson, 1995; Whipp and Pittard, 1995; Herrmann and Weaver, 1999). In plants, different numbers of SK isoforms are found in several species; only one in green algae, lycophytes, and bryophytes but between one and three in monocot and dicot plants (Table 2). A phylogenetic analysis of SK genes presents five major clades consisting of (i) microphyte, (ii) bryophyte, (iii) dicot woody species-specific clade, (iv) monocot clade, and (v) dicot species clade (Figure 2Ad). Anaylsis of the SK protein of Spinacia olerancea revealed that it was modulated by energy status and is therefore similar to bacterial SK protein and other ATP-utilizing enzymes (Pacold and Anderson, 1973; Huang et al., 1975; Schmidt et al., 1990). For this reason it has recently been postulated that SK may link to energy requiring shikimate pathway to the cellular energy balance (Maeda and Dudareva, 2012), however, direct experimental support for this hypothesis is currently lacking. In Arabidopsis, homologous genes named SKL1 and SKL2, which are functionally required for chloroplast biogenesis have been demonstrated to have arisen from SK gene duplication (Fucile et al., 2008). SKL1 and SKL2 orthologs have been found in several seed plant species, but not in green algae (Table 2).

5-enolypyruvylshikimate 3-Phosphate Synthase

The 5-enolypyruvylshikimate 3-phosphate synthase (EPSPS, 3-phosphoshikimate 1-carboxyvintltransferase) is the sixth step and here a second PEP is condensed with S3P to form 5-enolpyruvylshiukimate 3-phosphate (EPSP). Since EPSPS is the only known target for the herbicide glyphosate (Steinrucken and Amrhein, 1980), isoforms of this enzyme are often classified according to their sensitivity of glyphosate, glyphosate sensitive EPSPS class I is present in bacteria and plant species, whilst glyphosate insensitive EPSPS class II which has been reported in certain bacteria such as Agrobacterium (Fucile et al., 2011). In plants, different number of EPSPS isoforms is found in several species; only a single isoform in green algae, lycophytes, and bryophytes, but either one or two are found in monocot and dicot species (Table 2). Phylogenetic analysis of EPSPS genes revealed, atypically for genes associated with shikimate metabolism, that five major groups could be observed; (i) microphyte, (ii) bryophyte, (iii) Brassicaceae specific clade, (iv) monocot species, and (v) dicot species clade (Figure 2Ae). There are clear indications that duplicated EPSPS genes in Arabidopsis, apple, grapevine, soybean, and poplar are the result of independent duplication events within their lineages with both copies being maintained in Arabidopsis (Hamberger et al., 2006), however, the reason for the unique divergence in this gene of the pathway is currently unclear.

Chorismate Synthase

Chorismate, the final product of the shikimate pathway, is subsequently formed by chorismate synthase (CS) which catalyzes the trans-1,4 elimination of phosphate from EPSP. CSs are categorized within one of two functional groups (i) fungal type bifunctional CS which are associated with NADPH-dependent flavin reductase or (ii) bacterial and plant type monofunctional CSs (Schaller et al., 1991; Maeda and Dudareva, 2012). The reaction catalyzed by CS requires flavin mononucleotide (FMN) and its overall reaction is redox neutral (Ramjee et al., 1991; Macheroux et al., 1999; Maclean and Ali, 2003). The FMN represents supplies an electron donor for EPSP which facilitates the cleavage of phosphate. The first cloned plant CS gene was that from C. sempervirens (Schaller et al., 1991) which contains a sole CS in its genome. Given that this gene has a 5′ plastid import signal sequence, these results indicate that there may be no CS outside of the plastid this species. Surveying other species revealed that one to two CS genes were present in green algae, lycophytes, and bryophytes as well as dicot specie but that one to three are present in the genomes of apple and leguminous species (Table 2). A phylogenetic analysis of CS genes reveals three major clades constituted by (i) microphyte, (ii) monocot, (iii) dicot species (Figure 2Af).

Chorismate Mutase

Chorismate mutase catalyzes the first step of phenylalanine and tyrosine biosynthesis and additionally represents a key step of toward the branch split of tryptophan biosynthesis. CM catalyzes the transformation of chorismate to prephenate via a Claisen rearrangement. The bacterial minor CM proteins (AroQ type, class I CM) display monofunctional enzymatic activity whilst several bifunctional CMs such as CM-PDT, CM-PDH, and CM-DAHP have been additionally been found in fungi and bacteria (class II CM, Euverink et al., 1995; Romero et al., 1995; Chen et al., 2003; Baez-Viveros et al., 2004). In spite of the fact of only one CM gene is present in algae and lycophyte genomes, more a single gene copy (two to five) are found in bryophytes as well as monocot and dicot species (Table 2). In seed plants, the CM1 bears a putative plastid transit peptide, but CM2 does not and is additionally usually insensitive to allosteric regulation by aromatic amino acids (Benesova and Bode, 1992; Eberhard et al., 1996; Maeda and Dudareva, 2012). Several plant species, especially dicot plants, have an additional CM3 family gene which displays high sequence similarity to CM2 yet bears a putative plastid transit peptide. For example, Arabidopsis has three isozymes named AtCM1 (At3g29200), AtCM2 (At5g10870), and AtCM3 (At1g69370) (Mobley et al., 1999; Tzin and Galili, 2010). Phylogenetic analysis of the CS genes reveals three major clades constituting of (i) AtCM2 clade, (ii) microphyte and bryophyte clade, and (iii) AtCM2 clade (Figure 2Ba). Additionally, clade iii shows two sub-groups, (iii-a) AtCM3 sub-groups and (iii-b) AtCM1 sub-group (Figure 2Ba) (Eberhard et al., 1996). In spite of that the CM2 sub-group contains all species of seed plants, monocot species are not contained into AtCM3 sub-group. Recently the importance of CM has been extended beyond intracellular metabolism, In Zea mays, the chorismate mutase Cmu1 secreted by Ustilago maydis, a widespread pathogen characterized by the development of large plant tumors and commonly known as smut, is a virulence factor. The uptake of the Ustilago CMu1 protein by plant cells allows rerouting of plant metabolism and changes the metabolic status of these cells via metabolic priming (Djamei et al., 2011). It now appears that secreted CMs are found in many plant-related microbes and this form of host manipulation would appear to be a general weapon in the arsenal of plant pathogens.

Prephenate Aminotransferase and Arogenate Dehydratase

Prephenate aminotransferase (PAT) and arogenate dehydratase (ADT) catalyze the final steps for production of phenylalanine. Whilst ADT was first cloned in 2007 (Cho et al., 2007; Huang et al., 2010), it is only more recently that PAT was cloned. Papers published in 2011 identified PAT in Petunia hybrid, Arabidopsis thaliana, and Solanum lycopersicum (Dal Cin et al., 2011; Maeda et al., 2011) and established that it directs carbon flux from prephenate to arogenate but also that it is strongly and co-ordinately upregulated with genes of primary metabolism and phenylalanine derived flavor volatiles. In plant species, a different number of PAT isoforms have been found. Although green algae only contain single PAT and ADT genes, monocot species have between one and two PATs and between two and four ADTs whilst dicot plants genomes contain the same number of PATs but two to eight ADTs (Table 2). Phylogenetic analysis of PAT genes shows three major clades of (i) microphyte, (ii) monocot, and (iii) dicot species (Figure 2Bb).

Genes Involved in Plant Phenolic Secondary Metabolisms

Phenolic secondary metabolism displays an immense chemical diversity due to the evolution of enzymatic genes which are involved in the various biosynthetic and decorative pathways. Such variation is caused by diversity and redundancy of several key genes of phenolic secondary metabolism such as PKSs, cytochrome P450s (CYPs), Fe2+/2-oxoglutarate-dependent dioxygenases (2ODDs), and UDP-glycosyltransferases (UGTs). On the other hand, there are other general phenylpropanoid related biosynthetic genes, phenylalanine ammonia-lyase (PAL), cinnamate 4-hydroxylase (C4H), and 4-coumarate:coenzyme A ligase (4CL), which are required in order to differentiate various classes of phenolic secondary metabolism. All of these core genes encode important enzymes which activate a number of hydroxycinnamic acids to provide precursors for the biosynthesis of lignins, monolignals, and indeed all other major phenolic secondary metabolites in higher plants (Lozoya et al., 1988; Allina et al., 1998; Hu et al., 1998; Ehlting et al., 1999; Lindermayr et al., 2002; Hamberger and Hahlbrock, 2004). Since phenolic secondary metabolism display considerable species-specificity, investigation of the genes encoding the responsible biosynthetic enzymes are frequently used as an example of chemotaxonomy for understanding plant evolution. However, considering the evolution of these genes in isolation is rather restrictive a deeper understanding is provided by combining this with investigation of the evolution of the shikimate-phenylalanine biosynthetic genes in the green lineage.

Conclusion

During the long evolutionary period covered from aquatic algae to land plants, plants have adapted to the environmental niches with the evolutionary strategies such as gene duplication and convergent evolution by the filtration of natural selection. Genes of plant shikimate biosynthesis have evolved accordingly (Figure 3). In this review, we demonstrated that biosynthetic genes of aromatic amino acid primary metabolism are well conserved between algae and all land plants. However, in contrast to algae species which have neither isoforms nor duplicated genes in their genomes, all land plants harbor gene duplications including tandem gene duplications which are particularly prominent in the cases of DAHPS, DHQD/SD, CS, CM, and ADT (Figure 3A; Table 2). Our phylogenetic analysis revealed clear separation between algae, monocots, dicots, woody species, and leguminous plants. Analysis of the presence and copy number of key genes across these species gives several hints as to how to improve our understanding of the scaffold from which these genes have evolved. However, the exact evolutionary pressures on genes of shikimate biosynthesis including the unique occurrence of the Arom complex will require considerable further studies. That said it is intriguing to compare and contrast biosynthetic genes of those downstream of them in the production of plant phenolics (Figure 3B). Interestingly, shikimate pathway genes are ubiquitous across the green lineage whilst this cannot be said for all downstream genes of phenylpropanoid biosynthesis. Furthermore, there is a much greater gene duplication within phenylpropanoid than shikimate biosynthesis (Figure 3A; Table 2). This fact also reflected in the level of chemical diversity of the respective pathways with the essentiality of the shikimate pathway preventing much diversity, but phenylpropanoid species often being redundant in function to one another. It would seem likely that the phenylpropanoid pathway initially arose via mutations accumulating in the shikimate pathway genes. However, whilst these were potentially beneficial in land plants for reasons we discuss in our recent review of these compounds (Tohge et al., 2013) they do not appear to share the essentiality of shikimate across the entire green lineage.

Figure 3.

Figure 3

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Heat map for isoforms of shikimate-phenylalanine biosynthetic genes in plant genomes and hypothetical scheme for the evolution of phenylalanine derived phenolic secondary metabolism. (A) Heap map overview of number of shikimate-phenylalanine biosynthetic gene isoforms in 25 species. (B) Hypothetical schematic figure for shikimate-phenylalanine biosynthetic genes and their evolution of phenolic secondary metabolism.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

Research activity of Takayuki Tohge is supported by the Alexander von Humboldt Foundation. Funding from the Max-Planck-Society (to Takayuki Tohge, Mutsumi Watanabe, Rainer Hoefgen, Alisdair R. Fernie) is gratefully acknowledged.

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