• Embed Doc
  • Readcast
  • Collections
  • CommentGo Back
Download
 
Engineering tocopherol biosynthetic pathway in
Arabidopsis
leaves and itseffect on antioxidant metabolism
Yin Li
a
, Yin Zhou
a
, Zinan Wang
a
, Xiaofen Sun
a
, Kexuan Tang
a,b,
*
a
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan-SJTU-Nottingham Plant Biotechnology R&D Center, Fudan University, Shanghai 200433, PR China
b
Plant Biotechnology Research Center, School of Agriculture and Biology, Fudan-SJTU-Nottingham Plant Biotechnology R&D Center,Shanghai Jiao Tong University, Shanghai 200030, PR China
1. Introduction
Vitamin E is an essential nutrient of daily diet for humans andanimals. Naturally occurring vitamin E exists in eight chemicalforms (
a
-,
b
-,
g
-, and
d
-tocopherol and
a
-,
b
-,
g
-, and
d
-tocotrienol) that have varying levels of biological activity. Thenutritional values of vitamin E were affirmed in 1922[1]. TheNational Institutes of Health (NIH) currently suggests a recom-mended daily allowance (RDA) of 15–19 mg
a
-tocopherol foradults (http://ods.od.nih.gov/factsheets/vitamine.asp). Higherdai-lyvitaminEdoseshavebeenneededforcancerreduction,immuneresponse, and cardiovascular benefits[2]. Among the family,
a
-tocopherol is believed to have the highest vitamin E activity tomeet human requirements, and it is preferentially retained anddistributed throughout the body[3]. Naturally synthesized
a
-tocopherol, which is a single (
R
,
R
,
R
) stereoisomer, has moreactivity than chemically synthesized
a
-tocopherol[4].Tocopherols can be synthesized only in photoautotrophyorganisms, including plants and other oxygenic, photosyntheticorganisms. Although the tocopherol biosynthetic pathway hadbeenelucidatedfrom1979[5],thegeneticanalysisofthepathwayand key enzymes had only commenced since 1990s, with theapproaches of genetic and genomics-based methodologies in themodel organisms
Arabidopsis thaliana
and
Synechocystis
sp.PCC6803.Tocopherolbiosynthesismainlytakesplaceinplastidsofhigherplants. The tocopherol biosynthetic pathway utilizes two com-pounds from different metabolic pathways as precursors, whichincludehomogentisicacid(HGA),derivedfromcytosolicshikimatemetabolic pathway for head group and phytyldiphosphate (PDP)[6]from the plastidic methylerythritol phosphate (MEP) pathwayfor tail synthesis[7,8](Fig. 1). There are at least five enzymes involved in the biosynthesis of tocopherols, excluding the bypasspathway of phytyl-tail synthesis and utilization (Table 1). HGA is
Plant Science 178 (2010) 312–320
A R T I C L E I N F O
 Article history:
Received 24 November 2009
Received in revised form 17 January 2010
Accepted 19 January 2010
Available online 28 January 2010
Keywords: Arabidopsis thaliana
Biosynthetic pathwayHalliwell–Asada cycleOver-expressionTocopherolVitamin E
A B S T R A C T
With genetic manipulation, five genes (
HPPD
,
VTE2
,
VTE3
,
VTE1
, and
VTE4
), which encode enzymesinvolved in tocopherol biosynthesis, were over-expressed in model plant
Arabidopsis thaliana
, eitheralone or in couple combinations (
VTE2
+
VTE4
and
VTE3
+
VTE4
), to value and compare the roles of enzymes played in tocopherol biosynthetic pathway under the same genetic background. Our resultssuggested that, elevated expression level of biosynthetic pathway gene affected either total tocopherolcontent or composition, it is recommended to choose two or more enzymes with different functions forgenetic manipulation. It was also found that metabolic engineering of tocopherol biosynthetic pathwayaffected endogenous ascorbate and glutathione pools in leaves. Further study suggested that expressionlevels of genes encoding enzymes of Halliwell–Asada cycle were up-regulated, such as
APX 
,
DHAR
and
MDAR
.Thesefindingsprovidehintsontherelationshipoflipid-solubleantioxidantvitaminEandwater-solubleantioxidantsvitaminCandglutathione,whichwillhelptoperfecttheoryinplantphysiologyandgive practical instruction for metabolic engineering.
ß
2010 Elsevier Ireland Ltd. All rights reserved.
 Abbreviations:
APX, ascorbic acid peroxidase; AsA, ascorbic acid (vitamin C); DHA,dehydroascorbic acid; DHAR, dehydroascorbic acid reductase; GDPME, GDP-
D
-mannose-3, 5-epimerase; GDPMPPase, GDP-
D
-mannose pyrophosphorylase; GSH,glutathione; GSSG, oxidized glutathione; HGA, homogentisic acid; HPLC, highperformance liquid chromatography; HPPD,
p
-hydroxyphenylpyruvic acid dioxy-genase;
-GalDH,
-galactose dehydrogenase;
-GalPPase,
-galactose 1-P phospha-tase;
-GLDH,
-galactono-
g
-lactone dehydrogenase; MDAR, monodehydroascorbicacid; MEP, methylerythritol phosphate; NC, non-transgenic control; PDP, phytyl-diphosphate; PQ8, plastochromanol-8; PUFAs, protect polyunsaturated fatty acidchains; RDA, recommended daily allowance; ROS, reactive oxygen species; VTC2,GDP-
-galactose phosphorylase; VTE1, tocopherol cyclase; VTE2, homogentisatephytyltransferase; VTE3, 2-methyl-6-phytylplastoquinol methyltransferases;VTE4,
g
-tocopherol methyltransferase.* Correspondingauthorat:StateKeyLaboratoryofGeneticEngineering,Schoolof Life Sciences, Fudan-SJTU-Nottingham Plant Biotechnology R&D Center, FudanUniversity, 220 Handan Road, Shanghai 200433, PR China.
E-mail addresses:
Contents lists available atScienceDirect
Plant Science
journal homepage: www.elsevier.com/locate/plantsci
0168-9452/$ – see front matter
ß
2010 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.plantsci.2010.01.004
 
produced from the tyrosine aromatic amino acid catabolite
p
-hydroxyphenylpyruvate (HPP) by the cytosolic enzyme 4-hydro-xyphenylpyruvate dioxygenase (HPPD)[9]. Condensation of HGAand PDP is catalyzed by homogentisate phytyltransferases (VTE2)[10]. The product of this reaction, 2-methyl-6-phytylbenzoquinol(MPBQ), is the first phytylquinol intermediate in the pathway andcan be methylated to 2,3-dimethyl-6-phytyl-1, 4-benzoquinol(DMPBQ)byMPBQmethyltransferase(VTE3)[11].BothMPBQandDMPBQ are substrates for tocopherol cyclase (VTE1) to yield thefirst tocopherols of the pathway,
d
-tocopherol and
g
-tocopherol,respectively[12]. Both
d
- and
g
-tocopherol can be methylated by
g
-tocopherol methyltransferase (VTE4) to yield
b
- and
a
-tocopherol, respectively[13].As a member of plant secondary metabolites, vitamin E hasvariousbiologicalandpharmaceuticalfunctionstohumansaswellas to plants. Crops and vegetables are the best source for naturalvitamin E. Nevertheless, vitamin E is of low content, and thecomposition of the eight forms needs to optimize. Recently,metabolic engineering has beenwidely applied in order to achievehigher yields of specific metabolites. The in-depth understandingof biosynthetic pathways, along with the increasing number of cloned genes involved in biosynthesis, enable the exploration of metabolicengineeringasapotentialeffectiveapproachtoincreasethe yield of specific metabolites by enhancing rate-limiting stepsor by blocking competitive pathways[14]. Increasing vitamin Econtentand
a
-tocopherolcompositioninvegetablesandcropshasbeen an important aim for metabolic engineering. Strategies as toover-expressingdifferentgenesinvolvedinthepathwayhavebeenemployed. Although significant work has been done[15], it is stillhard to assess the relative importance of each enzyme intocopherol biosynthetic pathway, due to different genetic back-groundandvariousmanipulationusedinformerstudies.Valuationof the contribution of different enzymes under the same geneticbackground will be essential to provide effective strategies forlarge-scale commercial production of biosynthetic tocopherol. Inthis work, genes encoding these enzymes were cloned from themodelplant
 A.thaliana
andconstitutivelyover-expressed,aloneorin combination, in order to achieve this assessment.In metabolic engineering, when target nutritional product isincreasing, other related nutritional products in the samebioreactor might be affected, in some cases they would decrease.Many studies reported the antioxidant properties of tocopherols,such as photo protection and reduction of lipid peroxidation byreducing lipid peroxyl radicals to their corresponding hydroper-oxides[16,17,18]. As lipid-soluble antioxidant, tocopherols locatemainlyonmembranesofmanycellularcompartments,andwillbeoxidized to tocopherol radical[19]. There are two importantwater-solubleantioxidantsinplantcells—ascorbicacid(vitaminC,AsA)andglutathione(GSH),andtheycanscavengereactiveoxygenspecies by Halliwell–Asada cycle during normal metabolism andparticularly during stress[20]. Especially vitamin C is not only animportant antioxidant in plant physiology, but also a metabolicproduct with important nutritional and physiological values forhumans and animals. Former works indicated there might berelationship existing among tocopherol, AsA and glutathionecontents[21,22]. It was reported[22]that deficiency in one antioxidant in tocopherol, AsA or glutathione led to increasedoxidative stress and the concomitant increase in alternativeantioxidants. In some other cases, such as sunflower cell lines,high content of tocopherols leads to higher content levels of ascorbateand glutathionepools[21].However,inthe studywhichobserved the plant responses to oxidant stress in the presence of Cu or Cd[23], the correlation between high tocopherol and lowascorbate/glutathione levels was not seen.In this study AsA and glutathione contents in transgenic linesover-expressing tocopherol biosynthetic pathway genes wereanalyzed in order to assess whether accumulation of vitamin Eaffected other antioxidants in plant. Furthermore, some studieswere done in order to explain the change of vitamin C andglutathione in transgenic lines.
2. Materials and methods
 2.1. Plant materials and growth conditions
Seeds of wild-type
Arabidopsis
(Columbia ecotype) weresterilized with chlorox and spread on Murashige and Skoog(1962) plates, then treated at 4
8
C for 3–5 days and induced forgermination in 24 h-white-light for 6 days. Then the seedlingswere transferred into soil at 20
8
C under 16-h photoperiod of lightat 120
m
mol m
À
2
s
À
1
.
 2.2. cDNA generation and vector construction
For construction of plant expression vectors,
myc 
tag was usedas screening labels and sub-cloned into
Xho
I and
Pst 
I sites of pBluescript SK+ vector (pBS; Stratagene) to form the vectorpBSmyc (a gift from Prof. Hongquan Yang, SIPPE, CAS). Total RNAwas isolated from leaves of 
Arabidopsis thaliana
(Columbiaecotype) by using TRIzol reagent (GIBCO/BRL). The cDNAs of 
 Table 1
Enzymes, basic functions, loci and genes encoding tocopherol biosynthetic enzymes in
Arabidopsis thaliana
.Pathway enzyme Basic function
Arabidopsis
Gene Locus
 p
-Hydroxyphenylpyruvic acid dioxygenase (HPPD) Head group synthesis
PDS1
At1g06570Homogentisate prenyltransferase (HPT) Prenylation of HGA
VTE2
At2g189502-Methyl-6-phytylbenzoquinone methyltransferase (MPBQ MT) Methylation of MPBQ and MGGBQ 
VTE3
At3g63410Tocopherol cyclase (TC) Cyclization
VTE1
At4g32770
g
-Tocopherol methyltransferase (
g
-TMT) Methylation o
d
- and
g
-tocopherol
VTE4
At1g64970
Fig. 1.
Simplified tocopherol biosynthetic pathway from shikimate and MEPpathways.
Y. Li et al./Plant Science 178 (2010) 312–320
313
 
 At-HPPD
,
VTE2
,
VTE3
,
VTE1
, and
VTE4
(Genbank accession Nos.AY072329,AY089963,AB054257,NM119430andAF104220)wereprepared by using TaKaRa One Step RT-PCR kit (Code No.:DRR024A, TaKaRa, Japan). The amplified cDNA fragments of 
At-HPPD
,
VTE2
,
VTE3
, and
VTE1
with an introduced
Hin
dIII site at thestart codon (ATG) and an introduced
Bam
HI site before the stopcodon were digested, and sub-cloned into
Hin
dIII–
Bam
HI site of vector pBSmyc to obtain the expression cassette with recombina-tion sequence of target gene and
myc 
. The amplified fragment of 
VTE4
with an introduced
Xho
I site at the start codon and anintroduced
Bam
HI site before the stop codon was digested, andsub-cloned into
Xho
I–
Bam
HI site of pBSmyc. The reading frame of pBS-target gene–
myc 
was confirmed to be correct by sequencingfrombothstrands.Therecombinantsequencesoftargetgene–
myc 
wereintroducedintopET28avectorandover-expressedin
E.coli
inorder to detect biological activity of fusing proteins
in vitro
. Therecombinant sequences of target gene–
myc 
were sub-cloned intothe botany expression vector PHB (a gift from Prof. HongquanYang, SIPPE, CAS)[24], located downstream of double 35S CaMVpromoters and upstream of rbcS polyA terminator (Fig. 2A).In order to explore the function of two enzymes in planttocopherol biosynthetic pathway, three of them were chosen fordual expression vector construction. Two co-expression combina-tions were designed:
VTE2
+
VTE4
and
VTE3
+
VTE4
. The targetgeneswerealsorecombinantwith
myc 
.Inordertoputtwogenesinonevector,theexpressioncassetteofvectorpBI121(Clontech)wasdigested with
Hin
dIII and
Eco
RI, and then sub-cloned into the
Hin
dIII–
Eco
RI site of pCAMBIA1304 vector to construct the co-expression vector.
VTE4
myc 
fraction was sub-cloned into
Xba
I–
Sac 
Isite,while
VTE2
myc 
and
VTE3–myc 
fragmentwereclonedinto
Bgl
II–
Bst 
EII site, respectively (Fig. 2B).[The primers used for cloning were listed inSupplement Table2].
 2.3. Transformation and screening of transgenic plants
The binary vector PHB contains hygromycin resistant gene andanti-herbicide gene (BAR) inside the T-DNA for the selection of transformants. The PHB:target gene constructs were transformedinto
Agrobacterium tumefaciens
C58C1 (pGV3101; rifampicinresistance) and the floral-dip method was used for
Arabidopsis
transformation[25]. The plants harboring empty plant expressionvector were used as non-transgenic control (NC). T
0
seeds werescreened on Murashige–Skoog (MS) basal medium supplementedwith 50
m
g mL 
À
1
hygromycin. More than fifty independent linesexpressingtransgeneweretransferredtosoilandscreenedwith1%herbicide (glufosinate-ammonium). Screening of T
1
and T
2
seedswere performed with herbicide in order to obtain transgenic lineswhich accorded with Mendel’s Law. Polymerase chain reaction(PCR) and protein gel blot analysis were also performed onindependent transgenic lines (random chosen) of each generation,inordertofurtherconfirmandcheckthehomozygosisandgeneticstability. Homozygous seeds could be obtained in T
4
generation.The screening of co-expression transgenic plants was performedwith PCR and western blot analysis, while herbicide could not beused because anti-herbicide gene was not contained in the binaryvectors.
 2.4. Molecular analysis of transgenic lines
Genomic DNA was isolated from the transgenic plants and NCplant with a CTAB method[26]. The presence of the transgene wasdetected by PCR.Proteingelblotanalysiswasperformedasdescribedpreviouslywith minor modifications[27]. Fifty
m
g of total protein, deter-mined by using the DC Protein Assay Kit (Bio-Rad, Hercules, CA),was fractionated on 12% SDS-PAGE mini-gel and blotted onto anitrocellulose membrane (PerkinElmer, 0.45
m
m). The blots wereprobed with the primary antibody c-Myc (9E10) (sc-40, mousemonoclonal IgG1, Santa Cruz Biotechnology) [diluted in PBST(80 mmol L 
À
1
Na
2
HPO
4
, 20 mmol
À
1
NaH
2
PO
4
, 100 mmol
À
1
NaCl, and 0.1% Tween 20)], washed with PBST three times, reactedwith goat anti-mouse IgG-AP (sc-2047, Santa Cruz Biotechnology),washed, and exposed with alkali phosphatase for 3 min.
 2.5. Real-time PCR
Total RNA was isolated and genomic DNA was removed bytreatment with RQ1-RNase free DNase (Promega, Madison, WI).One microgram of total RNA was reverse transcribed to generatecDNAin20
m
LreactionsforeachsampleusingaToyoboReverTra-Plus-Kit according to manufacturer’s recommendations (Toyobo,Osaka, Japan). An aliquot of cDNA corresponding to 10 pg – 10 ngtotal RNA was used in each real-time PCR assay (SYBR 
1
ExScriptRT-PCR Kit, TaKaRa, Shiga, Japan). Ubiquitin RNA was used tonormalize RNA concentrations. Standard curves were constructed
Fig. 2.
Schematic representation of the transformation vector construct used in this study. (A) Schematic representation of the single-gene transformation vector. (B)Schematic representation of dual-gene transformation vector. LB, left border; RB, right border; 35S, cauliflower mosaic virus 35S promoter; 35S polyA, cauliflower mosaicvirus 35S polyA terminator; Nos, nopaline synthase gene terminator.
Y. Li et al./Plant Science 178 (2010) 312–320
314
of 00

Leave a Comment

You must be to leave a comment.
Submit
Characters: ...
You must be to leave a comment.
Submit
Characters: ...