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Biosynthesis of Sesquiterpene Lactones in Plants and Metabolic Engineering for Their Biotechnological Production

  • María Perassolo
  • Alejandra Beatriz Cardillo
  • Víctor Daniel Busto
  • Ana María Giulietti
  • Julián Rodríguez Talou
Chapter

Abstract

In the present chapter, we review some aspects of the biosynthesis of sesquiterpene lactones and its regulation in different medicinal and aromatic plants used in the pharmaceutical industry. In this sense, we describe the mevalonate and the 2-C-methyl-D-erythritol 4-phosphate pathways, which generate the corresponding isoprenoid precursors (isopentenyl diphosphate and dimethylallyl diphosphate), as well as the late pathways that lead to sesquiterpene lactone biosynthesis. This chapter also analyses the role of the transcription factors involved in the regulation of sesquiterpene lactone biosynthesis and the different biotechnological approaches that have been developed for sesquiterpene lactone production. In vitro plant cell cultures (comprising micropropagation and plant cell suspension, shoot and root cultures) have emerged as a production platform for many plant secondary metabolites, since they allow their production under controlled conditions and shorter production cycles. The characterisation and isolation of genes involved in the regulation of sesquiterpene lactone biosynthetic pathways have allowed the design of metabolic engineering strategies to increase the production of these metabolites. Moreover, we discuss different strategies to increase sesquiterpene lactone production through genetic engineering. We also focus on the metabolic engineering of the artemisinin biosynthetic pathway in Artemisia annua. This metabolic pathway has become a model system not only for the biotechnological production of sesquiterpene lactones but also for the improvement of other plant secondary metabolic pathways. Finally, we analyse the successful expression of the complete artemisinin biosynthetic pathway in Escherichia coli and Saccharomyces cerevisiae, which has led to the efficient accumulation of artemisinic acid in these microorganisms.

Keywords

Sesquiterpene lactones Metabolic engineering Secondary metabolism Transcription factors Plant cell culture Artemisinin Yeast Escherichia coli 

Abbreviations

AA

Artemisinic acid

AACT

Acetoacetyl-CoA thiolase

ABA

Abscisic acid

ABREs

ABA-responsive elements

ADHI

Alcohol dehydrogenase 1

ADS

Amorpha-4,11-diene synthase

ALDH1

Aldehyde dehydrogenase

AOC

Allene oxide cyclase

AP2/ERF

APETALA2/ethylene response factor

atoB

Acetoacetyl-CoA thiolase gene

bgl1

β-Glucosidase gene

bZIP

Basic leucine zipper

CaMV35S

Cauliflower mosaic virus promoter

CDP-ME

4-Diphosphocytidyl-2-C-methyl-D-erythritol

CDP-ME2P

4-(Cytidine 5′-diphospho)-2-C-methyl-D-erythritol phosphate

CMK

CDP-ME kinase

COS

Costunolide synthase

CPR1

Cytochrome P450 reductase

CYB5

Cytochrome b5

CYP71AV1

Cytochrome P450 monooxygenase

DBR2

Artemisinic aldehyde Δ11 (13) reductase

DMAPP

Dimethylallyl diphosphate

DXR

1-Deoxy-D-xylulose 5-phosphate reductoisomerase

DXS

1-Deoxy-D-xylulose 5-phosphate synthase

EMSA

Electrophoretic mobility shift assay

ERG10

Acetoacetyl-CoA thiolase gene

ERG12

Mevalonate kinase

ERG13

HMG-CoA synthase

ERG20

Farnesyl diphosphate synthase gene

ERG8

Phosphomevalonate kinase

FDS

Farnesyl diphosphate synthase

FPP

Farnesyl diphosphate

FRET

Fluorescence resonance energy transfer

GA

Germacrene A

GA-3P

Glyceraldehyde-3-phosphate

GAA

4,11 (13)-Trien-12-oic acid

GAH

Germacrene A hydroxylase

GAO

Germacrene A oxidase

GAS

Germacrene A synthase

GMP

Good manufacturing practices

GSH

Glutathione

GST

Glandular secretory trichomes

GSW1

GLANDULAR TRICHOME-SPECIFIC WRKY 1

GUS

β-Glucuronidase reporter gene system

HDR

(E)-4-Hydroxy-3-methylbut-2-enyl diphosphate reductase

HDS

1-Hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase

HMBPP

(E)-4-Hydroxy-3-methylbut-2-enyl diphosphate

HMG-CoA

3-Hydroxy-3-methylglutaryl-CoA

HMGR

HMG-CoA reductase

HMGS

HMG-CoA synthase

IDI

Isopentenyl diphosphate isomerase

idi

Isopentenyl diphosphate isomerase gene

IPP

Isopentenyl diphosphate

ipt

Isopentenyl transferase gene

ispA

Farnesyl diphosphate synthase gene

Ja

Jasmonic acid

MAP

Medicinal and aromatic plants

MCT

2-C-Methyl-D-erythritol 4-phosphate cytidylyltransferase

MDS

2-C-Methyl-D-erythritol 2,4-cyclodiphosphate synthase

ME −2,4cPP

2-C-Methyl-D-erythritol 2,4-cyclodiphosphate

MeJ

Methyl jasmonate

MEP

2-C-Methyl-D-erythritol 4-phosphate

MEP

2-C-Methyl-D-erythritol 4-phosphate pathway

MSI

Mass spectrometry imaging

MVA

Mevalonate pathway

mvaA

HMG-CoA reductase gene

mvaS

HMG-CoA synthase gene

MVD

Mevalonate diphosphate decarboxylase

MVD1

Mevalonate diphosphate decarboxylase gene

MVDP

Mevalonate-5-diphosphate

MVK

Mevalonate kinase

MVP

Mevalonate-5-phosphate

PCC

Plant cell culture

PDR

Pleiotropic drug resistance

PMK

Phosphomevalonate kinase

PTS

Parthenolide synthase

PTS

Patchoulol synthase

RNAi

RNA interference

SA

Salicylic acid

SQS

Squalene synthase

SS

Santalene synthase

STLs

Sesquiterpene lactones

STPS

Sesquiterpene synthases

TAR1

TRICHOME AND ARTEMISININ REGULATOR 1

TFs

Transcription factors

tHMRG

Truncated HMG-CoA reductase

TP

Terpene synthase

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • María Perassolo
    • 1
    • 2
  • Alejandra Beatriz Cardillo
    • 1
    • 2
  • Víctor Daniel Busto
    • 1
    • 2
  • Ana María Giulietti
    • 2
  • Julián Rodríguez Talou
    • 1
    • 2
  1. 1.Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología y Biotecnología, Cátedra de BiotecnologíaBuenos AiresArgentina
  2. 2.CONICET-Universidad de Buenos Aires, Instituto de Nanobiotecnología (NANOBIOTEC)Buenos AiresArgentina

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