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



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.


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



Artemisinic acid


Acetoacetyl-CoA thiolase


Abscisic acid


ABA-responsive elements


Alcohol dehydrogenase 1


Amorpha-4,11-diene synthase


Aldehyde dehydrogenase


Allene oxide cyclase


APETALA2/ethylene response factor


Acetoacetyl-CoA thiolase gene


β-Glucosidase gene


Basic leucine zipper


Cauliflower mosaic virus promoter




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


CDP-ME kinase


Costunolide synthase


Cytochrome P450 reductase


Cytochrome b5


Cytochrome P450 monooxygenase


Artemisinic aldehyde Δ11 (13) reductase


Dimethylallyl diphosphate


1-Deoxy-D-xylulose 5-phosphate reductoisomerase


1-Deoxy-D-xylulose 5-phosphate synthase


Electrophoretic mobility shift assay


Acetoacetyl-CoA thiolase gene


Mevalonate kinase


HMG-CoA synthase


Farnesyl diphosphate synthase gene


Phosphomevalonate kinase


Farnesyl diphosphate synthase


Farnesyl diphosphate


Fluorescence resonance energy transfer


Germacrene A




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


Germacrene A hydroxylase


Germacrene A oxidase


Germacrene A synthase


Good manufacturing practices




Glandular secretory trichomes




β-Glucuronidase reporter gene system


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


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


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




HMG-CoA reductase


HMG-CoA synthase


Isopentenyl diphosphate isomerase


Isopentenyl diphosphate isomerase gene


Isopentenyl diphosphate


Isopentenyl transferase gene


Farnesyl diphosphate synthase gene


Jasmonic acid


Medicinal and aromatic plants


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


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

ME −2,4cPP

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


Methyl jasmonate


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


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


Mass spectrometry imaging


Mevalonate pathway


HMG-CoA reductase gene


HMG-CoA synthase gene


Mevalonate diphosphate decarboxylase


Mevalonate diphosphate decarboxylase gene




Mevalonate kinase




Plant cell culture


Pleiotropic drug resistance


Phosphomevalonate kinase


Parthenolide synthase


Patchoulol synthase


RNA interference


Salicylic acid


Squalene synthase


Santalene synthase


Sesquiterpene lactones


Sesquiterpene synthases




Transcription factors


Truncated HMG-CoA reductase


Terpene synthase


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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  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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