The potential of the mevalonate pathway for enhanced isoprenoid production.

The cytosol-localised mevalonic acid (MVA) pathway delivers the basic isoprene unit isopentenyl diphosphate (IPP). In higher plants, this central metabolic intermediate is also synthesised by the plastid-localised methylerythritol phosphate (MEP) pathway. Both MVA and MEP pathways conspire through exchange of intermediates and regulatory interactions. Products downstream of IPP such as phytosterols, carotenoids, vitamin E, artemisinin, tanshinone and paclitaxel demonstrate antioxidant, cholesterol-reducing, anti-ageing, anticancer, antimalarial, anti-inflammatory and antibacterial activities. Other isoprenoid precursors including isoprene, isoprenol, geraniol, farnesene and farnesol are economically valuable. An update on the MVA pathway and its interaction with the MEP pathway is presented, including the improvement in the production of phytosterols and other isoprenoid derivatives. Such attempts are for instance based on the bioengineering of microbes such as Escherichia coli and Saccharomyces cerevisiae, as well as plants. The function of relevant genes in the MVA pathway that can be utilised in metabolic engineering is reviewed and future perspectives are presented.

[1]  Nicholas W. Kwiecien,et al.  A role for the mevalonate pathway in early plant symbiotic signaling , 2015, Proceedings of the National Academy of Sciences.

[2]  Lydia Tabernero,et al.  Coenzyme a Reductases Class Ii 3-hydroxy-3-methylglutaryl , 2022 .

[3]  W. Eisenreich,et al.  Studies on the biosynthesis of taxol: the taxane carbon skeleton is not of mevalonoid origin. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Thevelein,et al.  Bioengineering of plant (tri)terpenoids: from metabolic engineering of plants to synthetic biology in vivo and in vitro. , 2013, The New phytologist.

[5]  H. Schaller,et al.  Overexpression of Arabidopsis thaliana farnesyl diphosphate synthase (FPS1S) in transgenic Arabidopsis induces a cell death/senescence-like response and reduced cytokinin levels. , 2002, The Plant journal : for cell and molecular biology.

[6]  G. Ruvkun,et al.  The mevalonate pathway regulates microRNA activity in Caenorhabditis elegans , 2012, Proceedings of the National Academy of Sciences.

[7]  C. Schwechheimer.  Gibberellin Signaling in Plants – The Extended Version , 2011, Front. Plant Sci..

[8]  J. Lenihan,et al.  Developing an industrial artemisinic acid fermentation process to support the cost‐effective production of antimalarial artemisinin‐based combination therapies , 2008, Biotechnology progress.

[9]  J. K. Kim,et al.  Enhanced accumulation of phytosterol and triterpene in hairy root cultures of Platycodon grandiflorum by overexpression of Panax ginseng 3-hydroxy-3-methylglutaryl-coenzyme A reductase. , 2013, Journal of agricultural and food chemistry.

[10]  P. Weathers,et al.  Evidence of artemisinin production from IPP stemming from both the mevalonate and the nonmevalonate pathways , 2007, Plant Cell Reports.

[11]  H. Chen,et al.  Tanshinone production in Ti-transformed Salvia miltiorrhiza cell suspension cultures. , 1997, Journal of biotechnology.

[12]  O. Voinnet,et al.  Isoprenoid biosynthesis is required for miRNA function and affects membrane association of ARGONAUTE 1 in Arabidopsis , 2012, Proceedings of the National Academy of Sciences.

[13]  B. M. Lange,et al.  Metabolic engineering of plant monoterpenes, sesquiterpenes and diterpenes--current status and future opportunities. , 2013, Plant biotechnology journal.

[14]  A. Boronat,et al.  Breaking new ground in the regulation of the early steps of plant isoprenoid biosynthesis. , 2015, Current opinion in plant biology.

[15]  Okamura Nobuyuki,et al.  Alkaloid Production by Hairy Root Cultures in Atropa belladonna , 1987 .

[16]  A. Hemmerlin.  Post-translational events and modifications regulating plant enzymes involved in isoprenoid precursor biosynthesis. , 2013, Plant science : an international journal of experimental plant biology.

[17]  M. Rodríguez-Concepcíon,et al.  Early Steps in Isoprenoid Biosynthesis: Multilevel Regulation of the Supply of Common Precursors in Plant Cells , 2006, Phytochemistry Reviews.

[18]  A. Fürholz,et al.  Crosstalk between cytosolic and plastidial pathways of isoprenoid biosynthesis in Arabidopsis thaliana , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  I. Chung,et al.  Production of β-carotene and acetate in recombinant Escherichia coli with or without mevalonate pathway at different culture temperature or pH , 2012, Biotechnology and Bioprocess Engineering.

[20]  Z. Deng,et al.  Targeted engineering and scale up of lycopene overproduction in Escherichia coli , 2015 .

[21]  G. Sandmann,et al.  Light-Stimulated Carotenoid Biosynthesis during Transformation of Maize Etioplasts Is Regulated by Increased Activity of Isopentenyl Pyrophosphate Isomerase , 1994, Plant physiology.

[22]  M. Mahfouz,et al.  RNA-guided transcriptional regulation in planta via synthetic dCas9-based transcription factors. , 2015, Plant biotechnology journal.

[23]  J. C. Salerno,et al.  Understanding the function of bacterial and eukaryotic thiolases II by integrating evolutionary and functional approaches. , 2014, Gene.

[24]  R. Verpoorte,et al.  Purification and characterization of mevalonate kinase from suspension-cultured cells of Catharanthus roseus (L.) G. Don. , 2000, Archives of biochemistry and biophysics.

[25]  Jianbo Xiao,et al.  Metabolic engineering tanshinone biosynthetic pathway in Salvia miltiorrhiza hairy root cultures. , 2011, Metabolic engineering.

[26]  M. Wüst,et al.  Methylerythritol and mevalonate pathway contributions to biosynthesis of mono-, sesqui-, and diterpenes in glandular trichomes and leaves of Stevia rebaudiana Bertoni. , 2014, Journal of agricultural and food chemistry.

[27]  E. Hinchliffe,et al.  Improving the nutritional value of Golden Rice through increased pro-vitamin A content , 2005, Nature Biotechnology.

[28]  Jay D Keasling,et al.  High‐level production of amorpha‐4,11‐diene in a two‐phase partitioning bioreactor of metabolically engineered Escherichia coli , 2006, Biotechnology and bioengineering.

[29]  N. Krinsky.  Antioxidant functions of carotenoids. , 1989, Free radical biology & medicine.

[30]  Sandrine Champenoy,et al.  Expression of the yeast mevalonate kinase gene in trangenic tobacco , 1998, Molecular Breeding.

[31]  G. Stephanopoulos,et al.  Selection and optimization of microbial hosts for biofuels production. , 2008, Metabolic engineering.

[32]  B. Pfeifer,et al.  Heterologous production of plant-derived isoprenoid products in microbes and the application of metabolic engineering and synthetic biology. , 2014, Current opinion in plant biology.

[33]  M. Schalk,et al.  Redirection of cytosolic or plastidic isoprenoid precursors elevates terpene production in plants , 2006, Nature Biotechnology.

[34]  A. Benabdelmouna,et al.  Pravastatin: A tool for investigating the availability of mevalonate metabolites for primary and secondary metabolism in Catharanthus roseus cell suspensions , 1996 .

[35]  R. Stroud,et al.  Domain structure of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a glycoprotein of the endoplasmic reticulum. , 1985, The Journal of biological chemistry.

[36]  B. M. Lange,et al.  Metabolic cross talk between cytosolic and plastidial pathways of isoprenoid biosynthesis: unidirectional transport of intermediates across the chloroplast envelope membrane. , 2003, Archives of biochemistry and biophysics.

[37]  Jean-Michel Ané,et al.  3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase1 Interacts with NORK and Is Crucial for Nodulation in Medicago truncatula , 2007, The Plant Cell Online.

[38]  T. Weber,et al.  Aspects related to mevalonate biosynthesis in plants , 1991, Lipids.

[39]  P. Beyer,et al.  Engineering the provitamin A (beta-carotene) biosynthetic pathway into (carotenoid-free) rice endosperm. , 2000, Science.

[40]  R. Verpoorte,et al.  Mevalonate kinase activity in Catharanthus roseus plants and suspension cultured cells , 2000 .

[41]  R. Brigelius-Flohé,et al.  Vitamin E: function and metabolism , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  H. Bouwmeester,et al.  Metabolic engineering of volatile isoprenoids in plants and microbes. , 2014, Plant, cell & environment.

[43]  M. Parrish,et al.  Identification of the sequences in HMG-CoA reductase required for karmellae assembly. , 1995, Molecular biology of the cell.

[44]  M. Brown,et al.  Regulation of cholesterol synthesis in rat adrenal gland through coordinate control of 3-hydroxy-3-methylglutaryl coenzyme A synthase and reductase activities. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Christopher D. Reeves,et al.  Microbial production of isoprenoids , 2011 .

[46]  Huizhong Wang,et al.  Deep Sequencing Identifies Tissue-Specific MicroRNAs and Their Target Genes Involving in the Biosynthesis of Tanshinones in Salvia miltiorrhiza , 2014, PloS one.

[47]  S. Matsuda,et al.  Metabolic engineering to produce sesquiterpenes in yeast. , 2003, Organic letters.

[48]  R. Safford,et al.  Co-expression of N-terminal truncated 3-hydroxy-3-methylglutaryl CoA reductase and C24-sterol methyltransferase type 1 in transgenic tobacco enhances carbon flux towards end-product sterols. , 2003, The Plant journal : for cell and molecular biology.

[49]  Long Liu,et al.  Toward metabolic engineering in the context of system biology and synthetic biology: advances and prospects , 2015, Applied Microbiology and Biotechnology.

[50]  Jay D. Keasling,et al.  Identification and microbial production of a terpene-based advanced biofuel , 2011, Nature communications.

[51]  Jiali Gu,et al.  Enhanced isoprene biosynthesis in Saccharomyces cerevisiae by engineering of the native acetyl-CoA and mevalonic acid pathways with a push-pull-restrain strategy. , 2014, Journal of biotechnology.

[52]  Xiaomei Lv,et al.  Sequential control of biosynthetic pathways for balanced utilization of metabolic intermediates in Saccharomyces cerevisiae. , 2015, Metabolic engineering.

[53]  Xueli Zhang,et al.  Production of miltiradiene by metabolically engineered Saccharomyces cerevisiae , 2012, Biotechnology and bioengineering.

[54]  Edward Baidoo,et al.  A kinetic‐based approach to understanding heterologous mevalonate pathway function in E. coli , 2015, Biotechnology and bioengineering.

[55]  J. Gershenzon,et al.  The Arabidopsis thaliana Type I Isopentenyl Diphosphate Isomerases Are Targeted to Multiple Subcellular Compartments and Have Overlapping Functions in Isoprenoid Biosynthesis[W] , 2008, The Plant Cell Online.

[56]  Jay D. Keasling,et al.  Production of amorphadiene in yeast, and its conversion to dihydroartemisinic acid, precursor to the antimalarial agent artemisinin , 2012, Proceedings of the National Academy of Sciences.

[57]  A. Aharoni,et al.  Metabolic Engineering of Terpenoid Biosynthesis in Plants , 2006, Phytochemistry Reviews.

[58]  J. Keasling,et al.  Correlation analysis of targeted proteins and metabolites to assess and engineer microbial isopentenol production , 2014, Biotechnology and bioengineering.

[59]  Y. Kamiya,et al.  GIBBERELLIN BIOSYNTHESIS: Enzymes, Genes and Their Regulation. , 1997, Annual review of plant physiology and plant molecular biology.

[60]  A. Hemmerlin,et al.  Brassica juncea HMG-CoA synthase: localization of mRNA and protein , 2005, Planta.

[61]  Jay D Keasling,et al.  Farnesol production from Escherichia coli by harnessing the exogenous mevalonate pathway , 2010, Biotechnology and bioengineering.

[62]  S. Vermeulen,et al.  Breeding Technologies to Increase Crop Production in a Changing World , 2010 .

[63]  Yanning Zheng,et al.  Bio-isoprene production using exogenous MVA pathway and isoprene synthase in Escherichia coli. , 2012, Bioresource technology.

[64]  Y. Kamiya,et al.  Contribution of the Mevalonate and Methylerythritol Phosphate Pathways to the Biosynthesis of Gibberellins inArabidopsis * , 2002, The Journal of Biological Chemistry.

[65]  H. Xue,et al.  CRISPR Primer Designer: Design primers for knockout and chromosome imaging CRISPR-Cas system. , 2015, Journal of integrative plant biology.

[66]  Dana J Morrone,et al.  Increasing diterpene yield with a modular metabolic engineering system in E. coli: comparison of MEV and MEP isoprenoid precursor pathway engineering , 2009, Applied Microbiology and Biotechnology.

[67]  J. Gershenzon,et al.  Both methylerythritol phosphate and mevalonate pathways contribute to biosynthesis of each of the major isoprenoid classes in young cotton seedlings. , 2014, Phytochemistry.

[68]  D. Bosch,et al.  Nicotiana benthamiana as a Production Platform for Artemisinin Precursors , 2010, PloS one.

[69]  D. Lowy,et al.  Inhibition of cell growth by lovastatin is independent of ras function. , 1991, Cancer research.

[70]  D. Weiss,et al.  Cytokinin Regulates Compound Leaf Development in Tomato[C][W] , 2010, Plant Cell.

[71]  Jay D Keasling,et al.  Enhanced lycopene production in Escherichia coli engineered to synthesize isopentenyl diphosphate and dimethylallyl diphosphate from mevalonate , 2006, Biotechnology and bioengineering.

[72]  J. Keasling.  Synthetic biology and the development of tools for metabolic engineering. , 2012, Metabolic engineering.

[73]  Seon-Won Kim,et al.  Engineering Escherichia coli for selective geraniol production with minimized endogenous dehydrogenation. , 2014, Journal of biotechnology.

[74]  Dirk Inzé,et al.  Plant cell factories in the post-genomic era: new ways to produce designer secondary metabolites. , 2004, Trends in plant science.

[75]  Karl G. Kugler,et al.  Brassinosteroids Are Master Regulators of Gibberellin Biosynthesis in Arabidopsis , 2015, Plant Cell.

[76]  J. Gershenzon,et al.  Protective perfumes: the role of vegetative volatiles in plant defense against herbivores. , 2009, Current opinion in plant biology.

[77]  T. Sun,et al.  Brassinosteroid, gibberellin, and phytochrome impinge on a common transcription module in Arabidopsis , 2012, Nature Cell Biology.

[78]  N. Sirinupong,et al.  Regulation of 3-Hydroxy-3-Methylglutaryl-CoA Synthase and 3-Hydroxy-3-Methylglutaryl-CoA Reductase and Rubber Biosynthesis of Hevea brasiliensis (B.H.K.) Mull. Arg , 2012 .

[79]  Tiangang Liu,et al.  In vitro reconstitution of mevalonate pathway and targeted engineering of farnesene overproduction in Escherichia coli , 2014, Biotechnology and bioengineering.

[80]  T. Bach.  Hydroxymethylglutaryl-CoA reductase, a key enzyme in phytosterol synthesis? , 2006, Lipids.

[81]  H. Puchta,et al.  The CRISPR/Cas system can be used as nuclease for in planta gene targeting and as paired nickases for directed mutagenesis in Arabidopsis resulting in heritable progeny. , 2014, The Plant journal : for cell and molecular biology.

[82]  A. Boronat,et al.  Targeting and topology in the membrane of plant 3-hydroxy-3-methylglutaryl coenzyme A reductase. , 1995, The Plant cell.

[83]  Regine Eibl,et al.  Growth and Ginsenoside Production in Hairy Root Cultures of Panax ginseng using a Novel Bioreactor , 2003, Planta medica.

[84]  J. Keasling,et al.  Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development , 2014, Nature Reviews Microbiology.

[85]  Huanan Jin.  Genetic, biochemical and physiological studies of acetyl-CoA metabolism via acyl-condensation , 2010 .

[86]  J. Tramper,et al.  Growth and thiophene production by hairy root cultures of Tagetes patula in various two-liquid-phase bioreactors. , 1991 .

[87]  K. Yoneyama,et al.  The strigolactone story. , 2010, Annual review of phytopathology.

[88]  Characterisation of the gene family encoding acetoacetyl-CoA thiolase in Arabidopsis. , 2008, Functional plant biology : FPB.

[89]  W. Maltese.  Posttranslational modification of proteins by isoprenoids in mammalian cells , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[90]  H. Rudney,et al.  The biosynthesis of beta-hydroxy-beta-methylglutaryl coenzyme A in yeast. I. Identification and purification of the hydroxymethylglutaryl coenzymecondensing enzyme. , 1959, The Journal of biological chemistry.

[91]  M. Koffas,et al.  Metabolic engineering for plant natural product biosynthesis in microbes. , 2008, Current opinion in biotechnology.

[92]  Qianfeng Li,et al.  An Interaction Between BZR1 and DELLAs Mediates Direct Signaling Crosstalk Between Brassinosteroids and Gibberellins in Arabidopsis , 2012, Science Signaling.

[93]  P. Gantet,et al.  Regulation of the terpene moiety biosynthesis of Catharanthus roseus terpene indole alkaloids , 2007, Phytochemistry Reviews.

[94]  H. Miziorko,et al.  Biochemical and structural basis for feedback inhibition of mevalonate kinase and isoprenoid metabolism. , 2008, Biochemistry.

[95]  S. Ishiguro,et al.  The Arabidopsis FLAKY POLLEN1 gene encodes a 3-hydroxy-3-methylglutaryl-coenzyme A synthase required for development of tapetum-specific organelles and fertility of pollen grains. , 2010, Plant & cell physiology.

[96]  Timothy S. Ham,et al.  Production of the antimalarial drug precursor artemisinic acid in engineered yeast , 2006, Nature.

[97]  J. Keasling,et al.  Remodeling the isoprenoid pathway in tobacco by expressing the cytoplasmic mevalonate pathway in chloroplasts. , 2012, Metabolic engineering.

[98]  Jay D Keasling,et al.  Combinatorial expression of bacterial whole mevalonate pathway for the production of beta-carotene in E. coli. , 2009, Journal of biotechnology.

[99]  Hongwei Yu,et al.  Construction of lycopene-overproducing Saccharomyces cerevisiae by combining directed evolution and metabolic engineering. , 2015, Metabolic engineering.

[100]  W. Eisenreich,et al.  Metabolic cross-talk between pathways of terpenoid backbone biosynthesis in spike lavender. , 2015, Plant physiology and biochemistry : PPB.

[101]  R. Schmidt,et al.  Evidence for post-translational incorporation of a product of mevalonic acid into Swiss 3T3 cell proteins. , 1984, The Journal of biological chemistry.

[102]  M. Rohmer.  The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants. , 1999, Natural product reports.

[103]  Stephen H. Bell,et al.  Metabolic engineering of higher plants and algae for isoprenoid production. , 2015, Advances in biochemical engineering/biotechnology.

[104]  David Eisenberg,et al.  A synthetic biochemistry system for the in vitro production of isoprene from glycolysis intermediates , 2014, Protein science : a publication of the Protein Society.

[105]  M. Hartmann,et al.  The Plastidial 2-C-Methyl-d-Erythritol 4-Phosphate Pathway Provides the Isoprenyl Moiety for Protein Geranylgeranylation in Tobacco BY-2 Cells[C][W] , 2009, The Plant Cell Online.

[106]  C. Reuzeau,et al.  Boosting Crop Yields with Plant Steroids[W] , 2012, Plant Cell.

[107]  Seon-Won Kim,et al.  Geranyl diphosphate synthase: an important regulation point in balancing a recombinant monoterpene pathway in Escherichia coli. , 2015, Enzyme and microbial technology.

[108]  Metabolic Engineering of Microorganisms for Isoprenoid Production , 2008 .

[109]  Bin Jia,et al.  Engineered biosynthesis of natural products in heterologous hosts. , 2015, Chemical Society reviews.

[110]  Jay D Keasling,et al.  Increased β‐Carotene Production in Recombinant Escherichia coli Harboring an Engineered Isoprenoid Precursor Pathway with Mevalonate Addition , 2008, Biotechnology progress.

[111]  Brian F. Pfleger,et al.  Application of Functional Genomics to Pathway Optimization for Increased Isoprenoid Production , 2008, Applied and Environmental Microbiology.

[112]  M. Rodríguez-Concepcíon,et al.  Distinct Light-Mediated Pathways Regulate the Biosynthesis and Exchange of Isoprenoid Precursors during Arabidopsis Seedling Development Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.016204. , 2004, The Plant Cell Online.

[113]  S. Fujioka,et al.  Sterols Regulate Development and Gene Expression in Arabidopsis1 , 2003, Plant Physiology.

[114]  Jay D Keasling,et al.  Balancing a heterologous mevalonate pathway for improved isoprenoid production in Escherichia coli. , 2007, Metabolic engineering.

[115]  Wei Liu,et al.  Enhancing Production of Bio-Isoprene Using Hybrid MVA Pathway and Isoprene Synthase in E. coli , 2012, PloS one.

[116]  R. Safford,et al.  Enhancement of seed phytosterol levels by expression of an N-terminal truncated Hevea brasiliensis (rubber tree) 3-hydroxy-3-methylglutaryl-CoA reductase. , 2003, Plant biotechnology journal.

[117]  Luis H. Reyes,et al.  Improving carotenoids production in yeast via adaptive laboratory evolution. , 2014, Metabolic engineering.

[118]  J. Gray,et al.  The inhibition of plant mevalonate kinase preparations by prenyl pyrophosphates. , 1972, Biochimica et biophysica acta.

[119]  Eui-Sung Choi,et al.  Metabolic engineering of Escherichia coli for α-farnesene production. , 2011, Metabolic engineering.

[120]  Jay D. Keasling,et al.  High-Level Production of Amorpha-4,11-Diene, a Precursor of the Antimalarial Agent Artemisinin, in Escherichia coli , 2009, PloS one.

[121]  D. L. Klayman,et al.  Qinghaosu (artemisinin): an antimalarial drug from China , 1985 .

[122]  W. Eisenreich,et al.  Quantitative assessment of crosstalk between the two isoprenoid biosynthesis pathways in plants by NMR spectroscopy , 2004, Phytochemistry Reviews.

[123]  Y. Kamiya,et al.  Agrobacterium tumefaciens increases cytokinin production in plastids by modifying the biosynthetic pathway in the host plant. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[124]  Neil K Garg,et al.  Synthetic chemistry fuels interdisciplinary approaches to the production of artemisinin. , 2015, Natural product reports.

[125]  Jens Nielsen,et al.  Enhancement of farnesyl diphosphate pool as direct precursor of sesquiterpenes through metabolic engineering of the mevalonate pathway in Saccharomyces cerevisiae , 2010, Biotechnology and bioengineering.

[126]  I. Ivshina,et al.  Bacterial transformation of terpenoids , 2014 .

[127]  J. Keasling,et al.  Synthetic Pathway for Production of Five-Carbon Alcohols from Isopentenyl Diphosphate , 2012, Applied and Environmental Microbiology.

[128]  J. Schnitzler,et al.  Biochemical properties of isoprene synthase in poplar (Populus × canescens) , 2005, Planta.

[129]  O. Borsani,et al.  The SUD1 Gene Encodes a Putative E3 Ubiquitin Ligase and Is a Positive Regulator of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity in Arabidopsis[C][W] , 2013, Plant Cell.

[130]  A. Hemmerlin,et al.  Cross-talk between the Cytosolic Mevalonate and the Plastidial Methylerythritol Phosphate Pathways in Tobacco Bright Yellow-2 Cells* , 2003, Journal of Biological Chemistry.

[131]  R. Rawat,et al.  Overexpression of Brassica juncea wild-type and mutant HMG-CoA synthase 1 in Arabidopsis up-regulates genes in sterol biosynthesis and enhances sterol production and stress tolerance. , 2012, Plant biotechnology journal.

[132]  K. Tang,et al.  Transgenic approach to increase artemisinin content in Artemisia annua L. , 2014, Plant Cell Reports.

[133]  P. Gantet,et al.  CaaX-prenyltransferases are essential for expression of genes involvedin the early stages of monoterpenoid biosynthetic pathwayin Catharanthus roseus cells , 2005, Plant Molecular Biology.

[134]  P. Bradford,et al.  Phytosterols as anticancer compounds. , 2007, Molecular nutrition & food research.

[135]  T. Woyengo,et al.  Anticancer effects of phytosterols , 2009, European Journal of Clinical Nutrition.

[136]  A. Aharoni,et al.  Gain and Loss of Fruit Flavor Compounds Produced by Wild and Cultivated Strawberry Species , 2004, The Plant Cell Online.

[137]  I. Chung,et al.  Production of β-carotene by recombinant Escherichia coli with engineered whole mevalonate pathway in batch and fed-batch cultures , 2009 .

[138]  Robert Gray,et al.  Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. , 2006, The New England journal of medicine.

[139]  C. López-Iglesias,et al.  Proliferation and Morphogenesis of the Endoplasmic Reticulum Driven by the Membrane Domain of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Plant Cells1[OPEN] , 2015, Plant Physiology.

[140]  F. Lynen.  Biosynthetic pathways from acetate to natural products , 1967, Pure and applied chemistry. Chimie pure et appliquee.

[141]  M. Chye,et al.  Brassica juncea 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase 1: expression and characterization of recombinant wild-type and mutant enzymes. , 2004, The Biochemical journal.

[142]  N. Misawa,et al.  Novel approach in the biosynthesis of functional carotenoids in Escherichia coli. , 2012, Methods in molecular biology.

[143]  S. Bouzid,et al.  Peroxisomal localisation of the final steps of the mevalonic acid pathway in planta , 2011, Planta.

[144]  J. Shanks,et al.  Effect of Elicitor Dosage and Exposure Time on Biosynthesis of Indole Alkaloids by Catharanthus roseus Hairy Root Cultures , 1998, Biotechnology progress.

[145]  John R. Haliburton,et al.  Optimization of a heterologous mevalonate pathway through the use of variant HMG-CoA reductases. , 2011, Metabolic engineering.

[146]  T. Bach,et al.  Occurrence of Two Acetoacetyl-Coenzyme A Thiolases with Distinct Expression Patterns and Subcellular Localization in Tobacco , 2012 .

[147]  K. B. Hicks,et al.  Phytosterols, phytostanols, and their conjugates in foods: structural diversity, quantitative analysis, and health-promoting uses. , 2002, Progress in lipid research.

[148]  G. Robinson,et al.  Cloning and characterization of ERG8, an essential gene of Saccharomyces cerevisiae that encodes phosphomevalonate kinase , 1991, Molecular and cellular biology.

[149]  K. Korth,et al.  Regulation of HMG-CoA reductase activity in plants. , 1994, Journal of lipid research.

[150]  J. Noel,et al.  Orthologs of the archaeal isopentenyl phosphate kinase regulate terpenoid production in plants , 2015, Proceedings of the National Academy of Sciences.

[151]  Deok-Chun Yang,et al.  Functional Analysis of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Encoding Genes in Triterpene Saponin-Producing Ginseng1[C][W] , 2014, Plant Physiology.

[152]  K. Hoyerová,et al.  Overexpression of Farnesyl Diphosphate Synthase in Arabidopsis Mitochondria Triggers Light-dependent Lesion Formation and Alters Cytokinin Homeostasis , 2006, Plant Molecular Biology.

[153]  Q. Qian,et al.  Brassinosteroid Regulates Cell Elongation by Modulating Gibberellin Metabolism in Rice[C][W][OPEN] , 2014, Plant Cell.

[154]  Jay D Keasling,et al.  Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid , 2008, BMC biotechnology.

[155]  I. Arrillaga,et al.  Up-regulation of an N-terminal truncated 3-hydroxy-3-methylglutaryl CoA reductase enhances production of essential oils and sterols in transgenic Lavandula latifolia. , 2007, Plant biotechnology journal.

[156]  N. Chua,et al.  Expression of the Hevea brasiliensis (H.B.K.) Mull. Arg. 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase 1 in Tobacco Results in Sterol Overproduction , 1995, Plant physiology.

[157]  E. Sakuradani,et al.  Overexpression of the gene encoding HMG-CoA reductase in Saccharomyces cerevisiae for production of prenyl alcohols , 2009, Applied Microbiology and Biotechnology.

[158]  Natalia Dudareva,et al.  Biosynthesis, function and metabolic engineering of plant volatile organic compounds. , 2013, The New phytologist.

[159]  G. Glevarec,et al.  A single gene encodes isopentenyl diphosphate isomerase isoforms targeted to plastids, mitochondria and peroxisomes in Catharanthus roseus , 2012, Plant Molecular Biology.

[160]  Anis Mohd,et al.  Enhancement of artemisinin content by constitutive expression of the HMG-CoA reductase gene in high-yielding strain of Artemisia annua L. , 2010, Plant Biotechnology Reports.

[161]  B. Demmig‐Adams,et al.  The role of xanthophyll cycle carotenoids in the protection of photosynthesis , 1996 .

[162]  J. Keasling,et al.  Recent applications of synthetic biology tools for yeast metabolic engineering. , 2014, FEMS yeast research.

[163]  T. Bach,et al.  Expression of Brassica juncea 3-hydroxy-3-methylglutaryl CoA synthase is developmentally regulated and stress-responsive. , 2000, The Plant journal : for cell and molecular biology.

[164]  S. Pastorino,et al.  In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells , 2014, British Journal of Cancer.

[165]  Wei Gao,et al.  Modular pathway engineering of diterpenoid synthases and the mevalonic acid pathway for miltiradiene production. , 2012, Journal of the American Chemical Society.

[166]  J. Keasling.  Manufacturing Molecules Through Metabolic Engineering , 2010, Science.

[167]  T. Weber,et al.  Some Properties of Enzymes Involved in the Biosynthesis and Metabolism of 3-Hydroxy-3-Methylglutaryl-CoA in Plants , 1990 .

[168]  B. M. Lange,et al.  Comprehensive Assessment of Transcriptional Regulation Facilitates Metabolic Engineering of Isoprenoid Accumulation in Arabidopsis1[OPEN] , 2015, Plant Physiology.

[169]  E. Nevoigt,et al.  Progress in Metabolic Engineering of Saccharomyces cerevisiae , 2008, Microbiology and Molecular Biology Reviews.

[170]  S. Potlakayala,et al.  Metabolic engineering of chloroplasts for artemisinic acid biosynthesis and impact on plant growth , 2014, Journal of Biosciences.

[171]  A. Hemmerlin,et al.  Past achievements, current status and future perspectives of studies on 3-hydroxy-3-methylglutaryl-CoA synthase (HMGS) in the mevalonate (MVA) pathway , 2014, Plant Cell Reports.

[172]  Wei Liu,et al.  Metabolic engineering of Escherichia coli for high-specificity production of isoprenol and prenol as next generation of biofuels , 2013, Biotechnology for Biofuels.

[173]  David E. García.  The in vitro characterization of heterologously expressed enzymes to inform in vivo biofuel production optimization , 2013 .

[174]  S. Howell,et al.  Cytokinins and shoot development. , 2003, Trends in plant science.

[175]  R. Backhaus,et al.  Molecular cloning of geranyl diphosphate synthase and compartmentation of monoterpene synthesis in plant cells. , 2000, The Plant journal : for cell and molecular biology.

[176]  T. Dairi,et al.  Heterologous Mevalonate Production in Streptomyces lividans TK23 , 2004, Bioscience, biotechnology, and biochemistry.

[177]  J. Goldstein,et al.  Regulation of the mevalonate pathway , 1990, Nature.

[178]  S. Ceci,et al.  National hiring experiments reveal 2:1 faculty preference for women on STEM tenure track , 2015, Proceedings of the National Academy of Sciences.

[179]  D. Gidoni,et al.  Peroxisomal Localization of Arabidopsis Isopentenyl Diphosphate Isomerases Suggests That Part of the Plant Isoprenoid Mevalonic Acid Pathway Is Compartmentalized to Peroxisomes1[W] , 2008, Plant Physiology.

[180]  J. Porter,et al.  The inhibition of mevalonic kinase by geranyl and farnesyl pyrophosphates. , 1968, The Journal of biological chemistry.

[181]  T. Bach,et al.  Two Radish Genes for 3-Hydroxy-3-Methylglutaryl-CoA Reductase Isozymes Complement Mevalonate Auxotrophy in a Yeast Mutant and Yield Membrane-Bound Active Enzyme , 1994 .

[182]  R. Dixon,et al.  Polyisoprenylation of Ras in vitro by a farnesyl-protein transferase. , 1990, Journal of Biological Chemistry.

[183]  J. Keasling,et al.  Kinetics of Phosphomevalonate Kinase from Saccharomyces cerevisiae , 2014, PloS one.

[184]  H. Rudney,et al.  The reduction of beta-hydroxy-beta-methyl-glutaryl coenzyme A to mevalonic acid. , 1960, The Journal of biological chemistry.

[185]  J. Harwood,et al.  A raison d'être for two distinct pathways in the early steps of plant isoprenoid biosynthesis? , 2012, Progress in lipid research.

[186]  L. Blanchard,et al.  Sterol pathway in yeast. Identification and properties of mutant strains defective in mevalonate diphosphate decarboxylase and farnesyl diphosphate synthetase , 1991, Lipids.

[187]  H. Schaller,et al.  The metabolic imbalance underlying lesion formation in Arabidopsis thaliana overexpressing farnesyl diphosphate synthase (isoform 1S) leads to oxidative stress and is triggered by the developmental decline of endogenous HMGR activity , 2004, Planta.

[188]  Li Liu,et al.  Both the mevalonate and the non-mevalonate pathways are involved in ginsenoside biosynthesis , 2014, Plant Cell Reports.

[189]  Jianbo Xiao,et al.  Increased accumulation of the cardio-cerebrovascular disease treatment drug tanshinone in Salvia miltiorrhiza hairy roots by the enzymes 3-hydroxy-3-methylglutaryl CoA reductase and 1-deoxy-d-xylulose 5-phosphate reductoisomerase , 2014, Functional & Integrative Genomics.

[190]  J. Chory,et al.  A Role for Brassinosteroids in Light-Dependent Development of Arabidopsis , 1996, Science.

[191]  K. Shanker,et al.  Sterol partitioning by HMGR and DXR for routing intermediates toward withanolide biosynthesis. , 2014, Physiologia plantarum.

[192]  K. Alleva,et al.  Acetoacetyl-CoA thiolase regulates the mevalonate pathway during abiotic stress adaptation. , 2011, Journal of experimental botany.

[193]  G. Oldroyd.  Speak, friend, and enter: signalling systems that promote beneficial symbiotic associations in plants , 2013, Nature Reviews Microbiology.

[194]  R. Finkelstein,et al.  Abscisic Acid Signaling in Seeds and Seedlings Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.010441. , 2002, The Plant Cell Online.

[195]  R. Cuellar,et al.  Is the Reaction Catalyzed by 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase a Rate-Limiting Step for Isoprenoid Biosynthesis in Plants? , 1995, Plant physiology.

[196]  M. Thurnher,et al.  Mevalonate metabolism in cancer. , 2015, Cancer letters.

[197]  R. Hampton,et al.  Effects of overproduction of the catalytic domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase on squalene synthesis in Saccharomyces cerevisiae , 1997, Applied and environmental microbiology.

[198]  Wenyu Lu,et al.  Insight into yeast: A study model of lipid metabolism and terpenoid biosynthesis , 2015, Biotechnology and applied biochemistry.

[199]  J. Keasling,et al.  High-level semi-synthetic production of the potent antimalarial artemisinin , 2013, Nature.

[200]  E. Vranová,et al.  Network analysis of the MVA and MEP pathways for isoprenoid synthesis. , 2013, Annual review of plant biology.

[201]  J. Keasling,et al.  Engineering a mevalonate pathway in Escherichia coli for production of terpenoids , 2003, Nature Biotechnology.

[202]  E. Pichersky,et al.  Cytosolic monoterpene biosynthesis is supported by plastid-generated geranyl diphosphate substrate in transgenic tomato fruits. , 2013, The Plant journal : for cell and molecular biology.

[203]  P. Fraser,et al.  Metabolic Engineering of the Mevalonate and Non-Mevalonate Pathways in Tomato , 2003 .

[204]  N. Nagata,et al.  Mevalonic acid partially restores chloroplast and etioplast development in Arabidopsis lacking the non-mevalonate pathway , 2002, Planta.

[205]  R. Verpoorte,et al.  Isopentenyl diphosphate isomerase: a core enzyme in isoprenoid biosynthesis. A review of its biochemistry and function. , 1997, Natural product reports.

[206]  M. Abbas,et al.  Molecular mechanism for the interaction between gibberellin and brassinosteroid signaling pathways in Arabidopsis , 2012, Proceedings of the National Academy of Sciences.

[207]  S. Hashimoto,et al.  Production of mevalonate by a metabolically-engineered Escherichia coli , 2004, Biotechnology Letters.

[208]  J. Görlach,et al.  Plastidic Isoprenoid Synthesis during Chloroplast Development : Change from Metabolic Autonomy to a Division-of-Labor Stage. , 1990, Plant physiology.

[209]  I. Weinstein,et al.  Effects of mevinolin and mevalonate on cell growth in several transformed cell lines , 1986, Journal of cellular physiology.

[210]  Steffen Klamt,et al.  In silico profiling of Escherichia coli and Saccharomyces cerevisiae as terpenoid factories , 2013, Microbial Cell Factories.

[211]  Zhihong Song,et al.  Reverse genetic characterization of two paralogous acetoacetyl CoA thiolase genes in Arabidopsis reveals their importance in plant growth and development. , 2012, The Plant journal : for cell and molecular biology.

[212]  M. Zhang,et al.  Dolichol Biosynthesis and Its Effects on the Unfolded Protein Response and Abiotic Stress Resistance in Arabidopsis[W][OA] , 2008, The Plant Cell Online.

[213]  C. Duan,et al.  Enhancement of β-Carotene Production by Over-Expression of HMG-CoA Reductase Coupled with Addition of Ergosterol Biosynthesis Inhibitors in Recombinant Saccharomyces cerevisiae , 2011, Current Microbiology.

[214]  M. Abdin,et al.  Over-expression of HMG-CoA reductase and amorpha-4,11-diene synthase genes in Artemisia annua L. and its influence on artemisinin content , 2011, Plant Cell Reports.

[215]  Hitoshi Sakakibara,et al.  Distinct Isoprenoid Origins of cis- and trans-Zeatin Biosyntheses in Arabidopsis* , 2004, Journal of Biological Chemistry.

[216]  P. Stewart,et al.  The Biosynthesis of β-Hydroxy-β-methylglutaryl Coenzyme A in Yeast IV. THE ORIGIN OF THE THIOESTER BOND OF β-HYDROXY-β-METHYLGLUTARYL COENZYME A , 1966 .

[217]  B. M. Lange,et al.  Biosynthesis and Biotechnology of High-Value p-Menthane Monoterpenes, Including Menthol, Carvone, and Limonene. , 2015, Advances in biochemical engineering/biotechnology.

[218]  Jay D Keasling,et al.  Metabolic engineering of microorganisms for isoprenoid production. , 2008, Natural product reports.

[219]  J. Gershenzon,et al.  Artemisinin biosynthesis in growing plants of Artemisia annua. A 13CO2 study. , 2010, Phytochemistry.

[220]  A. Cyr,et al.  A modular approach for facile biosynthesis of labdane-related diterpenes. , 2007, Journal of the American Chemical Society.

[221]  F. Ouyang,et al.  Production of artemisinin by hairy root cultures of Artemisia annua L , 1997, Biotechnology Letters.

[222]  H. Rudney,et al.  The biosynthesis of beta-hydroxy-beta-methylglutaryl coenzyme A in yeast. II. The formation of hydroxymethylglutaryl coenzyme A via the condensation of acetyl coenzyme A and acetoacetyl coenzyme A. , 1959, The Journal of biological chemistry.

[223]  J. Keasling,et al.  Targeted proteomics for metabolic pathway optimization: application to terpene production. , 2011, Metabolic engineering.

[224]  E. Grotewold,et al.  Metabolic engineering to enhance the value of plants as green factories. , 2015, Metabolic engineering.

[225]  M. Raizada,et al.  Chemical inhibitors suggest endophytic fungal paclitaxel is derived from both mevalonate and non-mevalonate-like pathways. , 2011, Journal of natural products.

[226]  A. Hemmerlin,et al.  S-Carvone Suppresses Cellulase-Induced Capsidiol Production in Nicotiana tabacum by Interfering with Protein Isoprenylation1[C][W] , 2013, Plant Physiology.

[227]  Kazuki Saito,et al.  Triterpenoid Biosynthesis and Engineering in Plants , 2011, Front. Plant Sci..

[228]  A. Aharoni,et al.  Terpenoid Metabolism in Wild-Type and Transgenic Arabidopsis Plants Online version contains Web-only data. Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.016253. , 2003, The Plant Cell Online.

[229]  Xueli Zhang,et al.  Yeast synthetic biology for high-value metabolites. , 2014, FEMS yeast research.

[230]  Jay D Keasling,et al.  Optimization of the mevalonate-based isoprenoid biosynthetic pathway in Escherichia coli for production of the anti-malarial drug precursor amorpha-4,11-diene. , 2009, Metabolic engineering.

[231]  Jing Wang,et al.  High-Level Production of Beta-Carotene in Saccharomyces cerevisiae by Successive Transformation with Carotenogenic Genes from Xanthophyllomyces dendrorhous , 2007, Applied and Environmental Microbiology.

[232]  H. Kawaide,et al.  Genetic evidence for the role of isopentenyl diphosphate isomerases in the mevalonate pathway and plant development in Arabidopsis. , 2008, Plant & cell physiology.

[233]  A. Bhangu-Uhlmann.  The mevalonate pathway , 2011 .

[234]  M. Chye,et al.  Transgenic Tobacco Overexpressing Brassica juncea HMG-CoA Synthase 1 Shows Increased Plant Growth, Pod Size and Seed Yield , 2014, PloS one.