Engineering biosynthesis of high-value compounds in photosynthetic organisms

Critical Reviews in Biotechnology

Volumn 37, Issue 6, 2017, Pages 779-802

  O’Neill, Ellis C ^a   Kelly, Steven ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

algae; genetic modification; metabolic engineering; natural products; plants; secondary metabolites; Synthetic biology

Indexed keywords

ALGAE; BIOCHEMISTRY; BIOLOGY; BIOMOLECULES; BIOSYNTHESIS; CHEMICAL CONTAMINATION; GENE EXPRESSION; GENETIC ENGINEERING; GENETICALLY MODIFIED PLANTS; INDUSTRIAL CHEMICALS; METABOLIC ENGINEERING; METABOLISM; METABOLITES; MOLECULAR BIOLOGY; PHYSIOLOGY; PLANTS (BOTANY);

GENETIC MODIFICATIONS; NATURAL PRODUCTS; PLANTS; SECONDARY METABOLITES; SYNTHETIC BIOLOGY;

INDUSTRIAL PLANTS;

ALKALOID DERIVATIVE; ALPHA TOCOPHEROL; ANTHOCYANIN; ASCORBIC ACID; BENZYLISOQUINOLINE DERIVATIVE; CARBOHYDRATE; CARBOHYDRATE DERIVATIVE; COSMETIC; CYANOGENIC GLUCOSIDE; DITERPENE; FOLIC ACID; GLUCOSINOLATE; HYDROGEN; INDOLE ALKALOID; INDUSTRIAL CHEMICAL; LONG CHAIN FATTY ACID; MINERAL; PLANT PROTEIN; PODOPHYLLOTOXIN DERIVATIVE; POLYUNSATURATED FATTY ACID; PURINE DERIVATIVE; RETINOL; SESQUITERPENE DERIVATIVE; SHORT CHAIN FATTY ACID; TERPENE DERIVATIVE; TERPENOID DERIVATIVE; TRITERPENE DERIVATIVE; TROPANE ALKALOID; UNCLASSIFIED DRUG;

ALGA; BIOSYNTHESIS; BIOTECHNOLOGICAL PRODUCTION; CELL COMPOSITION; CELL WALL; DNA MODIFICATION; FATTY ACID ANALYSIS; GENETIC ENGINEERING; LIPID COMPOSITION; METABOLIC ENGINEERING; NONHUMAN; NUTRITIONAL VALUE; ORGANISMS BY PHOTOSYNTHETIC PATHWAY; PLANT CELL; PLANT METABOLISM; PRIORITY JOURNAL; REVIEW; STORAGE; SYNTHETIC BIOLOGY; BIOTECHNOLOGY; PHOTOSYNTHESIS; PLANT; SACCHAROMYCES CEREVISIAE;

BIOTECHNOLOGY; GENETIC ENGINEERING; METABOLIC ENGINEERING; PHOTOSYNTHESIS; PLANTS; SACCHAROMYCES CEREVISIAE;

EID: 84990194896     PISSN: 07388551     EISSN: 15497801     Source Type: Journal    
DOI: 10.1080/07388551.2016.1237467     Document Type: Review

References (183)

1. Borodina I, Nielsen J., Advances in metabolic engineering of yeast Saccharomyces cerevisiae for production of chemicals. Biotechnol J. 2014;9:609–620.
2. Leonard E, Runguphan W, O'Connor S, et al. Opportunities in metabolic engineering to facilitate scalable alkaloid production. Nat Chem Biol. 2009;5:292–300.
3. Patron NJ, Orzaez D, Marillonnet S, et al. Standards for plant synthetic biology:a common syntax for exchange of DNA parts. New Phytol. 2015;208:13–19.
4. Scaife MA, Nguyen GTDT, Rico J, et al. Establishing Chlamydomonas reinhardtii as an industrial biotechnology host. Plant J. 2015;82:532–546.
5. Ort DR, Merchant SS, Alric J, et al. Redesigning photosynthesis to sustainably meet global food and bioenergy demand. Proc Natl Acad Sci USA. 2015;112:8529–8536.
6. Diouf J., FAO's Director-General on how to feed the world in 2050. Popul Dev Rev. 2009;35:837–839.
7. Jobling S., Improving starch for food and industrial applications. Curr Opin Plant Biol. 2004;7:210–218.
8. O'Neill EC, Field RA., Underpinning starch biology with in vitro studies on carbohydrate-active enzymes and biosynthetic glycomaterials. Front Bioeng Biotechnol. 2015;3:136.
9. Jobling SA, Westcott RJ, Tayal A, et al. Production of a freeze-thaw-stable potato starch by antisense inhibition of three starch synthase genes. Nat Biotechnol. 2002;20:295–299.
10. Visser RGF, Somhorst I, Kuipers GJ, et al. Inhibition of the expression of the gene for granule-bound starch synthase in potato by antisense constructs. Mol Gen Genet. 1991;225:289–296.
11. Lorberth R, Ritte G, Willmitzer L, et al. Inhibition of a starch-granule-bound protein leads to modified starch and repression of cold sweetening. Nat Biotechnol. 1998;16:473–477.
12. Dauvillée D, Delhaye S, Gruyer S, et al. Engineering the chloroplast targeted malarial vaccine antigens in Chlamydomonas starch granules. PLoS One. 2010;5:e15424.
13. Vijn I, Van Dijken A, Sprenger N, et al. Fructan of the inulin neoseries is synthesized in transgenic chicory plants (Cichorium intybus L.) harbouring onion (Allium cepa L.) fructan:fructan 6G-fructosyltransferase. Plant J. 1997;11:387–398.
14. Sevenier R, Hall RD, van der Meer IM, et al. High level fructan accumulation in a transgenic sugar beet. Nat Biotechnol. 1998;16:843–846.
15. Hellwege EM, Czapla S, Jahnke A, et al. Transgenic potato (Solanum tuberosum) tubers synthesize the full spectrum of inulin molecules naturally occurring in globe artichoke (Cynara scolymus) roots. Proc Natl Acad Sci USA. 2000;97:8699–8704.
16. Furtado A, Lupoi JS, Hoang NV, et al. Modifying plants for biofuel and biomaterial production. Plant Biotechnol J. 2014;12:1246–1258.
17. Loqué D, Scheller HV, Pauly M., Engineering of plant cell walls for enhanced biofuel production. Curr Opin Plant Biol. 2015;25:151–161.
18. Jung YH, Cho HJ, Lee J-S, et al. Evaluation of a transgenic poplar as a potential biomass crop for biofuel production. Bioresour Technol. 2013;129:639–641.
19. Yang F, Mitra P, Zhang L, et al. Engineering secondary cell wall deposition in plants. Plant Biotechnol J. 2013;11:325–335.
20. Maloney VJ, Mansfield SD., Characterization and varied expression of a membrane-bound endo-beta-1,4-glucanase in hybrid poplar. Plant Biotechnol J. 2010;8:294–307.
21. Borkhardt B, Harholt J, Ulvskov P, et al. Autohydrolysis of plant xylans by apoplastic expression of thermophilic bacterial endo-xylanases. Plant Biotechnol J. 2010;8:363–374.
22. Wilkerson CG, Mansfield SD, Lu F, et al. Monolignol ferulate transferase introduces chemically labile linkages into the lignin backbone. Science. 2014;344:90–93.
23. Buanafina MMdO, Langdon T, Hauck B, et al. Targeting expression of a fungal ferulic acid esterase to the apoplast, endoplasmic reticulum or golgi can disrupt feruloylation of the growing cell wall and increase the biodegradability of tall fescue (Festuca arundinacea). Plant Biotechnol J. 2010;8:316–331.
24. Zhao Q, Dixon RA., Altering the cell wall and its impact on plant disease:from forage to bioenergy. Annu Rev Phytopathol. 2014;52:69–91.
25. Meyer BJ., Are we consuming enough long chain omega-3 polyunsaturated fatty acids for optimal health?. Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA). 2011;85:275–280.
26. Lu X., A perspective:Photosynthetic production of fatty acid-based biofuels in genetically engineered cyanobacteria. Biotechnol Adv. 2010;28:742–746.
27. Blatti JL, Michaud J, Burkart MD., Engineering fatty acid biosynthesis in microalgae for sustainable biodiesel. Curr Opin Chem Biol. 2013;17:496–505.
28. Thelen JJ, Ohlrogge JB., Metabolic engineering of fatty acid biosynthesis in plants. Metab Eng. 2002;4:12–21.
29. Bellou S, Triantaphyllidou I-E, Aggeli D, et al. Microbial oils as food additives:recent approaches for improving microbial oil production and its polyunsaturated fatty acid content. Curr Opin Biotechnol. 2016;37:24–35.
30. Niu Y-F, Zhang M-H, Li D-W, et al. Improvement of neutral lipid and polyunsaturated fatty acid biosynthesis by overexpressing a type 2 diacylglycerol acyltransferase in marine diatom Phaeodactylum tricornutum. Mar Drugs. 2013;11:4558–4569.
31. Trentacoste EM, Shrestha RP, Smith SR, et al. Metabolic engineering of lipid catabolism increases microalgal lipid accumulation without compromising growth. Proc Natl Acad Sci USA. 2013;110:19748–19753.
32. Liu X, Sheng J, Curtiss R., III, Fatty acid production in genetically modified cyanobacteria. Proc Natl Acad Sci USA. 2011;108:6899–6904.
33. Xu C, Shanklin J., Triacylglycerol metabolism, function, and accumulation in plant vegetative tissues. Annu Rev Plant Biol. 2016;67:179–206.
34. Vanhercke T, Petrie JR, Singh SP., Energy densification in vegetative biomass through metabolic engineering. Biocat Agri Biotechnol. 2014;3:75–80.
35. Andrianov V, Borisjuk N, Pogrebnyak N, et al. Tobacco as a production platform for biofuel:overexpression of Arabidopsis DGAT and LEC2 genes increases accumulation and shifts the composition of lipids in green biomass. Plant Biotechnol J. 2010;8:277–287.
36. Sanjaya Durrett TP, Weise SE, et al. Increasing the energy density of vegetative tissues by diverting carbon from starch to oil biosynthesis in transgenic Arabidopsis. Plant Biotechnol J. 2011;9:874–883.
37. Fan J, Yan C, Zhang X, et al. Dual role for phospholipid:diacylglycerol acyltransferase:enhancing fatty acid synthesis and diverting fatty acids from membrane lipids to triacylglycerol in arabidopsis leaves. The Plant Cell. 2013;25:3506–3518.
38. Vanhercke T, El Tahchy A, Liu Q, et al. Metabolic engineering of biomass for high energy density:oilseed-like triacylglycerol yields from plant leaves. Plant Biotechnol J. 2014;12:231–239.
39. Voelker TA, Worrell AC, Anderson L, et al. Fatty acid biosynthesis redirected to medium chains in transgenic oilseed plants. Science. 1992;257:72–74.
40. Radakovits R, Eduafo PM, Posewitz MC., Genetic engineering of fatty acid chain length in Phaeodactylum tricornutum. Metab Eng. 2011;13:89–95.
41. Surette ME., Dietary omega-3 PUFA and health:stearidonic acid-containing seed oils as effective and sustainable alternatives to traditional marine oils. Mol Nutr Food Res. 2013;57:748–759.
42. Chen G, Qu S, Wang Q, et al. Transgenic expression of delta-6 and delta-15 fatty acid desaturases enhances omega-3 polyunsaturated fatty acid accumulation in Synechocystis sp. PCC6803. Biotechnology for Biofuels. 2014;7:32.
43. Hamilton ML, Haslam RP, Napier JA, et al. Metabolic engineering of Phaeodactylum tricornutum for the enhanced accumulation of omega-3 long chain polyunsaturated fatty acids. Metab Eng. 2014;22:3–9.
44. Ruiz-Lopez N, Usher S, Sayanova O, et al. Modifying the lipid content and composition of plant seeds:engineering the production of LC-PUFA. Appl Microbiol Biotechnol. 2015;99:143–154.
45. Domergue F, Abbadi A, Ott C, et al. Acyl carriers used as substrates by the desaturases and elongases involved in very long-chain polyunsaturated fatty acids biosynthesis reconstituted in yeast. J Biol Chem. 2003;278:35115–35126.
46. Qi B, Fraser T, Mugford S, et al. Production of very long chain polyunsaturated omega-3 and omega-6 fatty acids in plants. Nat. Biotechnol. 2004;22:739–745.
47. Bates PD, Stymne S, Ohlrogge J., Biochemical pathways in seed oil synthesis. Curr Opin Plant Biol. 2013;16:358–364.
48. Ruiz-Lopez N, Haslam RP, Napier JA, et al. Successful high-level accumulation of fish oil omega-3 long-chain polyunsaturated fatty acids in a transgenic oilseed crop. Plant J. 2014;77:198–208.
49. Ding B-J, Hofvander P, Wang H-L, et al. A plant factory for moth pheromone production. Nat Commun. 2014;5:3353.
50. Scott J, Rébeillé F, Fletcher J., Folic acid and folates:the feasibility for nutritional enhancement in plant foods. J Sci Food Agric. 2000;80:795–824.
51. de la Garza RD, Quinlivan EP, Klaus SMJ, et al. Folate biofortification in tomatoes by engineering the pteridine branch of folate synthesis. Proc Natl Acad Sci USA. 2004;101:13720–13725.
52. Díaz de la Garza RI, Gregory JF, Hanson AD., Folate biofortification of tomato fruit. Proc Natl Acad Sci USA. 2007;104:4218–4222.
53. Apel W, Bock R., Enhancement of carotenoid biosynthesis in transplastomic tomatoes by induced lycopene-to-provitamin A conversion. Plant Physiol. 2009;151:59–66.
54. Ye X, Al-Babili S, Klöti A, et al. Engineering the provitamin A (beta-carotene) biosynthetic pathway into (carotenoid-free) rice endosperm. Science. 2000;287:303–305.
55. Paine JA, Shipton CA, Chaggar S, et al. Improving the nutritional value of Golden Rice through increased pro-vitamin A content. Nat Biotechnol. 2005;23:482–487.
56. Diretto G, Al-Babili S, Tavazza R, et al. Metabolic engineering of potato carotenoid content through tuber-specific overexpression of a bacterial mini-pathway. PLoS One. 2007;2:e350.
57. Munne-Bosch S, Alegre L., The function of tocopherols and tocotrienols in plants. Crit Rev Plant Sci. 2002;21:31–57.
58. Shintani D, DellaPenna D., Elevating the vitamin E content of plants through metabolic engineering. Science. 1998;282:2098–2100.
59. Lu Y, Rijzaani H, Karcher D, et al. Efficient metabolic pathway engineering in transgenic tobacco and tomato plastids with synthetic multigene operons. Proc Natl Acad Sci USA. 2013;110:E623–E632.
60. Noctor G, Foyer CH., Ascorbate and glutathione:keeping active oxygen under control. Annu Rev Plant Physiol Plant Mol Biol. 1998;49:249–279.
61. Jain A, Nessler C., Metabolic engineering of an alternative pathway for ascorbic acid biosynthesis in plants. Mol Breed. 2000;6:73–78.
62. Agius F, Gonzalez-Lamothe R, Caballero JL, et al. Engineering increased vitamin C levels in plants by overexpression of a D-galacturonic acid reductase. Nat Biotechnol. 2003;21:177–181.
63. Bulley S, Wright M, Rommens C, et al. Enhancing ascorbate in fruits and tubers through over-expression of the l-galactose pathway gene GDP-l-galactose phosphorylase. Plant Biotechnol J. 2012;10:390–397.
64. Naqvi S, Zhu C, Farre G, et al. Transgenic multivitamin corn through biofortification of endosperm with three vitamins representing three distinct metabolic pathways. Proc Natl Acad Sci USA. 2009;106:7762–7767.
65. Vasconcelos M, Datta K, Oliva N, et al. Enhanced iron and zinc accumulation in transgenic rice with the ferritin gene. Plant Sci. 2003;164:371–378.
66. Borg S, Brinch-Pedersen H, Tauris B, et al. Wheat ferritins:improving the iron content of the wheat grain. J Cereal Sci. 2012;56:204–213.
67. Lucca P, Hurrell R, Potrykus I., Fighting iron deficiency anemia with iron-rich rice. J Am Coll Nutr. 2002;21:184S–190S.
68. Lee S, An G., Over-expression of OsIRT1 leads to increased iron and zinc accumulations in rice. Plant Cell Environ. 2009;32:408–416.
69. Masuda H, Aung MS, Nishizawa NK., Iron biofortification of rice using different transgenic approaches. Rice (N Y). 2013;6:40.
70. Baskar V, Gururani M, Yu J, et al. Engineering glucosinolates in plants:current knowledge and potential uses. Appl Biochem Biotechnol. 2012;168:1694–1717.
71. Brader G, Mikkelsen MD, Halkier BA, et al. Altering glucosinolate profiles modulates disease resistance in plants. Plant J. 2006;46:758–767.
72. Kliebenstein DJ, Osbourn A. Making new molecules:evolution of pathways for novel metabolites in plants. Curr Opin Plant Biol. 2012;15:415–423.
73. Mithen R, Faulkner K, Magrath R, et al. Development of isothiocyanate-enriched broccoli, and its enhanced ability to induce phase 2 detoxification enzymes in mammalian cells. Theor Appl Genet. 2003;106:727–734.
74. Bak S, Olsen CE, Halkier BA, et al. Transgenic tobacco and Arabidopsis plants expressing the two multifunctional sorghum cytochrome P450 enzymes, CYP79A1 and CYP71E1, are cyanogenic and accumulate metabolites derived from intermediates in Dhurrin biosynthesis. Plant Physiol. 2000;123:1437–1448.
75. Nielsen AZ, Ziersen B, Jensen K, et al. Redirecting photosynthetic reducing power toward bioactive natural product synthesis. ACS Synthetic Biol. 2013;2:308–315.
76. Mikkelsen MD, Olsen CE, Halkier BA., Production of the cancer-preventive glucoraphanin in tobacco. Molecular Plant. 2010;3:751–759.
77. Gordaliza M, Garcı´a PA, Miguel del Corral JM, et al. Podophyllotoxin:distribution, sources, applications and new cytotoxic derivatives. Toxicon. 2004;44:441–459.
78. Gordaliza M, Castro MA, del Corral JMM, et al. Antitumor properties of podophyllotoxin and related compounds. Curr Pharm Des. 2000;6:1811–1839.
79. Fleming RA, Miller AA, Stewart CF., Etoposide:an update. Clin Pharm. 1989;8:274–293.
80. Marques JV, Kim K-W, Lee C, et al. Next generation sequencing in predicting gene function in podophyllotoxin biosynthesis. J Biol Chem. 2013;288:466–479.
81. Lau W, Sattely ES., Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone. Science. 2015;349:1224–1228.
82. Harker M, Hirschberg J. Biosynthesis of ketocarotenoids in transgenic cyanobacteria expressing the algal gene for beta-C-4-oxygenase, crtO. FEBS Lett. 1997;404:129–134.
83. Huang J-C, Zhong Y-J, Liu J, et al. Metabolic engineering of tomato for high-yield production of astaxanthin. Metab Eng. 2013;17:59–67.
84. Paddon CJ, Westfall PJ, Pitera DJ, et al. High-level semi-synthetic production of the potent antimalarial artemisinin. Nature. 2013;496:528–532.
85. Pitera DJ, Paddon CJ, Newman JD, et al. Balancing a heterologous mevalonate pathway for improved isoprenoid production in Escherichia coli. Metab Eng. 2007;9:193–207.
86. Orlova I, Nagegowda DA, Kish CM, et al. The small subunit of snapdragon geranyl diphosphate synthase modifies the chain length specificity of tobacco geranylgeranyl diphosphate synthase in planta. The Plant Cell. 2009;21:4002–4017.
87. Dai Z, Cui G, Zhou S-F, et al. Cloning and characterization of a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase gene from Salvia miltiorrhiza involved in diterpenoid tanshinone accumulation. J Plant Physiol. 2011;168:148–157.
88. Kai G, Xu H, Zhou C, et al. Metabolic engineering tanshinone biosynthetic pathway in Salvia miltiorrhiza hairy root cultures. Metab Eng. 2011;13:319–327.
89. Lücker J, Schwab W, van Hautum B, et al. Increased and altered fragrance of tobacco plants after metabolic engineering using three monoterpene synthases from lemon. Plant Physiol. 2004;134:510–519.
90. Lewinsohn E, Schalechet F, Wilkinson J, et al. Enhanced levels of the aroma and flavor compound S-linalool by metabolic engineering of the terpenoid pathway in tomato fruits. Plant Physiol. 2001;127:1256–1265.
91. Lücker J, Bouwmeester HJ, Schwab W, et al. Expression of Clarkia S-linalool synthase in transgenic petunia plants results in the accumulation of S-linalyl-beta-D-glucopyranoside. Plant J. 2001;27:315–324.
92. Masakapalli SK, Ritala A, Dong L, et al. Metabolic flux phenotype of tobacco hairy roots engineered for increased geraniol production. Phytochemistry. 2014;99:73–85.
93. Davidovich-Rikanati R, Sitrit Y, Tadmor Y, et al. Enrichment of tomato flavor by diversion of the early plastidial terpenoid pathway. Nat. Biotechnol. 2007;25:899–901.
94. Gutensohn M, Nguyen TTH, McMahon Iii RD, et al. Metabolic engineering of monoterpene biosynthesis in tomato fruits via introduction of the non-canonical substrate neryl diphosphate. Metab Eng. 2014;24:107–116.
95. Schilmiller AL, Schauvinhold I, Larson M, et al. Monoterpenes in the glandular trichomes of tomato are synthesized from a neryl diphosphate precursor rather than geranyl diphosphate. Proc Natl Acad Sci USA. 2009;106:10865–10870.
96. Reinsvold RE, Jinkerson RE, Radakovits R, et al. The production of the sesquiterpene β-caryophyllene in a transgenic strain of the cyanobacterium Synechocystis. J Plant Physiol. 2011;168:848–852.
97. Kappers IF, Aharoni A, van Herpen TWJM, et al. Genetic engineering of terpenoid metabolism attracts bodyguards to Arabidopsis. Science. 2005;309:2070–2072.
98. Wu S, Schalk M, Clark A, et al. Redirection of cytosolic or plastidic isoprenoid precursors elevates terpene production in plants. Nat. Biotechnol. 2006;24:1441–1447.
99. Liu Q, Majdi M, Cankar K, et al. Reconstitution of the costunolide biosynthetic pathway in yeast and Nicotiana benthamiana. PLoS One. 2011;6:e23255.
100. van Herpen TWJM, Cankar K, Nogueira M, et al. Nicotiana benthamiana as a production platform for artemisinin precursors. PLoS One. 2010;5:e14222.
101. Peplow M., Synthetic biology’s first malaria drug meets market resistance. Nature. 2016;530:389–390.
102. Brückner K, Tissier A., High-level diterpene production by transient expression in Nicotiana benthamiana. Plant Methods. 2013;9:46.
103. Pan X-W, Han L, Zhang Y-H, et al. Sclareol production in the moss Physcomitrella patens and observations on growth and terpenoid biosynthesis. Plant Biotechnol Rep. 2015;9:149–159.
104. Wang E, Wang R, DeParasis J, et al. Suppression of a P450 hydroxylase gene in plant trichome glands enhances natural-product-based aphid resistance. Nat Biotech. 2001;19:371–374.
105. Englund E, Andersen-Ranberg J, Miao R, et al. Metabolic engineering of Synechocystis sp. PCC 6803 for production of the plant diterpenoid manoyl oxide. ACS Synthetic Biol. 2015;4:1270–1278.
106. Thimmappa R, Geisler K, Louveau T, et al. Triterpene biosynthesis in plants. Annu Rev Plant Biol. 2014;65:225–257.
107. Pasoreck EK, Su J, Silverman IM, et al. Terpene metabolic engineering via nuclear or chloroplast genomes profoundly and globally impacts off-target pathways through metabolite signaling. Plant Biotechnol J. 2016;14:1862–1875.
108. Confalonieri M, Cammareri M, Biazzi E, et al. Enhanced triterpene saponin biosynthesis and root nodulation in transgenic barrel medic (Medicago truncatula Gaertn.) expressing a novel β-amyrin synthase (AsOXA1) gene. Plant Biotechnol J. 2009;7:172–182.
109. Krokida A, Delis C, Geisler K, et al. A metabolic gene cluster in Lotus japonicus discloses novel enzyme functions and products in triterpene biosynthesis. New Phytol. 2013;200:675–690.
110. Mugford ST, Qi X, Bakht S, et al. A serine carboxypeptidase-like acyltransferase is required for synthesis of antimicrobial compounds and disease resistance in oats. The Plant Cell Online. 2009;21:2473–2484.
111. Mugford ST, Louveau T, Melton R, et al. Modularity of plant metabolic gene clusters:a trio of linked genes that are collectively required for acylation of triterpenes in oat. The Plant Cell. 2013;25:1078–1092.
112. Geisler K, Hughes RK, Sainsbury F, et al. Biochemical analysis of a multifunctional cytochrome P450 (CYP51) enzyme required for synthesis of antimicrobial triterpenes in plants. Proc Natl Acad Sci USA. 2013;110:E3360–E33E7.
113. Santos CNS, Koffas M, Stephanopoulos G., Optimization of a heterologous pathway for the production of flavonoids from glucose. Metab Eng. 2011;13:392–400.
114. Zhang Y, Butelli E, Martin C., Engineering anthocyanin biosynthesis in plants. Curr Opin Plant Biol. 2014;19:81–90.
115. Muir SR, Collins GJ, Robinson S, et al. Overexpression of petunia chalcone isomerase in tomato results in fruit containing increased levels of flavonols. Nat Biotechnol. 2001;19:470–474.
116. Verhoeyen ME, Bovy A, Collins G, et al. Increasing antioxidant levels in tomatoes through modification of the flavonoid biosynthetic pathway. J Exp Bot. 2002;53:2099–2106.
117. Borevitz JO, Xia Y, Blount J, et al. Activation tagging identifies a conserved MYB regulator of phenylpropanoid biosynthesis. The Plant Cell. 2000;12:2383–2393.
118. Espley RV, Hellens RP, Putterill J, et al. Red colouration in apple fruit is due to the activity of the MYB transcription factor, MdMYB10. Plant J. 2007;49:414–427.
119. Zuluaga DL, Gonzali S, Loreti E, et al. Arabidopsis thaliana MYB75/PAP1 transcription factor induces anthocyanin production in transgenic tomato plants. Funct Plant Biol. 2008;35:606–618.
120. Butelli E, Titta L, Giorgio M, et al. Enrichment of tomato fruit with health-promoting anthocyanins by expression of select transcription factors. Nat Biotechnol. 2008;26:1301–1308.
121. Zhang Y, Butelli E, De Stefano R, et al. Anthocyanins double the shelf life of tomatoes by delaying overripening and reducing susceptibility to gray mold. Curr Biol. 2013;23:1094–1100.
122. Geekiyanage S, Takase T, Ogura Y, et al. Anthocyanin production by over-expression of grape transcription factor gene VlmybA2 in transgenic tobacco and Arabidopsis. Plant Biotechnol Rep. 2007;1:11–18.
123. Giovinazzo G, D’Amico L, Paradiso A, et al. Antioxidant metabolite profiles in tomato fruit constitutively expressing the grapevine stilbene synthase gene. Plant Biotechnol J. 2005;3:57–69.
124. Nishihara M, Nakatsuka T., Genetic engineering of flavonoid pigments to modify flower color in floricultural plants. Biotechnol Lett. 2011;33:433–441.
125. Nakatsuka T, Mishiba K-i, Abe Y, et al. Flower color modification of gentian plants by RNAi-mediated gene silencing. Plant Biotechnol. 2008;25:61–68.
126. Kovinich N, Saleem A, Rintoul T, et al. Coloring genetically modified soybean grains with anthocyanins by suppression of the proanthocyanidin genes ANR1 and ANR2. Transgenic Res. 2012;21:757–771.
127. Meyer P, Heidmann I, Forkmann G, et al. A new petunia flower colour generated by transformation of a mutant with a maize gene. Nature. 1987;330:677–678.
128. Rosati C, Simoneau P, Treutter D, et al. Engineering of flower color in forsythia by expression of two independently-transformed dihydroflavonol 4-reductase and anthocyanidin synthase genes of flavonoid pathway. Mol Breed. 2003;12:197–208.
129. Ono E, Fukuchi-Mizutani M, Nakamura N, et al. Yellow flowers generated by expression of the aurone biosynthetic pathway. Proc Natl Acad Sci USA. 2006;103:11075–11080.
130. Noda N, Aida R, Kishimoto S, et al. Genetic engineering of novel bluer-colored chrysanthemums produced by accumulation of delphinidin-based anthocyanins. Plant Cell Physiol. 2013;54:1684–1695.
131. Mol J, Cornish E, Mason J, et al. Novel coloured flowers. Curr Opin Biotechnol. 1999;10:198–201.
132. Fukui Y, Tanaka Y, Kusumi T, et al. A rationale for the shift in colour towards blue in transgenic carnation flowers expressing the flavonoid 3',5'-hydroxylase gene. Phytochemistry. 2003;63:15–23.
133. Katsumoto Y, Fukuchi-Mizutani M, Fukui Y, et al. Engineering of the rose flavonoid biosynthetic pathway successfully generated blue-hued flowers accumulating delphinidin. Plant Cell Physiol. 2007;48:1589–1600.
134. Ziegler J, Facchini PJ., Alkaloid biosynthesis:metabolism and trafficking. Annu Rev Plant Biol. 2008;59:735–769.
135. Kato M, Mizuno K, Crozier A, et al. Caffeine synthase gene from tea leaves. Nature. 2000;406:956–957.
136. Ogita S, Uefuji H, Yamaguchi Y, et al. RNA interference:producing decaffeinated coffee plants. Nature. 2003;423:823.
137. Uefuji H, Tatsumi Y, Morimoto M, et al. Caffeine production in tobacco plants by simultaneous expression of three coffee N-methyltrasferases and its potential as a pest repellant. Plant Mol Biol. 2005;59:221–227.
138. Grynkiewicz G, Gadzikowska M., Tropane alkaloids as medicinally useful natural products and their synthetic derivatives as new drugs. Pharmacol Rep. 2008;60:439–463.
139. Jouhikainen K, Lindgren L, Jokelainen T, et al. Enhancement of scopolamine production in Hyoscyamus muticus L. hairy root cultures by genetic engineering. Planta. 1999;208:545–551.
140. Yun DJ, Hashimoto T, Yamada Y., Metabolic engineering of medicinal plants:transgenic Atropa belladonna with an improved alkaloid composition. Proc Natl Acad Sci USA. 1992;89:11799–11803.
141. O'Hagan D, J, Robins R, Wilson M, W., Wong C, et al. Fluorinated tropane alkaloids generated by directed biosynthesis in transformed root cultures of Datura stramonium. J Chem Soc Perkin Trans. 1999;1:2117–2120.
142. Larkin PJ, Miller JA, Allen RS, et al. Increasing morphinan alkaloid production by over‐expressing codeinone reductase in transgenic Papaver somniferum. Plant Biotechnol J. 2007;5:26–37.
143. Sato F, Hashimoto T, Hachiya A, et al. Metabolic engineering of plant alkaloid biosynthesis. Proc Natl Acad Sci USA. 2001;98:367–372.
144. Frick S, Kramell R, Kutchan TM., Metabolic engineering with a morphine biosynthetic P450 in opium poppy surpasses breeding. Metab Eng. 2007;9:169–176.
145. O'Connor SE, Maresh JJ., Chemistry and biology of monoterpene indole alkaloid biosynthesis. Nat Prod Rep. 2006;23:532–547.
146. O'Connor SE., Chapter Nine - strategies for engineering plant natural products:the iridoid-derived monoterpene indole alkaloids of Catharanthus roseus. In:David AH, editor. Methods Enzymol. Vol 515. Cambridge (MA):Academic Press; 2012. p. 189–206.
147. Geerlings A, Hallard D, Martinez Caballero A, et al. Alkaloid production by a Cinchona officinalis 'Ledgeriana' hairy root culture containing constitutive expression constructs of tryptophan decarboxylase and strictosidine synthase cDNAs from Catharanthus roseus. Plant Cell Rep. 1999;19:191–196.
148. van Der Heijden R, Jacobs DI, Snoeijer W, et al. The Catharanthus alkaloids:pharmacognosy and biotechnology. Curr Med Chem. 2004;11:607–628.
149. Canel C, Lopes-Cardoso MI, Whitmer S, et al. Effects of over-expression of strictosidine synthase and tryptophan decarboxylase on alkaloid production by cell cultures of Catharanthus roseus. Planta. 1998;205:414–419.
150. Hong S-B, Peebles CAM, Shanks JV, et al. Expression of the Arabidopsis feedback-insensitive anthranilate synthase holoenzyme and tryptophan decarboxylase genes in Catharanthus roseus hairy roots. J Biotechnol. 2006;122:28–38.
151. McCoy E, O'Connor SE., Directed biosynthesis of alkaloid analogs in the medicinal plant Catharanthus roseus. J Am Chem Soc. 2006;128:14276–14277.
152. Runguphan W, O'Connor SE. Metabolic reprogramming of periwinkle plant culture. Nat Chem Biol. 2009;5:151–153.
153. Runguphan W, Qu X, O/'Connor SE., Integrating carbon-halogen bond formation into medicinal plant metabolism. Nature. 2010;468:461–464.
154. Runguphan W, O’Connor SE., Diversification of monoterpene indole alkaloid analogs through cross-coupling. Org Lett. 2013;15:2850–2853.
155. Oliver JK, Atsumi S., Metabolic design for cyanobacterial chemical synthesis. Photosyn Res. 2014;120:249–261.
156. Bohmert K, Balbo I, Kopka J, et al. Transgenic Arabidopsis plants can accumulate polyhydroxybutyrate to up to 4% of their fresh weight. Planta. 2000;211:841–845.
157. Slater S, Mitsky TA, Houmiel KL, et al. Metabolic engineering of Arabidopsis and Brassica for poly(3-hydroxybutyrate-co-3-hydroxyvalerate) copolymer production. Nat Biotechnol. 1999;17:1011–1016.
158. Saruul P, Srienc F, Somers DA, et al. Production of a biodegradable plastic polymer, poly-β-hydroxybutyrate, in transgenic alfalfa. Crop Sci. 2002;42:919–927.
159. Petrasovits LA, Zhao LH, McQualter RB, et al. Enhanced polyhydroxybutyrate production in transgenic sugarcane. Plant Biotechnol J. 2012;10:569–578.
160. Bohmert-Tatarev K, McAvoy S, Daughtry S, et al. High levels of bioplastic are produced in fertile transplastomic tobacco plants engineered with a synthetic operon for the production of polyhydroxybutyrate. Plant Physiol. 2011;155:1690–1708.
161. Imashimizu M, Bernát G, Sunamura E-I, et al. Regulation of F0F1-ATPase from Synechocystis sp. PCC 6803 by gamma and epsilon subunits is significant for light/dark adaptation. J Biol Chem. 2011;286:26595–26602.
162. Ducat DC, Sachdeva G, Silver PA., Rewiring hydrogenase-dependent redox circuits in cyanobacteria. Proc Natl Acad Sci USA. 2011;108:3941–3946.
163. McCormick AJ, Bombelli P, Lea-Smith DJ, et al. Hydrogen production through oxygenic photosynthesis using the cyanobacterium Synechocystis sp. PCC 6803 in a bio-photoelectrolysis cell (BPE) system. Energy Environ Sci. 2013;6:2682–2690.
164. Peyret H, Lomonossoff GP., The pEAQ vector series:the easy and quick way to produce recombinant proteins in plants. Plant Mol Biol. 2013;83:51–58.
165. Kanagarajan S, Muthusamy S, Gliszczynska A, et al. Functional expression and characterization of sesquiterpene synthases from Artemisia annua L. using transient expression system in Nicotiana benthamiana. Plant Cell Rep. 2012;31:1309–1319.
166. Landry N, Ward BJ, Trépanier S, et al. Preclinical and clinical development of plant-made virus-like Particle vaccine against avian H5N1 influenza. PLoS One. 2010;5:e15559.
167. Peyret H, Gehin A, Thuenemann EC, et al. Tandem fusion of hepatitis B core antigen allows assembly of virus-like particles in bacteria and plants with enhanced capacity to accommodate foreign proteins. PLoS One. 2015;10:e0120751.
168. Rasala BA, Mayfield SP., Photosynthetic biomanufacturing in green algae; production of recombinant proteins for industrial, nutritional, and medical uses. Photosyn Res. 2015;123:227–239.
169. Jones C, Luong T, Hannon M, et al. Heterologous expression of the C-terminal antigenic domain of the malaria vaccine candidate Pfs48/45 in the green algae Chlamydomonas reinhardtii. Appl Microbiol Biotechnol. 2013;97:1987–1995.
170. Barrera DJ, Rosenberg JN, Chiu JG, et al. Algal chloroplast produced camelid VHH antitoxins are capable of neutralizing botulinum neurotoxin. Plant Biotechnol J. 2015;13:117–124.
171. Chen Y, Wang Y, Sun Y, et al. Highly efficient expression of rabbit neutrophil peptide-1 gene in Chlorella ellipsoidea cells. Curr Genet. 2001;39:365–370.
172. Feng S, Feng W, Zhao L, et al. Preparation of transgenic Dunaliella salina for immunization against white spot syndrome virus in crayfish. Arch Virol. 2014;159:519–525.
173. Eichler-Stahlberg A, Weisheit W, Ruecker O, et al. Strategies to facilitate transgene expression in Chlamydomonas reinhardtii. Planta. 2009;229:873–883.
174. Vardakou M, Sainsbury F, Rigby N, et al. Expression of active recombinant human gastric lipase in Nicotiana benthamiana using the CPMV-HT transient expression system. Protein Expr Purif. 2012;81:69–74.
175. Vezina LP, Faye L, Lerouge P, et al. Transient co-expression for fast and high-yield production of antibodies with human-like N-glycans in plants. Plant Biotechnol J. 2009;7:442–455.
176. Castilho A, Strasser R, Stadlmann J, et al. In planta protein sialylation through overexpression of the respective mammalian pathway. J Biol Chem. 2010;285:15923–15930.
177. Sweetlove LJ, Fernie AR., The spatial organization of metabolism within the plant cell. Annu Rev Plant Biol. 2013;64:723–746.
178. Keeling PJ., The endosymbiotic origin, diversification and fate of plastids. Phil Trans Royal Soc B:Biol Sci. 2010;365:729–748.
179. O’Neill EC, Trick M, Henrissat B, et al. Euglena in time:evolution, control of central metabolic processes and multi-domain proteins in carbohydrate and natural product biochemistry. Perspect Sci. 2015;6:84–93.
180. O'Neill EC, Trick M, Hill L, et al. The transcriptome of Euglena gracilis reveals unexpected metabolic capabilities for carbohydrate and natural product biochemistry. Mol Biosyst. 2015;11:2808–2820.
181. O'Neill EC, Saalbach G, Field RA., Gene discovery for synthetic biology:exploring the novel natural product biosynthetic capacity of eukaryotic microalgae. Methods Enzymol. 2016;576:99–120.
182. Temme K, Zhao D, Voigt CA., Refactoring the nitrogen fixation gene cluster from Klebsiella oxytoca. Proc Natl Acad Sci USA. 2012;109:7085–7090.
183. Smanski MJ, Bhatia S, Zhao D, et al. Functional optimization of gene clusters by combinatorial design and assembly. Nat Biotechnol. 2014;32:1241–1249.