A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules

Metabolic Engineering

Volumn 42, Issue , 2017, Pages 185-193

  Reed, James ^a   Stephenson, Michael J ^a   Miettinen, Karel ^b   Brouwer, Bastiaan ^a   Leveau, Aymeric ^a   Brett, Paul ^a   Goss, Rebecca J M ^c,d   Goossens, Alain ^b   O'Connell, Maria A ^c   Osbourn, Anne ^a  

^a NORWICH RESEARCH PARK   (United Kingdom)

^b GHENT UNIVERSITY   (Belgium)

^c UNIVERSITY OF EAST ANGLIA   (United Kingdom)

^d UNIVERSITY OF ST ANDREWS   (United Kingdom)

Author keywords

Combinatorial biosynthesis; Drug discovery; Synthetic biology; Terpenes; Transient plant expression technology; Triterpenoids

Indexed keywords

BIOCHEMISTRY; BIOLOGY; BIOSYNTHESIS; DRUG PRODUCTS; GENES; MOLECULES; SYNTHESIS (CHEMICAL); TERPENES;

COMBINATORIAL BIOSYNTHESIS; DRUG DISCOVERY; PLANT EXPRESSIONS; SYNTHETIC BIOLOGY; TRITERPENOIDS;

PLANTS (BOTANY);

11 OXO BETA AMYRIN; 11 OXO,24 HYDROXY BETA AMYRIN; 11ALPHA HYDROXY BETA AMYRIN; 24 HYDROXY BETA AMYRIN; 30 HYDROXY BETA AMYRIN; BARDOXOLONE METHYL; BETA AMYRIN; ERYTHRODIOL; GLYCYRRHETINIC ACID; OLEANOLIC ACID; PLANT EXTRACT; TRITERPENE; TRITERPENE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; COMBINATORIAL CHEMISTRY; CONTROLLED STUDY; DRUG SYNTHESIS; GLYCYRRHIZA GLABRA; METABOLIC ENGINEERING; NICOTIANA BENTHAMIANA; NONHUMAN; PLANT LEAF; PRIORITY JOURNAL; STRUCTURE ACTIVITY RELATION; SYNTHETIC BIOLOGY; TRANSIENT EXPRESSION; TRANSIENT TRANSFECTION; ALGORITHM; AVENA; COMOVIRUS; DRUG DEVELOPMENT; ENZYMOLOGY; GENETICS; METABOLISM; PLANT GENOME; PROCEDURES; TOBACCO; VIRUS GENOME;

ALGORITHMS; AVENA; COMOVIRUS; DRUG DISCOVERY; GENOME, PLANT; GENOME, VIRAL; SYNTHETIC BIOLOGY; TOBACCO; TRITERPENES;

EID: 85022047056     PISSN: 10967176     EISSN: 10967184     Source Type: Journal    
DOI: 10.1016/j.ymben.2017.06.012     Document Type: Article

References (48)

1. Alberti, S., Gitler, A.D., Lindquist, S., A suite of Gateway cloning vectors for high-throughput genetic analysis in Saccharomyces cerevisiae. Yeast 24 (2007), 913–919.
2. Anarat-Cappillino, G., Sattely, E.S., The chemical logic of plant natural product biosynthesis. Curr. Opin. Plant Biol. 19 (2014), 51–58.
3. Andersen-Ranberg, J., Kongstad, K.T., Nielsen, M.T., Jensen, N.B., Pateraki, I., Bach, S.S., Hamberger, B., Zerbe, P., Staerk, D., Bohlmann, J., Moller, B.L., Hamberger, B., Expanding the landscape of Diterpene structural diversity through stereochemically controlled combinatorial biosynthesis. Angew. Chem. (Int. Ed. Engl.). 55 (2016), 2142–2146.
4. Biazzi, E., Carelli, M., Tava, A., Abbruscato, P., Losini, I., Avato, P., Scotti, C., Calderini, O., CYP72A67 catalyzes a key oxidative step in Medicago truncatula Hemolytic Saponin biosynthesis. Mol. Plant. 8 (2015), 1493–1506.
5. Boutanaev, A.M., Moses, T., Zi, J., Nelson, D.R., Mugford, S.T., Peters, R.J., Osbourn, A., Investigation of terpene diversification across multiple sequenced plant genomes. Proc. Natl. Acad. Sci. USA 112 (2015), E81–E88.
6. Brown, S., Clastre, M., Courdavault, V., O'Connor, S.E., De novo production of the plant-derived alkaloid strictosidine in yeast. Proc. Natl. Acad. Sci. USA 112 (2015), 3205–3210.
7. Carelli, M., Biazzi, E., Panara, F., Tava, A., Scaramelli, L., Porceddu, A., Graham, N., Odoardi, M., Piano, E., Arcioni, S., May, S., Scotti, C., Calderini, O., Medicago truncatula CYP716A12 is a multifunctional oxidase involved in the biosynthesis of hemolytic saponins. Plant Cell. 23 (2011), 3070–3081.
8. DeLoache, W.C., Russ, Z.N., Narcross, L., Gonzales, A.M., Martin, V.J., Dueber, J.E., An enzyme-coupled biosensor enables (S)-reticuline production in yeast from glucose. Nat. Chem. Biol. 11 (2015), 465–471.
9. Fukushima, E.O., Seki, H., Ohyama, K., Ono, E., Umemoto, N., Mizutani, M., Saito, K., Muranaka, T., CYP716A subfamily members are multifunctional oxidases in triterpenoid biosynthesis. Plant Cell Physiol. 52 (2011), 2050–2061.
10. Fukushima, E.O., Seki, H., Sawai, S., Suzuki, M., Ohyama, K., Saito, K., Muranaka, T., Combinatorial biosynthesis of legume natural and rare triterpenoids in engineered yeast. Plant Cell Physiol. 54 (2013), 740–749.
11. Galanie, S., Thodey, K., Trenchard, I.J., Filsinger Interrante, M., Smolke, C.D., Complete biosynthesis of opioids in yeast. Science 349 (2015), 1095–1100.
12. Geisler, K., Hughes, R.K., Sainsbury, F., Lomonossoff, G.P., Rejzek, M., Fairhurst, S., Olsen, C.E., Motawia, M.S., Melton, R.E., Hemmings, A.M., Bak, S., Osbourn, A., Biochemical analysis of a multifunctional cytochrome P450 (CYP51) enzyme required for synthesis of antimicrobial triterpenes in plants. Proc. Natl. Acad. Sci. USA 110 (2013), E3360–E3367.
13. Geu-Flores, F., Nielsen, M.T., Nafisi, M., Moldrup, M.E., Olsen, C.E., Motawia, M.S., Halkier, B.A., Glucosinolate engineering identifies a gamma-glutamyl peptidase. Nat. Chem. Biol. 5 (2009), 575–577.
14. Harvey, A.L., Edrada-Ebel, R., Quinn, R.J., The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug Discov. 14 (2015), 111–129.
15. Hill, R.A., Connolly, J.D., Triterpenoids. Nat. Prod. Rep. 29 (2012), 780–818.
16. Itkin, M., Davidovich-Rikanati, R., Cohen, S., Portnoy, V., Doron-Faigenboim, A., Oren, E., Freilich, S., Tzuri, G., Baranes, N., Shen, S., Petreikov, M., Sertchook, R., Ben-Dor, S., Gottlieb, H., Hernandez, A., Nelson, D.R., Paris, H.S., Tadmor, Y., Burger, Y., Lewinsohn, E., Katzir, N., Schaffer, A., The biosynthetic pathway of the nonsugar, high-intensity sweetener mogroside V from Siraitia grosvenorii. Proc. Natl. Acad. Sci. USA 113 (2016), E7619–E7628.
17. Kemen, A.C., Honkanen, S., Melton, R.E., Findlay, K.C., Mugford, S.T., Hayashi, K., Haralampidis, K., Rosser, S.J., Osbourn, A., Investigation of triterpene synthesis and regulation in oats reveals a role for β-amyrin in determining root epidermal cell patterning. Proc. Natl. Acad. Sci. USA 111 (2014), 8679–8684.
18. Khakimov, B., Kuzina, V., Erthmann, P.O., Fukushima, E.O., Augustin, J.M., Olsen, C.E., Scholtalbers, J., Volpin, H., Andersen, S.B., Hauser, T.P., Muranaka, T., Bak, S., Identification and genome organization of saponin pathway genes from a wild crucifer, and their use for transient production of saponins in Nicotiana benthamiana. Plant J. 84 (2015), 478–490.
19. Kwok, R., Five hard truths for synthetic biology. Nature 463 (2010), 288–290.
20. Li, Y., Smolke, C.D., Engineering biosynthesis of the anticancer alkaloid noscapine in yeast. Nat. Commun., 7, 2016, 12137.
21. Liby, K.T., Sporn, M.B., Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol. Rev. 64 (2012), 972–1003.
22. Marsian, J., Lomonossoff, G.P., Molecular pharming - VLPs made in plants. Curr. Opin. Biotechnol. 37 (2016), 201–206.
23. Medema, M.H., Osbourn, A., Computational genomic identification and functional reconstitution of plant natural product biosynthetic pathways. Nat. Prod. Rep. 33 (2016), 951–962.
24. Miettinen, K., Dong, L., Navrot, N., Schneider, T., Burlat, V., Pollier, J., Woittiez, L., van der Krol, S., Lugan, R., Ilc, T., Verpoorte, R., Oksman-Caldentey, K.M., Martinoia, E., Bouwmeester, H., Goossens, A., Memelink, J., Werck-Reichhart, D., The seco-iridoid pathway from Catharanthus roseus. Nat. Commun., 5, 2014, 3606.
25. Miettinen, K., Pollier, J., Buyst, D., Arendt, P., Csuk, R., Sommerwerk, S., Moses, T., Mertens, J., Sonawane, P.D., Pauwels, L., Aharoni, A., Martins, J., Nelson, D.R., Goossens, A., The ancient CYP716 family is a major contributor to the diversification of eudicot triterpenoid biosynthesis. Nat. Commun., 8, 2017, 14153.
26. Moses, T., Papadopoulou, K.K., Osbourn, A., Metabolic and functional diversity of saponins, biosynthetic intermediates and semi-synthetic derivatives. Crit. Rev. Biochem. Mol. Biol. 49 (2014), 439–462.
27. Moses, T., Pollier, J., Almagro, L., Buyst, D., Van Montagu, M., Pedreno, M.A., Martins, J.C., Thevelein, J.M., Goossens, A., Combinatorial biosynthesis of sapogenins and saponins in Saccharomyces cerevisiae using a C-16α hydroxylase from Bupleurum falcatum. Proc. Natl. Acad. Sci. USA 111 (2014), 1634–1639.
28. Moses, T., Pollier, J., Faizal, A., Apers, S., Pieters, L., Thevelein, J.M., Geelen, D., Goossens, A., Unravelling the triterpenoid saponin biosynthesis of the African shrub Maesa lanceolata. Mol. Plant. 8 (2015), 122–135.
29. Moses, T., Pollier, J., Shen, Q., Soetaert, S., Reed, J., Erffelinck, M.L., Van Nieuwerburgh, F.C., Vanden Bossche, R., Osbourn, A., Thevelein, J.M., Deforce, D., Tang, K., Goossens, A., OSC2 and CYP716A14v2 catalyze the biosynthesis of triterpenoids for the cuticle of aerial organs of Artemisia annua. Plant Cell. 27 (2015), 286–301.
30. Moses, T., Thevelein, J.M., Goossens, A., Pollier, J., Comparative analysis of CYP93E proteins for improved microbial synthesis of plant triterpenoids. Phytochemistry 108 (2014), 47–56.
31. Nielsen, J., Keasling, J.D., Engineering Cellular Metabolism. Cell 164 (2016), 1185–1197.
32. Owen, C., Patron, N.J., Huang, A., Osbourn, A., Harnessing plant metabolic diversity. Curr. Opin. Chem. Biol. 40 (2017), 24–30.
33. Paddon, C.J., Westfall, P.J., Pitera, D.J., Benjamin, K., Fisher, K., McPhee, D., Leavell, M.D., Tai, A., Main, A., Eng, D., Polichuk, D.R., Teoh, K.H., Reed, D.W., Treynor, T., Lenihan, J., Fleck, M., Bajad, S., Dang, G., Dengrove, D., Diola, D., Dorin, G., Ellens, K.W., Fickes, S., Galazzo, J., Gaucher, S.P., Geistlinger, T., Henry, R., Hepp, M., Horning, T., Iqbal, T., Jiang, H., Kizer, L., Lieu, B., Melis, D., Moss, N., Regentin, R., Secrest, S., Tsuruta, H., Vazquez, R., Westblade, L.F., Xu, L., Yu, M., Zhang, Y., Zhao, L., Lievense, J., Covello, P.S., Keasling, J.D., Reiling, K.K., Renninger, N.S., Newman, J.D., High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496 (2013), 528–532.
34. Patron, N.J., Orzaez, D., Marillonnet, S., Warzecha, H., Matthewman, C., Youles, M., Raitskin, O., Leveau, A., Farre, G., Rogers, C., Smith, A., Hibberd, J., Webb, A.A., Locke, J., Schornack, S., Ajioka, J., Baulcombe, D.C., Zipfel, C., Kamoun, S., Jones, J.D., Kuhn, H., Robatzek, S., Van Esse, H.P., Sanders, D., Oldroyd, G., Martin, C., Field, R., O'Connor, S., Fox, S., Wulff, B., Miller, B., Breakspear, A., Radhakrishnan, G., Delaux, P.M., Loque, D., Granell, A., Tissier, A., Shih, P., Brutnell, T.P., Quick, W.P., Rischer, H., Fraser, P.D., Aharoni, A., Raines, C., South, P.F., Ane, J.M., Hamberger, B.R., Langdale, J., Stougaard, J., Bouwmeester, H., Udvardi, M., Murray, J.A., Ntoukakis, V., Schafer, P., Denby, K., Edwards, K.J., Osbourn, A., Haseloff, J., Standards for plant synthetic biology: a common syntax for exchange of DNA parts. New Phytol. 208 (2015), 13–19.
35. Polturak, G., Breitel, D., Grossman, N., Sarrion-Perdigones, A., Weithorn, E., Pliner, M., Orzaez, D., Granell, A., Rogachev, I., Aharoni, A., Elucidation of the first committed step in betalain biosynthesis enables the heterologous engineering of betalain pigments in plants. New Phytol. 210 (2016), 269–283.
36. Qu, Y., Easson, M.L., Froese, J., Simionescu, R., Hudlicky, T., De Luca, V., Completion of the seven-step pathway from tabersonine to the anticancer drug precursor vindoline and its assembly in yeast. Proc. Natl. Acad. Sci. USA 112 (2015), 6224–6229.
37. Rajniak, J., Barco, B., Clay, N.K., Sattely, E.S., A new cyanogenic metabolite in Arabidopsis required for inducible pathogen defence. Nature 525 (2015), 376–379.
38. Sainsbury, F., Saxena, P., Geisler, K., Osbourn, A., Lomonossoff, G.P., Using a virus-derived system to manipulate plant natural product biosynthetic pathways. Methods Enzymol. 517 (2012), 185–202.
39. Sainsbury, F., Thuenemann, E.C., Lomonossoff, G.P., pEAQ: versatile expression vectors for easy and quick transient expression of heterologous proteins in plants. Plant Biotechnol. J. 7 (2009), 682–693.
40. Salmon, M., Thimmappa, R.B., Minto, R.E., Melton, R.E., Hughes, R.K., O'Maille, P.E., Hemmings, A.M., Osbourn, A., A conserved amino acid residue critical for product and substrate specificity in plant triterpene synthases. Proc. Natl. Acad. Sci. USA 113 (2016), E4407–E4414.
41. Seki, H., Ohyama, K., Sawai, S., Mizutani, M., Ohnishi, T., Sudo, H., Akashi, T., Aoki, T., Saito, K., Muranaka, T., Licorice β-amyrin 11-oxidase, a cytochrome P450 with a key role in the biosynthesis of the triterpene sweetener glycyrrhizin. Proc. Natl. Acad. Sci. USA 105 (2008), 14204–14209.
42. Seki, H., Tamura, K., Muranaka, T., P450s and UGTs: key players in the structural diversity of triterpenoid saponins. Plant Cell Physiol. 56 (2015), 1463–1471.
43. Shang, Y., Ma, Y., Zhou, Y., Zhang, H., Duan, L., Chen, H., Zeng, J., Zhou, Q., Wang, S., Gu, W., Liu, M., Ren, J., Gu, X., Zhang, S., Wang, Y., Yasukawa, K., Bouwmeester, H.J., Qi, X., Zhang, Z., Lucas, W.J., Huang, S., Biosynthesis, regulation, and domestication of bitterness in cucumber. Science 346 (2014), 1084–1088.
44. Shibuya, M., Hoshino, M., Katsube, Y., Hayashi, H., Kushiro, T., Ebizuka, Y., Identification of β-amyrin and sophoradiol 24-hydroxylase by expressed sequence tag mining and functional expression assay. FEBS J. 273 (2006), 948–959.
45. Thimmappa, R., Geisler, K., Louveau, T., O'Maille, P., Osbourn, A., Triterpene biosynthesis in plants. Annu. Rev. Plant Biol. 65 (2014), 225–257.
46. Wang, B., Kashkooli, A.B., Sallets, A., Ting, H.M., de Ruijter, N.C., Olofsson, L., Brodelius, P., Pottier, M., Boutry, M., Bouwmeester, H., van der Krol, A.R., Transient production of artemisinin in Nicotiana benthamiana is boosted by a specific lipid transfer protein from A. annua. Metab. Eng. 38 (2016), 159–169.
47. Yasumoto, S., Fukushima, E.O., Seki, H., Muranaka, T., Novel triterpene oxidizing activity of Arabidopsis thaliana CYP716A subfamily enzymes. FEBS Lett. 590 (2016), 533–540.
48. Zhang, J., Dai, L., Yang, J., Liu, C., Men, Y., Zeng, Y., Cai, Y., Zhu, Y., Sun, Y., Oxidation of cucurbitadienol catalyzed by CYP87D18 in the biosynthesis of mogrosides from Siraitia grosvenorii. Plant Cell Physiol. 57 (2016), 1000–1007.