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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2014, Vol. 8 Issue (3) : 285-293     DOI: 10.1007/s11684-014-0350-2
Biosynthetic pathway of terpenoid indole alkaloids in Catharanthus roseus
Xiaoxuan Zhu1,Xinyi Zeng1,Chao Sun1,*(),Shilin Chen2,*()
1. Institute of Medicinal Plant Development, China Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China
2. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
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Catharanthus roseus is one of the most extensively investigated medicinal plants, which can produce more than 130 alkaloids, including the powerful antitumor drugs vinblastine and vincristine. Here we review the recent advances in the biosynthetic pathway of terpenoid indole alkaloids (TIAs) in C. roseus, and the identification and characterization of the corresponding enzymes involved in this pathway. Strictosidine is the central intermediate in the biosynthesis of different TIAs, which is formed by the condensation of secologanin and tryptamine. Secologanin is derived from terpenoid (isoprenoid) biosynthetic pathway, while tryptamine is derived from indole biosynthetic pathway. Then various specific end products are produced by different routes during downstream process. Although many genes and corresponding enzymes have been characterized in this pathway, our knowledge on the whole TIA biosynthetic pathway still remains largely unknown up to date. Full elucidation of TIA biosynthetic pathway is an important prerequisite to understand the regulation of the TIA biosynthesis in the medicinal plant and to produce valuable TIAs by synthetic biological technology.

Keywords Catharanthus roseus      terpenoidindole alkaloids      biosynthetic pathway      vinblastine      vincristine     
Corresponding Authors: Chao Sun   
Online First Date: 25 August 2014    Issue Date: 09 October 2014
URL:     OR
Fig.1  An overview of the pathways leading to TIAs biosynthesis. Solid arrows indicate one-step reaction; dashed arrows indicate uncharacterized steps; white arrows indicate multi-step reactions.
Fig.2  The biosynthesis of IPP via MVA pathway and MEP pathway. Abbreviations: AACT: acetoacetyl-CoA thiolase; HMGS: hydroxymethyglutaryl-CoA synthase; HMGR: hydroxymethyglutaryl-CoA reductase; MVK: mevalonate kinase; PMK: mevalonate 5-phosphate kinase; MVD: mevalonate 5-diphosphate decarboxylase; DXS: 1-deoxy-D-xylulose-5-phosphate synthase; DXR: 1-deoxy-D-xylulose-5-phosphate reductoisomerase; CMS: 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase; CMK: 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase; MECS: 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase; HDS: 1-hydroxy-2-methyl-2-butenyl 4-diphosphate synthase; HDR: 1-hydroxy-2-methyl-2-butenyl 4-diphosphate reductase; IDI: isopentenyldiphosphateisomerase.
Fig.3  The biosynthesis of secologanin from GPP. Abbreviations: G10H: geraniol 10-hydroxylase; 10-HGO: 10-hydroxygeraniol oxidoreductase; IRS: iridoid synthase; 7DLS: 7-deoxyloganetic acid synthase; DLGT: 7-deoxyloganetic acid glucosyltransferase; DL7H: 7-deoxyloganic acid 7-hydroxylase; LAMT: loganic acid O-methyltransferase; SLS: secologanin synthase.
Names of enzymeA Abbreviations AbbreviationsAccession numbersReferences
Hydroxymethylglutaryl-CoA reductaseHMGRM96068.1[14]
Mevalonate kinaseMVKHM462019.1[19]
Mevalonate 5-phosphate kinasePMKHM462020.1[19]
Mevalonate 5-diphosphate decarboxylaseMVDHM462021.1[19]
1-deoxy-D-xylulose-5-phosphate synthaseDXSKC625536.1; DQ848672.1; AJ011840.2[9,21]
1-deoxy-D-xylulose-5-phosphate reductoisomeraseDXRAF250235.1[22]
4-diphosphocytidyl-2-C-methyl-D-erythritol kinaseCMKDQ848671.1Unpublished
2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthaseMECSAF250236.1[22]
1-hydroxy-2-methyl-2-butenyl 4-diphosphate synthaseHDSJN217103.1[23]
1-hydroxy-2-methyl-2-butenyl 4-diphosphate reductaseHDRDQ848676.1Unpublished
Cytochrome P450 reductaseCPRX69791.1[24]
Geraniol synthaseGESJN882024.1[25]
Geraniol 10-hydroxylaseG10HAJ251269.1[26]
10-hydroxygeraniol oxidoreductase10-HGOAY352047.1Unpublished
Iridoid synthaseIRSJX974564.1[27]
7-deoxyloganetic acid synthase7DLS[28]
7-deoxyloganetic acid glucosyltransferaseDLGTAB733667.1[29]
7-deoxyloganic acid 7-hydroxylaseDL7HKF415115.1[30]
Loganic acid O-methyltransferaseLAMTEU057974.1[31]
Secologanin synthaseSLSL10081.1[32,33]
Anthranilate synthaseα subunitASαAJ250008.1Unpublished
Tryptophan decarboxylaseTDC[34]
Strictosidine synthaseSTRX53602.1[35]
Strictosidine β-d-glucosidaseSGDAF112888.1[36]
Tabersonine 16- hydroxylaseT16HFJ647194.1[37]
16-hydroxytabersonine O-methyltransferase16OMTEF444544.1[38]
deacetylvindoline 4-O-acetyltransferaseDATAF053307.1[39]
Peroxidase 1PRX1AM236087.1[40]
Tab.1  Molecular characterization of enzymes involved in the biosynthetic pathway of TIAs in C. roseus
Fig.4  The biosynthesis of catharanthine and vindoline. Abbreviations: STR: strictosidine synthase; SGD: strictosidine β-D-glucosidase. Dashed arrows indicate uncharacterized steps.
Fig.5  The biosynthesis of vinblastine and vincristine. Abbreviations: T16H: tabersonine 16-hydroxylase; OMT: O-methyltransferase; NMT: N-methyltransferase; D4H: desacetoxyvindoline 4-hydroxylase; DAT: deacetylvindoline-4-O-acetyltransferase; PRX1: peroxidase 1. Dashed arrows indicate uncharacterized steps.
1 Oudin A, Courtois M, Rideau M, Clastre M. The iridoid pathway in Catharanthus roseus alkaloid biosynthesis. Phytochem Rev2007; 6(2–3): 259–276
doi: 10.1007/s11101-006-9054-9
2 Facchini PJ, De Luca V. Opium poppy and Madagascar periwinkle: model non-model systems to investigate alkaloid biosynthesis in plants. Plant J2008; 54(4): 763–784
3 El-Sayed M, Verpoorte R. Catharanthus terpenoid indole alkaloids: biosynthesis and regulation. Phytochem Rev2007; 6(2–3): 277–305
doi: 10.1007/s11101-006-9047-8
4 van Der Heijden R, Jacobs DI, Snoeijer W, Hallard D, Verpoorte R. The Catharanthus alkaloids: pharmacognosy and biotechnology. Curr Med Chem2004; 11(5): 607–628
doi: 10.2174/0929867043455846 pmid: 15032608
5 van Tellingen O, Sips JH, Beijnen JH, Bult A, Nooijen WJ. Pharmacology, bio-analysis and pharmacokinetics of the vinca alkaloids and semi-synthetic derivatives. Anticancer Res1992; 12(5): 1699–1715
pmid: 1444238
6 Zhao L, Sander GW, Shanks JV. Perspectives of the metabolic engineering of terpenoid indole alkaloids in Catharanthus roseus hairy roots. Adv Biochem Eng Biotechnol2013; 134: 23–54
doi: 10.1007/10_2013_182 pmid: 23576053
7 Contin A, van der Heijden R, Lefeber AW, Verpoorte R. The iridoid glucoside secologanin is derived from the novel triose phosphate/pyruvate pathway in a Catharanthus roseus cell culture. FEBS Lett1998; 434(3): 413–416
doi: 10.1016/S0014-5793(98)01022-9 pmid: 9742965
8 Courdavault V, Burlat V, St-Pierre B, Giglioli-Guivarc’h N. Characterisation of CaaX-prenyltransferases in Catharanthus roseus: relationships with the expression of genes involved in the early stages of monoterpenoid biosynthetic pathway. Plant Sci2005; 168(4): 1097–1107
doi: 10.1016/j.plantsci.2004.12.010
9 Chahed K, Oudin A, Guivarc’h N, Hamdi S, Chénieux JC, Rideau M, Clastre M. 1-Deoxy-D-xylulose 5-phosphate synthase from periwinkle: cDNA identification and induced gene expression in terpenoid indole alkaloid-producing cells. Plant Physiol Biochem2000; 38(7): 559–566
doi: 10.1016/S0981-9428(00)00781-6
10 Cunningham FX Jr, Lafond TP, Gantt E. Evidence of a role for LytB in the nonmevalonate pathway of isoprenoid biosynthesis. J Bacteriol2000; 182(20): 5841–5848
doi: 10.1128/JB.182.20.5841-5848.2000 pmid: 11004185
11 Newman JD, Chappell J. Isoprenoid biosynthesis in plants: carbon partitioning within the cytoplasmic pathway. Crit Rev Biochem Mol Biol1999; 34(2): 95–106
doi: 10.1080/10409239991209228 pmid: 10333387
12 Lange BM, Croteau R. Isopentenyl diphosphate biosynthesis via a mevalonate-independent pathway: isopentenyl monophosphate kinase catalyzes the terminal enzymatic step. Proc Natl Acad Sci USA1999; 96(24): 13714–13719
doi: 10.1073/pnas.96.24.13714 pmid: 10570138
13 Van der Heijden R, Verpoorte R, Duine J. Biosynthesis of 3S-hydroxy-3-methylglutaryl-coenzyme A in Catharanthus roseus: acetoacetyl-CoA thiolase and HMG-CoA synthase show similar chromatographic behaviour. Plant Physiol Biochem1994; 32(6): 807–812
14 Maldonado-Mendoza IE, Burnett RJ, Nessler CL. Nucleotide sequence of a cDNA encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase from Catharanthus roseus. Plant Physiol1992; 100(3): 1613–1614
doi: 10.1104/pp.100.3.1613 pmid: 16653173
15 Schulte AE, van der Heijden R, Verpoorte R. Purification and characterization of mevalonate kinase from suspension-cultured cells of Catharanthus roseus (L.) G. Don. Arch Biochem Biophys2000; 378(2): 287–298
doi: 10.1006/abbi.2000.1779 pmid: 10860546
16 Schulte AE, Llamas Durán EM, van der Heijden R, Verpoorte R. Mevalonate kinase activity in Catharanthus roseus plants and suspension cultured cells. Plant Sci2000; 150(1): 59–69
doi: 10.1016/S0168-9452(99)00164-8
17 Schulte AE, van der Heijden R, Verpoorte R. Purification and characterization of phosphomevalonate kinase from Catharanthus roseus. Phytochemistry1999; 52(6): 975–983
doi: 10.1016/S0031-9422(99)00382-9
18 Ramos-Valdivia AC, van der Heijden R, Verpoorte R. Isopentenyl diphosphate isomerase and prenyltransferase activities in rubiaceous and apocynaceous cultures. Phytochemistry1998; 48(6): 961–969
doi: 10.1016/S0031-9422(98)00145-9
19 Simkin AJ, Guirimand G, Papon N, Courdavault V, Thabet I, Ginis O, Bouzid S, Giglioli-Guivarc’h N, Clastre M. Peroxisomal localisation of the final steps of the mevalonic acid pathway in planta. Planta2011; 234(5): 903–914
doi: 10.1007/s00425-011-1444-6 pmid: 21655959
20 Guirimand G, Guihur A, Phillips MA, Oudin A, Glévarec G, Melin C, Papon N, Clastre M, St-Pierre B, Rodríguez-Concepción M, Burlat V, Courdavault V. A single gene encodes isopentenyl diphosphate isomerase isoforms targeted to plastids, mitochondria and peroxisomes in Catharanthus roseus. Plant Mol Biol2012; 79(4-5): 443–459
doi: 10.1007/s11103-012-9923-0 pmid: 22638903
21 Han M, Heppel SC, Su T, Bogs J, Zu Y, An Z, Rausch T. Enzyme inhibitor studies reveal complex control of methyl-D-erythritol 4-phosphate (MEP) pathway enzyme expression in Catharanthus roseus. PLoS ONE2013; 8(5): e62467
doi: 10.1371/journal.pone.0062467 pmid: 23650515
22 Veau B, Courtois M, Oudin A, Chénieux JC, Rideau M, Clastre M. Cloning and expression of cDNAs encoding two enzymes of the MEP pathway in Catharanthus roseus. Biochimica et Biophysica Acta (BBA)—. Gene Structure and Expression2000; 1517(1): 159–163
doi: 10.1016/S0167-4781(00)00240-2
23 Ginis O, Courdavault V, Melin C, Lanoue A, Giglioli-Guivarc’h N, St-Pierre B, Courtois M, Oudin A. Molecular cloning and functional characterization of Catharanthus roseus hydroxymethylbutenyl 4-diphosphate synthase gene promoter from the methyl erythritol phosphate pathway. Mol Biol Rep2012; 39(5): 5433–5447
doi: 10.1007/s11033-011-1343-8 pmid: 22160472
24 Meijer AH, Lopes Cardoso MI, Voskuilen JT, de Waal A, Verpoorte R, Hoge JHC. Isolation and characterization of a cDNA clone from Catharanthus roseus encoding NADPH:cytochrome P-450 reductase, an enzyme essential for reactions catalysed by cytochrome P-450 mono-oxygenases in plants. Plant J1993; 4(1): 47–60
doi: 10.1046/j.1365-313X.1993.04010047.x pmid: 8220474
25 Simkin AJ, Miettinen K, Claudel P, Burlat V, Guirimand G, Courdavault V, Papon N, Meyer S, Godet S, St-Pierre B, Giglioli-Guivarc’h N, Fischer MJ, Memelink J, Clastre M. Characterization of the plastidial geraniol synthase from Madagascar periwinkle which initiates the monoterpenoid branch of the alkaloid pathway in internal phloem associated parenchyma. Phytochemistry2013; 85: 36–43
doi: 10.1016/j.phytochem.2012.09.014 pmid: 23102596
26 Collu G, Unver N, Peltenburg-Looman AM, van der Heijden R, Verpoorte R, Memelink J. Geraniol 10-hydroxylase, a cytochrome P450 enzyme involved in terpenoid indole alkaloid biosynthesis. FEBS Lett2001; 508(2): 215–220
doi: 10.1016/S0014-5793(01)03045-9 pmid: 11718718
27 Geu-Flores F, Sherden NH, Courdavault V, Burlat V, Glenn WS, Wu C, Nims E, Cui Y, O’Connor SE. An alternative route to cyclic terpenes by reductive cyclization in iridoid biosynthesis. Nature2012; 492(7427): 138–142
doi: 10.1038/nature11692 pmid: 23172143
28 Salim V, Wiens B, Masada-Atsumi S, Yu F, De Luca V. 7-deoxyloganetic acid synthase catalyzes a key 3 step oxidation to form 7-deoxyloganetic acid in Catharanthus roseus iridoid biosynthesis. Phytochemistry2014; 101: 23–31
doi: 10.1016/j.phytochem.2014.02.009 pmid: 24594312
29 Asada K, Salim V, Masada-Atsumi S, Edmunds E, Nagatoshi M, Terasaka K, Mizukami H, De Luca V. A 7-deoxyloganetic acid glucosyltransferase contributes a key step in secologanin biosynthesis in Madagascar periwinkle. Plant Cell2013; 25(10): 4123–4134
doi: 10.1105/tpc.113.115154 pmid: 24104568
30 Salim V, Yu F, Altarejos J, De Luca V. Virus-induced gene silencing identifies Catharanthus roseus 7-deoxyloganic acid-7-hydroxylase, a step in iridoid and monoterpene indole alkaloid biosynthesis. Plant J2013; 76(5): 754–765
doi: 10.1111/tpj.12330 pmid: 24103035
31 Murata J, Roepke J, Gordon H, De Luca V. The leaf epidermome of Catharanthus roseus reveals its biochemical specialization. Plant Cell2008; 20(3): 524–542
doi: 10.1105/tpc.107.056630 pmid: 18326827
32 Vetter HP, Mangold U, Schr?der G, Marner FJ, Werck-Reichhart D, Schr?der J. Molecular analysis and heterologous expression of an inducible cytochrome P-450 protein from periwinkle (Catharanthus roseus L.). Plant Physiol1992; 100(2): 998–1007
doi: 10.1104/pp.100.2.998 pmid: 16653087
33 Irmler S, Schr?der G, St-Pierre B, Crouch NP, Hotze M, Schmidt J, Strack D, Matern U, Schr?der J. Indole alkaloid biosynthesis in Catharanthus roseus: new enzyme activities and identification of cytochrome P450 CYP72A1 as secologanin synthase. Plant J2000; 24(6): 797–804
doi: 10.1046/j.1365-313x.2000.00922.x pmid: 11135113
34 De Luca V, Marineau C, Brisson N. Molecular cloning and analysis of cDNA encoding a plant tryptophan decarboxylase: comparison with animal dopa decarboxylases. Proc Natl Acad Sci USA1989; 86(8): 2582–2586
doi: 10.1073/pnas.86.8.2582 pmid: 2704736
35 McKnight TD, Roessner CA, Devagupta R, Scott AI, Nessler CL. Nucleotide sequence of a cDNA encoding the vacuolar protein strictosidine synthase from Catharanthus roseus. Nucleic Acids Res1990; 18(16): 4939–4939
doi: 10.1093/nar/18.16.4939 pmid: 2395663
36 Geerlings A, Iba?ez MML, Memelink J, van Der Heijden R, Verpoorte R. Molecular cloning and analysis of strictosidine β-D-glucosidase, an enzyme in terpenoid indole alkaloid biosynthesis in Catharanthus roseus. J Biol Chem2000; 275(5): 3051–3056
doi: 10.1074/jbc.275.5.3051 pmid: 10652285
37 Guirimand G, Guihur A, Poutrain P, Héricourt F, Mahroug S, St-Pierre B, Burlat V, Courdavault V. Spatial organization of the vindoline biosynthetic pathway in Catharanthus roseus. J Plant Physiol2011; 168(6): 549–557
doi: 10.1016/j.jplph.2010.08.018 pmid: 21047699
38 Levac D, Murata J, Kim WS, De Luca V. Application of carborundum abrasion for investigating the leaf epidermis: molecular cloning of Catharanthus roseus 16-hydroxytabersonine-16-O-methyltransferase. Plant J2008; 53(2): 225–236
doi: 10.1111/j.1365-313X.2007.03337.x pmid: 18053006
39 St-Pierre B, Laflamme P, Alarco AM, De Luca V. The terminal O-acetyltransferase involved in vindoline biosynthesis defines a new class of proteins responsible for coenzyme A-dependent acyl transfer. Plant J1998; 14(6): 703–713
doi: 10.1046/j.1365-313x.1998.00174.x pmid: 9681034
40 Costa MMR, Hilliou F, Duarte P, Pereira LG, Almeida I, Leech M, Memelink J, Barceló AR, Sottomayor M. Molecular cloning and characterization of a vacuolar class III peroxidase involved in the metabolism of anticancer alkaloids in Catharanthus roseus. Plant Physiol2008; 146(2): 403–417
doi: 10.1104/pp.107.107060 pmid: 18065566
41 Yamamoto H, Katano N, Ooi A, Inoue K. Secologanin synthase which catalyzes the oxidative cleavage of loganin into secologanin is a cytochrome P450. Phytochemistry2000; 53(1): 7–12
doi: 10.1016/S0031-9422(99)00471-9 pmid: 10656401
42 Li J, Last RL. The Arabidopsis thaliana trp5 mutant has a feedback-resistant anthranilate synthase and elevated soluble tryptophan. Plant Physiol1996; 110(1): 51–59
doi: 10.1104/pp.110.1.51 pmid: 8587994
43 Noé W, Mollenschott C, Berlin J. Tryptophan decarboxylase from Catharanthus roseus cell suspension cultures: purification, molecular and kinetic data of the homogenous protein. Plant Mol Biol1984; 3(5): 281–288
doi: 10.1007/BF00017782 pmid: 24310513
44 Pasquali G, Goddijn OJ, de Waal A, Verpoorte R, Schilperoort RA, Hoge JHC, Memelink J. Coordinated regulation of two indole alkaloid biosynthetic genes from Catharanthus roseus by auxin and elicitors. Plant Mol Biol1992; 18(6): 1121–1131
doi: 10.1007/BF00047715 pmid: 1600148
45 Menke FL, Champion A, Kijne JW, Memelink J. A novel jasmonate- and elicitor-responsive element in the periwinkle secondary metabolite biosynthetic gene Str interacts with a jasmonate- and elicitor-inducible AP2-domain transcription factor, ORCA2. EMBO J1999; 18(16): 4455–4463
doi: 10.1093/emboj/18.16.4455 pmid: 10449411
46 Besseau S, Kellner F, Lanoue A, Thamm AM, Salim V, Schneider B, Geu-Flores F, H?fer R, Guirimand G, Guihur A, Oudin A, Glevarec G, Foureau E, Papon N, Clastre M, Giglioli-Guivarc’h N, St-Pierre B, Werck-Reichhart D, Burlat V, De Luca V, O’Connor SE, Courdavault V. A pair of tabersonine 16-hydroxylases initiates the synthesis of vindoline in an organ-dependent manner in Catharanthus roseus. Plant Physiol2013; 163(4): 1792–1803
doi: 10.1104/pp.113.222828 pmid: 24108213
47 Schr?der G, Unterbusch E, Kaltenbach M, Schmidt J, Strack D, De Luca V, Schr?der J. Light-induced cytochrome P450-dependent enzyme in indole alkaloid biosynthesis: tabersonine 16-hydroxylase. FEBS Lett1999; 458(2): 97–102
doi: 10.1016/S0014-5793(99)01138-2 pmid: 10481044
48 Li CY, Leopold AL, Sander GW, Shanks JV, Zhao L, Gibson SI. The ORCA2 transcription factor plays a key role in regulation of the terpenoid indole alkaloid pathway. BMC Plant Biol2013; 13(1): 155
doi: 10.1186/1471-2229-13-155 pmid: 24099172
49 Suttipanta N, Pattanaik S, Kulshrestha M, Patra B, Singh SK, Yuan L. The transcription factor CrWRKY1 positively regulates the terpenoid indole alkaloid biosynthesis in Catharanthus roseus. Plant Physiol2011; 157(4): 2081–2093
doi: 10.1104/pp.111.181834 pmid: 21988879
50 Martin VJ, Pitera DJ, Withers ST, Newman JD, Keasling JD. Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat Biotechnol2003; 21(7): 796–802
doi: 10.1038/nbt833 pmid: 12778056
51 Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MC, Withers ST, Shiba Y, Sarpong R, Keasling JD. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature2006; 440(7086): 940–943
doi: 10.1038/nature04640 pmid: 16612385
52 Ro DK, Ouellet M, Paradise EM, Burd H, Eng D, Paddon CJ, Newman JD, Keasling JD. Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid. BMC Biotechnol2008; 8(1): 83
doi: 10.1186/1472-6750-8-83 pmid: 18983675
53 Tsuruta H, Paddon CJ, Eng D, Lenihan JR, Horning T, Anthony LC, Regentin R, Keasling JD, Renninger NS, Newman JD. High-level production of amorpha-4,11-diene, a precursor of the antimalarial agent artemisinin, in Escherichia coli. PLoS ONE2009; 4(2): e4489
doi: 10.1371/journal.pone.0004489 pmid: 19221601
54 Paddon CJ, Westfall PJ, Pitera DJ, Benjamin K, Fisher K, McPhee D, Leavell MD, Tai A, Main A, Eng D, Polichuk DR, Teoh KH, Reed DW, Treynor T, Lenihan J, Fleck M, Bajad S, Dang G, Dengrove D, Diola D, Dorin G, Ellens KW, Fickes S, Galazzo J, Gaucher SP, 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 LF, Xu L, Yu M, Zhang Y, Zhao L, Lievense J, Covello PS, Keasling JD, Reiling KK, Renninger NS, Newman JD. High-level semi-synthetic production of the potent antimalarial artemisinin. Nature2013; 496(7446): 528–532
doi: 10.1038/nature12051 pmid: 23575629
55 Guerra-Bubb J, Croteau R, Williams RM. The early stages of taxol biosynthesis: an interim report on the synthesis and identification of early pathway metabolites. Nat Prod Rep2012; 29(6): 683–696
doi: 10.1039/c2np20021j pmid: 22547034
56 Jiang M, Stephanopoulos G, Pfeifer BA. Downstream reactions and engineering in the microbially reconstituted pathway for Taxol. Appl Microbiol Biotechnol2012; 94(4): 841–849
doi: 10.1007/s00253-012-4016-1 pmid: 22460591
57 Dai Z, Liu Y, Huang L, Zhang X. Production of miltiradiene by metabolically engineered Saccharomyces cerevisiae. Biotechnol Bioeng2012; 109(11): 2845–2853
doi: 10.1002/bit.24547 pmid: 22566191
58 Zhou YJ, Gao W, Rong Q, Jin G, Chu H, Liu W, Yang W, Zhu Z, Li G, Zhu G, Huang L, Zhao ZK. Modular pathway engineering of diterpenoid synthases and the mevalonic acid pathway for miltiradiene production. J Am Chem Soc2012; 134(6): 3234–3241
doi: 10.1021/ja2114486 pmid: 22280121
59 Guo J, Zhou YJ, Hillwig ML, Shen Y, Yang L, Wang Y, Zhang X, Liu W, Peters RJ, Chen X, Zhao ZK, Huang L. CYP76AH1 catalyzes turnover of miltiradiene in tanshinones biosynthesis and enables heterologous production of ferruginol in yeasts. Proc Natl Acad Sci USA2013; 110(29): 12108–12113
doi: 10.1073/pnas.1218061110 pmid: 23812755
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