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Perspectives and limits of engineering the isoprenoid metabolism in heterologous hosts

  • Remco Muntendam
  • Elena Melillo
  • Annamargareta Ryden
  • Oliver Kayser
Mini-Review

Abstract

Terpenoids belong to the largest class of natural compounds and are produced in all living organisms. The isoprenoid skeleton is based on assembling of C5 building blocks, but the biosynthesis of a great variety of terpenoids ranging from monoterpenoids to polyterpenoids is not fully understood today. Terpenoids play a fundamental role in human nutrition, cosmetics, and medicine. In the past 10 years, many metabolic engineering efforts have been undertaken in plants but also in microorganisms to improve the production of various terpenoids like artemisinin and paclitaxel. Recently, inverse metabolic engineering and combinatorial biosynthesis as main strategies in synthetic biology have been applied to produce high-cost natural products like artemisinin and paclitaxel in heterologous microorganisms. This review describes the recent progresses made in metabolic engineering of the terpenoid pathway with particular focus on fundamental aspects of host selection, vector design, and system biotechnology.

Keywords

Metabolic engineering Synthetic biology Terpenoids Artemisinin Paclitaxel Biosynthesis 

References

  1. Alberts AW (1988) Discovery, biochemistry and biology of lovastatin. Am J Cardiol 62(15):10J–15JCrossRefGoogle Scholar
  2. Alberts AW (1990) Lovastatin and simvastatin—inhibitors of HMG CoA reductase and cholesterol biosynthesis. Cardiology 77(Suppl 4):14–21CrossRefGoogle Scholar
  3. Alper H, Jin Y-S, Moxley JF, Stephanopoulos G (2005) Identifying gene targets for the metabolic engineering of lycopene biosynthesis in Escherichia coli. Metab Eng 7(3):155CrossRefGoogle Scholar
  4. An GH, Schuman DB, Johnson EA (1989) Isolation of Phaffia rhodozyma mutants with increased astaxanthin content. Appl Environ Microbiol 55(1):116–124Google Scholar
  5. An GH, Cho MH, Johnson EA (1999) Monocyclic carotenoid biosynthetic pathway in the yeast Phaffia rhodozyma (Xanthophyllomyces dendrorhous). J Biosci Bioeng 88(2):189–193CrossRefGoogle Scholar
  6. Anderson MS, Muehlbacher M, Street IP, Proffitt J, Poulter CD (1989) Isopentenyl diphosphate: dimethylallyl diphosphate isomerase. An improved purification of the enzyme and isolation of the gene from Saccharomyces cerevisiae. J Biol Chem 264(32):19169–19175Google Scholar
  7. Arsenault PR, Wobbe KK, Weathers PJ (2008) Recent advances in artemisinin production through heterologous expression. Curr Med Chem 15(27):2886–2896CrossRefGoogle Scholar
  8. Back K, Chappell J (1996) Identifying functional domains within terpene cyclases using a domain-swapping strategy. Proc Natl Acad Sci USA 93(13):6841–6845CrossRefGoogle Scholar
  9. Barkovich R, Liao JC (2001) Metabolic engineering of isoprenoids. Metab Eng 3(1):27–39CrossRefGoogle Scholar
  10. Basson ME, Thorsness M, Rine J (1986) Saccharomyces cerevisiae contains two functional genes encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proc Natl Acad Sci 83(15):5563–5567CrossRefGoogle Scholar
  11. Bender-Machado L, Bäuerlein M, Carrari F, Schauer N, Lytovchenko A, Gibon Y, Kelly AA, Loureiro M, Müller-Röber B, Willmitzer L, Fernie AR (2004) Expression of a yeast acetyl CoA hydrolase in the mitochondrion of tobacco plants inhibits growth and restricts photosynthesis. Plant Mol Biol 55(5):645–662CrossRefGoogle Scholar
  12. Berry S (2002) The chemical basis of membrane bioenergetics. J Mol Evol 54(5):595–613CrossRefGoogle Scholar
  13. Bertea CM, Freije JR, van der Woude H, Verstappen FW, Perk L, Marquez V, De Kraker JW, Posthumus MA, Jansen BJ, de Groot A, Franssen MC, Bouwmeester HJ (2005) Identification of intermediates and enzymes involved in the early steps of artemisinin biosynthesis in Artemisia annua. Planta Med 71(1):40–47CrossRefGoogle Scholar
  14. Besumbes O, Sauret-Güeto S, Phillips MA, Imperial S, Rodríguez-Concepción M, Boronat A (2004) Metabolic engineering of isoprenoid biosynthesis in Arabidopsis for the production of taxadiene, the first committed precursor of taxol. Biotechnol Bioeng 88(2):168–175CrossRefGoogle Scholar
  15. Bhosale P, Bernstein PS (2005) Microbial xanthophylls. Appl Microbiol Biotechnol 68(4):445–455CrossRefGoogle Scholar
  16. Bhuvaneswari V, Nagini S (2005) Lycopene: a review of its potential as an anticancer agent. Curr Med Chem Anticancer Agents 5(6):627–635CrossRefGoogle Scholar
  17. Bick JA, Lange BM (2003) Metabolic cross talk between cytosolic and plastidial pathways of isoprenoid biosynthesis: unidirectional transport of intermediates across the chloroplast envelope membrane. Arch Biochem Biophys 415(2):146–154CrossRefGoogle Scholar
  18. Bloch K (1992) Sterol molecule: structure, biosynthesis, and function. Steroids 57(8):378–383CrossRefGoogle Scholar
  19. Bone RA, Landrum JT, Cao Y, Howard AN, Alvarez-Calderon F (2007) Macular pigment response to a supplement containing meso-zeaxanthin, lutein and zeaxanthin. Nutr Metab (Lond) 4:12CrossRefGoogle Scholar
  20. Borrmann S, Issifou S, Esser G, Adegnika AA, Ramharter M, Matsiegui PB, Oyakhirome S, Mawili-Mboumba DP, Missinou MA, Kun JF, Jomaa H, Kremsner PG (2004) Fosmidomycin-clindamycin for the treatment of Plasmodium falciparum malaria. J Infect Dis 190(9):1534–1540CrossRefGoogle Scholar
  21. Botella-Pavía P, Besumbes O, Phillips MA, Carretero-Paulet L, Boronat A, Rodríguez-Concepción M (2004) Regulation of carotenoid biosynthesis in plants: evidence for a key role of hydroxymethylbutenyl diphosphate reductase in controlling the supply of plastidial isoprenoid precursors. Plant J 40(2):188–199CrossRefGoogle Scholar
  22. Boucher Y, Doolittle WF (2000) The role of lateral gene transfer in the evolution of isoprenoid biosynthesis pathways. Mol Microbiol 37(4):703–716CrossRefGoogle Scholar
  23. Bouwmeester HJ, Wallaart TE, Janssen MH, van Loo B, Jansen BJ, Posthumus MA, Schmidt CO, De Kraker JW, Konig WA, Franssen MC (1999) Amorpha-4, 11-diene synthase catalyses the first probable step in artemisinin biosynthesis. Phytochemistry 52(5):843–854CrossRefGoogle Scholar
  24. Caelles C, Ferrer A, Balcells L, Hegardt FG, Boronat A (1989) Isolation and structural characterization of a cDNA encoding Arabidopsis thaliana 3-hydroxy-3-methylglutaryl coenzyme A reductase. Plant Mol Biol 13(6):627–638CrossRefGoogle Scholar
  25. Campbell M, Hahn FM, Poulter CD, Leustek T (1998) Analysis of the isopentenyl diphosphate isomerase gene family from Arabidopsis thaliana. Plant Mol Biol 36(2):323–328CrossRefGoogle Scholar
  26. Carrari F, Urbanczyk-Wochniak E, Willmitzer L, Fernie AR (2003) Engineering central metabolism in crop species: learning the system. Metab Eng 5(3):191–200CrossRefGoogle Scholar
  27. Carretero-Paulet L, Cairó A, Botella-Pavía P, Besumbes O, Campos N, Boronat A, Rodríguez-Concepción M (2006) Enhanced flux through the methylerythritol 4-phosphate pathway in Arabidopsis plants overexpressing deoxyxylulose 5-phosphate reductoisomerase. Plant Mol Biol 62(4):683–695CrossRefGoogle Scholar
  28. Carrie C, Murcha MW, Millar AH, Smith SM, Whelan J (2007) Nine 3-ketoacyl-CoA thiolases (KATs) and acetoacetyl-CoA thiolases (ACATs) encoded by five genes in Arabidopsis thaliana are targeted either to peroxisomes or cytosol but not to mitochondria. Plant Mol Biol 63(1):97–108CrossRefGoogle Scholar
  29. Chappell J, Wolf F, Proulx J, Cuellar R, Saunders C (1995) Is the reaction catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A reductase a rate-limiting step for isoprenoid biosynthesis in plants? Plant Physiol 109(4):1337–1343Google Scholar
  30. Chen D, Ye H, Li G (2000) Expression of a chimeric farnesyl diphosphate synthase gene in Artemisia annua L. transgenic plants via Agrobacterium tumefaciens-mediated transformation. Plant Sci 155(2):179–185CrossRefGoogle Scholar
  31. Chew BP, Park JS, Wong MW, Wong TS (1999) A comparison of the anticancer activities of dietary β-carotene, canthaxanthin and astaxanthin in mice in vivo. Anticancer Res 19(3A):1849–1853Google Scholar
  32. Christianson DW (2008) Unearthing the roots of the terpenome. Curr Opin Chem Biol 12(2):141–150CrossRefGoogle Scholar
  33. Covello PS, Teoh KH, Polichuk DR, Reed DW, Nowak G (2007) Functional genomics and the biosynthesis of artemisinin. Phytochemistry 68(14):1864–1871CrossRefGoogle Scholar
  34. Croteau RB, Davis EM, Ringer KL, Wildung MR (2005) (−)-Menthol biosynthesis and molecular genetics. Naturwissenschaften 92(12):562–577CrossRefGoogle Scholar
  35. Dejong JM, Liu Y, Bollon AP, Long RM, Jennewein S, Williams D, Croteau RB (2006) Genetic engineering of taxol biosynthetic genes in Saccharomyces cerevisiae. Biotechnol Bioeng 93(2):212–224CrossRefGoogle Scholar
  36. Dudareva N, Andersson S, Orlova I, Gatto N, Reichelt M, Rhodes D, Boland W, Gershenzon J (2005) The nonmevalonate pathway supports both monoterpene and sesquiterpene formation in snapdragon flowers. Proc Natl Acad Sci 102(3):933–938CrossRefGoogle Scholar
  37. Eckstein-Ludwig U, Webb RJ, Van Goethem ID, East JM, Lee AG, Kimura M, O'Neill PM, Bray PG, Ward SA, Krishna S (2003) Artemisinins target the SERCA of Plasmodium falciparum. Nature 424(6951):957–961CrossRefGoogle Scholar
  38. Endo A, Kuroda M, Tanzawa K (1976) Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett 72(2):323–326CrossRefGoogle Scholar
  39. Engels B, Dahm P, Jennewein S (2008) Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards taxol (paclitaxel) production. Metab Eng 10(3–4):201CrossRefGoogle Scholar
  40. Enjuto M, Balcells L, Campos N, Caelles C, Arro M, Boronat A (1994) Arabidopsis thaliana contains two differentially expressed 3-hydroxy-3-methylglutaryl-CoA reductase genes, which encode microsomal forms of the enzyme. Proc Natl Acad Sci 91(3):927–931CrossRefGoogle Scholar
  41. Ernst&Young (2007) Sustained progress, the European perspective. Beyond borders: the global biotechnology report 2007, pp 44–47Google Scholar
  42. Estévez JM, Cantero A, Romero C, Kawaide H, Jimenez LF, Kuzuyama T, Seto H, Kamiya Y, León P (2000) Analysis of the expression of CLA1, a gene that encodes the 1-deoxyxylulose 5-phosphate synthase of the 2-C-methyl-d-erythritol-4-phosphate pathway in Arabidopsis. Plant Physiol 124(1):95–104CrossRefGoogle Scholar
  43. Estévez JM, Cantero A, Reindl A, Reichler S, León P (2001) 1-Deoxy-d-xylulose-5-phosphate synthase, a limiting enzyme for plastidic isoprenoid biosynthesis in plants. J Biol Chem 276(25):22901–22909CrossRefGoogle Scholar
  44. Faulks RM, Southon S (2005) Challenges to understanding and measuring carotenoid bioavailability. Biochim Biophys Acta 1740(2):95–100Google Scholar
  45. Feist AM, Herrgard MJ, Thiele I, Reed JL, Palsson BO (2009) Reconstruction of biochemical networks in microorganisms. Nat Rev Microbiol 7(2):129–143CrossRefGoogle Scholar
  46. Fischbach MA, Clardy J (2007) One pathway, many products. Nat Chem Biol 3(7):353–355CrossRefGoogle Scholar
  47. Gardner RG, Hampton RY (1999) A highly conserved signal controls degradation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in eukaryotes. J Biol Chem 274(44):31671–31678CrossRefGoogle Scholar
  48. Geng S, Ma M, Ye HC, Liu BY, Li GF, Kang C (2001) Effect of ipt gene expression on the physiological and chemical characteristics of Artemisia annua. Plant Sci 160:691–698CrossRefGoogle Scholar
  49. Gerjets T, Sandmann G (2006) Ketocarotenoid formation in transgenic potato. J Exp Bot 57(14):3639–3645CrossRefGoogle Scholar
  50. Gershenzon J, Dudareva N (2007) The function of terpene natural products in the natural world. Nat Chem Biol 3(7):408–414CrossRefGoogle Scholar
  51. Ghassemian M, Lutes J, Tepperman JM, Chang HS, Zhu T, Wang X, Quail PH, Lange BM (2006) Integrative analysis of transcript and metabolite profiling data sets to evaluate the regulation of biochemical pathways during photomorphogenesis. Arch Biochem Biophys 448(1–2):45–59CrossRefGoogle Scholar
  52. Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343(6257):425–430CrossRefGoogle Scholar
  53. Guerin M, Huntley ME, Olaizola M (2003) Haematococcus astaxanthin: applications for human health and nutrition. Trends Biotechnol 21(5):210–216CrossRefGoogle Scholar
  54. Hahn FM, Hurlburt AP, Poulter CD (1999) Escherichia coli open reading frame 696 is idi, a nonessential gene encoding isopentenyl diphosphate isomerase. J Bacteriol 181(15):4499–4504Google Scholar
  55. Hampel D, Mosandl A, Wust M (2005) Biosynthesis of mono- and sesquiterpenes in carrot roots and leaves (Daucus carota L.): metabolic cross talk of cytosolic mevalonate and plastidial methylerythritol phosphate pathways. Phytochemistry 66(3):305–311CrossRefGoogle Scholar
  56. Harada H, Yu F, et al. (2009) Efficient synthesis of functional isoprenoids from acetoacetate through metabolic pathway-engineered Escherichia coli. Appl Microbiol Biotechnol 81(5):915–925.CrossRefGoogle Scholar
  57. Harker M, Holmberg N, Clayton JC, Gibbard CL, Wallace AD, Rawlins S, Hellyer SA, Lanot A, Safford R (2003) Enhancement of seed phytosterol levels by expression of an N-terminal truncated Hevea brasiliensis (rubber tree) 3-hydroxy-3-methylglutaryl-CoA reductase. Plant Biotechnol J 1(2):113–121CrossRefGoogle Scholar
  58. Hasunuma T, Miyazawa SI, Yoshimura S, Shinzaki Y, Tomizawa KI, Shindo K, Choi SK, Misawa N, Miyake C (2008) Biosynthesis of astaxanthin in tobacco leaves by transplastomic engineering. Plant J 55:857–868CrossRefGoogle Scholar
  59. Haynes RK, Fugmann B, Stetter J, Rieckmann K, Heilmann HD, Chan HW, Cheung MK, Lam WL, Wong HN, Croft SL, Vivas L, Rattray L, Stewart L, Peters W, Robinson BL, Edstein MD, Kotecka B, Kyle DE, Beckermann B, Gerisch M, Radtke M, Schmuck G, Steinke W, Wollborn U, Schmeer K, Romer A (2006) Artemisone—a highly active antimalarial drug of the artemisinin class. Angew Chem Int Ed Engl 45(13):2082–2088CrossRefGoogle Scholar
  60. Hecht S, Eisenreich W, Adam P, Amslinger S, Kis K, Bacher A, Arigoni D, Rohdich F (2001) Studies on the nonmevalonate pathway to terpenes: the role of the GcpE (IspG) protein. Proc Natl Acad Sci USA 98(26):14837–14842CrossRefGoogle Scholar
  61. Hélène C, Christian L, Francis K, Thierry B (1999) The Saccharomyces cerevisiae mevalonate diphosphate decarboxylase (Erg19p) forms homodimers in vivo, and a single substitution in a structurally conserved region impairs dimerization. Curr Microbiol 38(5):290–294CrossRefGoogle Scholar
  62. Hemmerlin A, Hoeffler JF, Meyer O, Tritsch D, Kagan IA, Grosdemange-Billiard C, Rohmer M, Bach TJ (2003) Cross-talk between the cytosolic mevalonate and the plastidial methylerythritol phosphate pathways in tobacco bright yellow-2 cells. J Biol Chem 278(29):26666–26676CrossRefGoogle Scholar
  63. Herz S, Wungsintaweekul J, Schuhr CA, Hecht S, Luttgen H, Sagner S, Fellermeier M, Eisenreich W, Zenk MH, Bacher A, Rohdich F (2000) Biosynthesis of terpenoids: YgbB protein converts 4-diphosphocytidyl-2C-methyl-d-erythritol 2-phosphate to 2C-methyl-d-erythritol 2, 4-cyclodiphosphate. Proc Natl Acad Sci USA 97(6):2486–2490CrossRefGoogle Scholar
  64. Hey SJ, Powers SJ, Beale MH, Hawkins ND, Ward JL, Halford NG (2006) Enhanced seed phytosterol accumulation through expression of a modified HMG-CoA reductase. Plant Biotechnol J 4(2):219–229CrossRefGoogle Scholar
  65. Hiser L, Basson ME, Rine J (1994) ERG10 from Saccharomyces cerevisiae encodes acetoacetyl-CoA thiolase. J Biol Chem 269(50):31383–31389Google Scholar
  66. Howitt CA, Pogson BJ (2006) Carotenoid accumulation and function in seeds and non-green tissues. Plant Cell Environ 29(3):435–445CrossRefGoogle Scholar
  67. Hsieh MH, Goodman HM (2005) The Arabidopsis IspH homolog is involved in the plastid nonmevalonate pathway of isoprenoid biosynthesis. Plant Physiol 138(2):641–653CrossRefGoogle Scholar
  68. Hsieh MH, Goodman HM (2006) Functional evidence for the involvement of Arabidopsis IspF homolog in the nonmevalonate pathway of plastid isoprenoid biosynthesis. Planta 223(4):779–784CrossRefGoogle Scholar
  69. Huang Q, Roessner CA, Croteau R, Scott AI (2001) Engineering Escherichia coli for the synthesis of taxadiene, a key intermediate in the biosynthesis of taxol. Bioorg Med Chem 9(9):2237–2242CrossRefGoogle Scholar
  70. Hunter WN (2007) The non-mevalonate pathway of isoprenoid precursor biosynthesis. J Biol Chem 282(30):21573–21577CrossRefGoogle Scholar
  71. Illingworth DR, Tobert JA (2001) HMG-CoA reductase inhibitors. Adv Protein Chem 56:77–114CrossRefGoogle Scholar
  72. Jäckel C, Kast P, Hilvert D (2008) Protein design by directed evolution. Annu Rev Biophys 37:153–173CrossRefGoogle Scholar
  73. Jackson H, Braun CL, Ernst H (2008) The chemistry of novel xanthophyll carotenoids. Am J Cardiol 101(10, Supplement 1):S50CrossRefGoogle Scholar
  74. Jennewein S, Long RM, Williams RM, Croteau R (2004) Cytochrome p450 taxadiene 5alpha-hydroxylase, a mechanistically unusual monooxygenase catalyzing the first oxygenation step of taxol biosynthesis. Chem Biol 11(3):379–387CrossRefGoogle Scholar
  75. Jin YS, Stephanopoulos G (2007) Multi-dimensional gene target search for improving lycopene biosynthesis in Escherichia coli. Metab Eng 9(4):337–347CrossRefGoogle Scholar
  76. Jingami H, Brown MS, Goldstein JL, Anderson RG, Luskey KL (1987) Partial deletion of membrane-bound domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase eliminates sterol-enhanced degradation and prevents formation of crystalloid endoplasmic reticulum. J Cell Biol 104(6):1693–1704CrossRefGoogle Scholar
  77. Kanehisa M, Goto S (2000) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28(1):27–30CrossRefGoogle Scholar
  78. Kanehisa M, Goto S, Hattori M, Aoki-Kinoshita KF, Itoh M, Kawashima S, Katayama T, Araki M, Hirakawa M, Database issue (2006) From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res 34:D354–D357CrossRefGoogle Scholar
  79. Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, Katayama T, Kawashima S, Okuda S, Tokimatsu T, Yamanishi Y (2008) KEGG for linking genomes to life and the environment. Nucleic Acids Res 36(database issue):D480–D484Google Scholar
  80. Kim SH, Heo K, Chang YJ, Park SH, Rhee SK, Kim SU (2006) Cyclization mechanism of amorpha-4, 11-diene synthase, a key enzyme in artemisinin biosynthesis. J Nat Prod 69(5):758–762CrossRefGoogle Scholar
  81. Klein-Marcuschamer D, Ajikumar PK, Stephanopoulos G (2007) Engineering microbial cell factories for biosynthesis of isoprenoid molecules: beyond lycopene. Trends Biotechnol 25(9):417CrossRefGoogle Scholar
  82. Kobayashi K, Suzuki M, Tang J, Nagata N, Ohyama K, Seki H, Kiuchi R, Kaneko Y, Nakazawa M, Matsui M, Matsumoto S, Yoshida S, Muranaka T (2007) Lovastatin insensitive 1, a novel pentatricopeptide repeat protein, is a potential regulatory factor of isoprenoid biosynthesis in Arabidopsis. Plant Cell Physiol 48(2):322–331CrossRefGoogle Scholar
  83. Kroll J, Steinle A, Reichelt R, Ewering C, Steinbüchel A (2009) Establishment of a novel anabolism-based addiction system with an artificially introduced mevalonate pathway: complete stabilization of plasmids as universal application in white biotechnology. Metab Eng 11(3):168CrossRefGoogle Scholar
  84. Kuzuyama T (2002) Mevalonate and nonmevalonate pathways for the biosynthesis of isoprene units. Biosci Biotechnol Biochem 66(8):1619–1627CrossRefGoogle Scholar
  85. Landrum JT, Bone RA (2001) Lutein, zeaxanthin, and the macular pigment. Arch Biochem Biophys 385(1):28–40CrossRefGoogle Scholar
  86. Lange BM, Rujan T, Martin W, Croteau R (2000) Isoprenoid biosynthesis: the evolution of two ancient and distinct pathways across genomes. Proc Natl Acad Sci USA 97(24):13172–13177CrossRefGoogle Scholar
  87. Laule O, Furholz A, Chang HS, Zhu T, Wang X, Heifetz PB, Gruissem W, Lange M (2003) Crosstalk between cytosolic and plastidial pathways of isoprenoid biosynthesis in Arabidopsis thaliana. Proc Natl Acad Sci USA 100(11):6866–6871CrossRefGoogle Scholar
  88. Learned RM, Fink GR (1989) 3-Hydroxy-3-methylglutaryl-coenzyme A reductase from Arabidopsis thaliana is structurally distinct from the yeast and animal enzymes. Proc Natl Acad Sci 86(8):2779–2783CrossRefGoogle Scholar
  89. Lee PC, Mijts BN, Schmidt-Dannert C (2004) Investigation of factors influencing production of the monocyclic carotenoid torulene in metabolically engineered Escherichia coli. Appl Microbiol Biotechnol 65(5):538–546CrossRefGoogle Scholar
  90. Lehrman MA (2007) Teaching dolichol-linked oligosaccharides more tricks with alternatives to metabolic radiolabeling. Glycobiology 17(8):75R–85RCrossRefGoogle Scholar
  91. Lell B, Ruangweerayut R, Wiesner J, Missinou MA, Schindler A, Baranek T, Hintz M, Hutchinson D, Jomaa H, Kremsner PG (2003) Fosmidomycin, a novel chemotherapeutic agent for malaria. Antimicrob Agents Chemother 47(2):735–738CrossRefGoogle Scholar
  92. Li L, Van Eck J (2007) Metabolic engineering of carotenoid accumulation by creating a metabolic sink. Transgenic Res 16(5):581–585CrossRefGoogle Scholar
  93. Li L, Paolillo DJ, Parthasarathy MV, Dimuzio EM, Garvin DF (2001) A novel gene mutation that confers abnormal patterns of β-carotene accumulation in cauliflower (Brassica oleracea var. botrytis). Plant J 26(1):59–67CrossRefGoogle Scholar
  94. Liang PH, Ko TP, Wang AH (2002) Structure, mechanism and function of prenyltransferases. Eur J Biochem 269(14):3339–3354CrossRefGoogle Scholar
  95. Lichtenthaler HK (2000) Non-mevalonate isoprenoid biosynthesis: enzymes, genes and inhibitors. Biochem Soc Trans 28(6):785–789CrossRefGoogle Scholar
  96. Lichtenthaler HK (2007) Biosynthesis, accumulation and emission of carotenoids, alpha-tocopherol, plastoquinone, and isoprene in leaves under high photosynthetic irradiance. Photosynth Res 92(2):163–179CrossRefGoogle Scholar
  97. Liu YS, Wu JY (2007) Optimization of cell growth and carotenoid production of Xanthophyllomyces dendrorhous through statistical experiment design. Biochem Eng J 36(2):182CrossRefGoogle Scholar
  98. Liu C, Zhao Y, Wang Y (2006) Artemisinin: current state and perspectives for biotechnological production of an antimalarial drug. Appl Microbiol Biotechnol 72(1):11–20CrossRefGoogle Scholar
  99. Lois LM, Campos N, Putra SR, Danielsen K, Rohmer M, Boronat A (1998) Cloning and characterization of a gene from Escherichia coli encoding a transketolase-like enzyme that catalyzes the synthesis of d-1-deoxyxylulose 5-phosphate, a common precursor for isoprenoid, thiamin, and pyridoxol biosynthesis. Proc Natl Acad Sci 95(5):2105–2110CrossRefGoogle Scholar
  100. Lorenz RT, Cysewski GR (2000) Commercial potential for Haematococcus microalgae as a natural source of astaxanthin. Trends Biotechnol 18(4):160–167CrossRefGoogle Scholar
  101. Lu S, Van Eck J, Zhou X, Lopez AB, O'Halloran DM, Cosman KM, Conlin BJ, Paolillo DJ, Garvin DF, Vrebalov J, Kochian LV, Kupper H, Earle ED, Cao J, Li L (2006) The cauliflower Or gene encodes a DnaJ cysteine-rich domain-containing protein that mediates high levels of β-carotene accumulation. Plant Cell 18(12):3594–3605CrossRefGoogle Scholar
  102. Lüttgen H, Rohdich F, Herz S, Wungsintaweekul J, Hecht S, Schuhr CA, Fellermeier M, Sagner S, Zenk MH, Bacher A, Eisenreich W (2000) Biosynthesis of terpenoids: YchB protein of Escherichia coli phosphorylates the 2-hydroxy group of 4-diphosphocytidyl-2C-methyl-d-erythritol. Proc Natl Acad Sci 97(3):1062–1067CrossRefGoogle Scholar
  103. Mann V, Harker M, Pecker I, Hirschberg J (2000) Metabolic engineering of astaxanthin production in tobacco flowers. Nat Biotechnol 18(8):888–892CrossRefGoogle Scholar
  104. Martin VJ, Pitera DJ, Withers ST, Newman JD, Keasling JD (2003) Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat Biotechnol 21(7):796–802CrossRefGoogle Scholar
  105. Mayne ST, Handelman GJ, Beecher G (1996) β-Carotene and lung cancer promotion in heavy smokers—a plausible relationship? J Natl Cancer Inst 88(21):1513–1515CrossRefGoogle Scholar
  106. McNulty H, Jacob RF, Mason RP (2008) Biologic activity of carotenoids related to distinct membrane physicochemical interactions. Am J Cardiol 101(10, Supplement 1):S20CrossRefGoogle Scholar
  107. Mercke P, Bengtsson M, Bouwmeester HJ, Posthumus MA, Brodelius PE (2000) Molecular cloning, expression, and characterization of amorpha-4, 11-diene synthase, a key enzyme of artemisinin biosynthesis in Artemisia annua L. Arch Biochem Biophys 381(2):173–180CrossRefGoogle Scholar
  108. Mercke P, Kappers IF, Verstappen FW, Vorst O, Dicke M, Bouwmeester HJ (2004) Combined transcript and metabolite analysis reveals genes involved in spider mite induced volatile formation in cucumber plants. Plant Physiol 135(4):2012–2024CrossRefGoogle Scholar
  109. Mine Y, Kamimura T, Nonoyama S, Nishida M, Goto S, Kuwahara S (1980) In vitro and in vivo antibacterial activities of FR-31564, a new phosphonic acid antibiotic. J Antibiot (Tokyo) 33(1):36–43Google Scholar
  110. Montamat F, Guilloton M, Karst F, Delrot S (1995) Isolation and characterization of a cDNA encoding Arabidopsis thaliana 3-hydroxy-3-methylglutaryl-coenzyme A synthase. Gene 167(1–2):197–201CrossRefGoogle Scholar
  111. Muñoz-Bertomeu J, Arrillaga I, Ros R, Segura J (2006) Up-regulation of 1-deoxy-d-xylulose-5-phosphate synthase enhances production of essential oils in transgenic spike lavender. Plant Physiol 142(3):890–900CrossRefGoogle Scholar
  112. Muñoz-Bertomeu J, Sales E, Ros R, Arrillaga I, Segura J (2007) Up-regulation of an N-terminal truncated 3-hydroxy-3-methylglutaryl CoA reductase enhances production of essential oils and sterols in transgenic Lavandula latifolia. Plant Biotechnol J 5(6):746–758CrossRefGoogle Scholar
  113. Mutabingwa TK (2005) Artemisinin-based combination therapies (ACTs): best hope for malaria treatment but inaccessible to the needy! Acta Trop 95(3):305–315CrossRefGoogle Scholar
  114. Newman JD, Marshall J, Chang M, Nowroozi F, Paradise E, Pitera D, Newman KL, Keasling JD (2006) High-level production of amorpha-4, 11-diene in a two-phase partitioning bioreactor of metabolically engineered Escherichia coli. Biotechnol Bioeng 95(4):684–691CrossRefGoogle Scholar
  115. Niklitschek M, Alcaino J, Barahona S, Sepulveda D, Lozano C, Carmona M, Marcoleta A, Martinez C, Lodato P, Baeza M, Cifuentes V (2008) Genomic organization of the structural genes controlling the astaxanthin biosynthesis pathway of Xanthophyllomyces dendrorhous. Biol Res 41(1):93–108CrossRefGoogle Scholar
  116. Nims E, Dubois CP, Roberts SC, Walker EL (2006) Expression profiling of genes involved in paclitaxel biosynthesis for targeted metabolic engineering. Metab Eng 8(5):385–394CrossRefGoogle Scholar
  117. Ohyama K, Suzuki M, Masuda K, Yoshida S, Muranaka T (2007) Chemical phenotypes of the hmg1 and hmg2 mutants of Arabidopsis demonstrate the in-planta role of HMG-CoA reductase in triterpene biosynthesis. Chem Pharm Bull (Tokyo) 55(10):1518–1521CrossRefGoogle Scholar
  118. Oulmouden A, Karst F (1990) Isolation of the ERG12 gene of Saccharomyces cerevisiae encoding mevalonate kinase. Gene 88(2):253–257CrossRefGoogle Scholar
  119. Palazon J, Cusido RM, Bonfill M, Morales C, Pinol MT (2003) Inhibition of paclitaxel and baccatin III accumulation by mevinolin and fosmidomycin in suspension cultures of Taxus baccata. J Biotechnol 101(2):157–163CrossRefGoogle Scholar
  120. Papon N, Bremer J, Vansiri A, Andreu F, Rideau M, Crèche J (2005) Cytokinin and ethylene control indole alkaloid production at the level of the MEP/terpenoid pathway in Catharanthus roseus suspension cells. Planta Med 71(6):572–574CrossRefGoogle Scholar
  121. Paradise EM, Kirby J, Chan R, Keasling JD (2008) Redirection of flux through the FPP branch-point in Saccharomyces cerevisiae by downregulating squalene synthase. Biotechnol Bioeng 100:371–378CrossRefGoogle Scholar
  122. Patel RN (1998) Tour de paclitaxel: biocatalysis for semisynthesis. Annu Rev Microbiol 52:361–395CrossRefGoogle Scholar
  123. Pfleger BF, Pitera DJ, Smolke CD, Keasling JD (2006) Combinatorial engineering of intergenic regions in operons tunes expression of multiple genes. Nat Biotechnol 24(8):1027–1032CrossRefGoogle Scholar
  124. Pfleger BF, Pitera DJ, Newman JD, Martin VJ, Keasling JD (2007) Microbial sensors for small molecules: development of a mevalonate biosensor. Metab Eng 9(1):30–38CrossRefGoogle Scholar
  125. Phillips MA, León P, Boronat A, Rodríguez-Concepción M (2008) The plastidial MEP pathway: unified nomenclature and resources. Trends Plant Sci 13(12):619–623CrossRefGoogle Scholar
  126. Picaud S, Olofsson L, Brodelius M, Brodelius PE (2005) Expression, purification, and characterization of recombinant amorpha-4, 11-diene synthase from Artemisia annua L. Arch Biochem Biophys 436(2):215–226CrossRefGoogle Scholar
  127. Picaud S, Mercke P, He X, Sterner O, Brodelius M, Cane DE, Brodelius PE (2006) Amorpha-4, 11-diene synthase: mechanism and stereochemistry of the enzymatic cyclization of farnesyl diphosphate. Arch Biochem Biophys 448(1–2):150–155CrossRefGoogle Scholar
  128. Pitera DJ, Paddon CJ, Newman JD, Keasling JD (2007) Balancing a heterologous mevalonate pathway for improved isoprenoid production in Escherichia coli. Metab Eng 9(2):193–207CrossRefGoogle Scholar
  129. Platis D, Labrou NE (2008) Chemical and genetic engineering strategies to improve the potency of pharmaceutical proteins and enzymes. Curr Med Chem 15(19):1940–1955CrossRefGoogle Scholar
  130. Querol J, Campos N, Imperial S, Boronat A, Rodríguez-Concepción M (2002) Functional analysis of the Arabidopsis thaliana GCPE protein involved in plastid isoprenoid biosynthesis. FEBS Lett 514(2–3):343–346CrossRefGoogle Scholar
  131. Rajasingh H, Oyehaug L, Vage DI, Omholt SW (2006) Carotenoid dynamics in Atlantic salmon. BMC Biol 4:10CrossRefGoogle Scholar
  132. Riou C, Tourte Y, Lacroute F, Karst F (1994) Isolation and characterization of a cDNA encoding Arabidopsis thaliana mevalonate kinase by genetic complementation in yeast. Gene 148(2):293–297CrossRefGoogle Scholar
  133. Rischer H, Oresic M, Seppänen-Laakso T, Katajamaa M, Lammertyn F, Ardiles-Diaz W, Van Montagu MC, Inzé D, Oksman-Caldentey KM, Goossens A (2006) Gene-to-metabolite networks for terpenoid indole alkaloid biosynthesis in Catharanthus roseus cells. Proc Natl Acad Sci 103(14):5614–5619CrossRefGoogle Scholar
  134. 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 (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440(7086):940–943CrossRefGoogle Scholar
  135. Rodríguez-Concepción M, Forés O, Martinez-Garcia JF, González V, Phillips MA, Ferrer A, Boronat A (2004) Distinct light-mediated pathways regulate the biosynthesis and exchange of isoprenoid precursors during Arabidopsis seedling development. Plant Cell 16(1):144–156CrossRefGoogle Scholar
  136. Rodríguez-Sáiz M, Sánchez-Porro C, De La Fuente JL, Mellado E, Barredo JL (2007) Engineering the halophilic bacterium Halomonas elongata to produce β-carotene. Appl Microbiol Biotechnol 77(3):637–643CrossRefGoogle Scholar
  137. Rodriguez-Vargas S, Estruch F, Randez-Gil F (2002) Gene expression analysis of cold and freeze stress in baker’s yeast. Appl Environ Microbiol 68(6):3024–3030CrossRefGoogle Scholar
  138. Rohdich F, Wungsintaweekul J, Fellermeier M, Sagner S, Herz S, Kis K, Eisenreich W, Bacher A, Zenk MH (1999) Cytidine 5′-triphosphate-dependent biosynthesis of isoprenoids: YgbP protein of Escherichia coli catalyzes the formation of 4-diphosphocytidyl-2-C-methylerythritol. Proc Natl Acad Sci 96(21):11758–11763CrossRefGoogle Scholar
  139. Rohdich F, Wungsintaweekul J, Eisenreich W, Richter G, Schuhr CA, Hecht S, Zenk MH, Bacher A (2000) Biosynthesis of terpenoids: 4-diphosphocytidyl-2C-methyl-d-erythritol synthase of Arabidopsis thaliana. Proc Natl Acad Sci USA 97(12):6451–6456CrossRefGoogle Scholar
  140. Rohdich F, Hecht S, Gartner K, Adam P, Krieger C, Amslinger S, Arigoni D, Bacher A, Eisenreich W (2002) Studies on the nonmevalonate terpene biosynthetic pathway: metabolic role of IspH (LytB) protein. Proc Natl Acad Sci 99(3):1158–1163CrossRefGoogle Scholar
  141. Rohmer M, Knani M, Simonin P, Sutter B, Sahm H (1993) Isoprenoid biosynthesis in bacteria: a novel pathway for the early steps leading to isopentenyl diphosphate. Biochem J 295(Pt 2):517–524Google Scholar
  142. Rudney H, Ferguson JJ Jr (1959) 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. J Biol Chem 234(5):1076–1080Google Scholar
  143. Rydén A-M, Kayser O (2007) Chemistry, biosynthesis and biological activity of artemisinin and related natural peroxides. Bioactive Heterocycles III:1CrossRefGoogle Scholar
  144. Schmidt-Dannert C, Umeno D, Arnold FH (2000) Molecular breeding of carotenoid biosynthetic pathways. Nat Biotechnol 18(7):750–753CrossRefGoogle Scholar
  145. Schwender J, Muller C, Zeidler J, Lichtenthaler HK (1999) Cloning and heterologous expression of a cDNA encoding 1-deoxy-d-xylulose-5-phosphate reductoisomerase of Arabidopsis thaliana. FEBS Lett 455(1–2):140–144CrossRefGoogle Scholar
  146. Seemann M, Tse Sum Bui B, Wolff M, Miginiac-Maslow M, Rohmer M (2006) Isoprenoid biosynthesis in plant chloroplasts via the MEP pathway: direct thylakoid/ferredoxin-dependent photoreduction of GcpE/IspG. FEBS Lett 580(6):1547–1552CrossRefGoogle Scholar
  147. Shiba Y, Paradise EM, Kirby J, Ro DK, Keasling JD (2007) Engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae for high-level production of isoprenoids. Metab Eng 9(2):160–168CrossRefGoogle Scholar
  148. Shimada H, Kondo K, Fraser PD, Miura Y, Saito T, Misawa N (1998) Increased carotenoid production by the food yeast Candida utilis through metabolic engineering of the isoprenoid pathway. Appl Environ Microbiol 64(7):2676–2680Google Scholar
  149. Skorupinska-Tudek K, Poznanski J, Wojcik J, Bienkowski T, Szostkiewicz I, Zelman-Femiak M, Bajda A, Chojnacki T, Olszowska O, Grunler J, Meyer O, Rohmer M, Danikiewicz W, Swiezewska E (2008) Contribution of the mevalonate and methylerythritol phosphate pathways to the biosynthesis of dolichols in plants. J Biol Chem 283:21024–21035CrossRefGoogle Scholar
  150. Suthers PF, Burgard AP, Dasika MS, Nowroozi F, Van Dien S, Keasling JD, Maranas CD (2007) Metabolic flux elucidation for large-scale models using 13C labeled isotopes. Metab Eng 9(5–6):387–405CrossRefGoogle Scholar
  151. Suzuki M, Kamide Y, Nagata N, Seki H, Ohyama K, Kato H, Masuda K, Sato S, Kato T, Tabata S, Yoshida S, Muranaka T (2004) Loss of function of 3-hydroxy-3-methylglutaryl coenzyme A reductase 1 (HMG1) in Arabidopsis leads to dwarfing, early senescence and male sterility, and reduced sterol levels. Plant J 37(5):750–761CrossRefGoogle Scholar
  152. Takahashi S, Kuzuyama T, Watanabe H, Seto H (1998a) A 1-deoxy-d-xylulose 5-phosphate reductoisomerase catalyzing the formation of 2-C-methyl-d-erythritol 4-phosphate in an alternative nonmevalonate pathway for terpenoid biosynthesis. Proc Natl Acad Sci USA 95(17):9879–9884CrossRefGoogle Scholar
  153. Takahashi S, Kuzuyama T, Watanabe H, Seto H (1998b) A 1-deoxy-d-xylulose 5-phosphate reductoisomerase catalyzing the formation of 2-C-methyl-d-erythritol 4-phosphate in an alternative nonmevalonate pathway for terpenoid biosynthesis. Proc Natl Acad Sci 95(17):9879–9884CrossRefGoogle Scholar
  154. Toth MJ, Huwyler L (1996) Molecular cloning and expression of the cDNAs encoding human and yeast mevalonate pyrophosphate decarboxylase. J Biol Chem 271(14):7895–7898CrossRefGoogle Scholar
  155. Towler MJ, Weathers PJ (2007) Evidence of artemisinin production from IPP stemming from both the mevalonate and the nonmevalonate pathways. Plant Cell Rep 26(12):2129–2136CrossRefGoogle Scholar
  156. Tsay YH, Robinson GW (1991) Cloning and characterization of ERG8, an essential gene of Saccharomyces cerevisiae that encodes phosphomevalonate kinase. Mol Cell Biol 11(2):620–631Google Scholar
  157. Van der Kooy F, Verpoorte R, Marion Meyer JJ (2008) Metabolomic quality control of claimed anti-malarial Artemisia afra herbal remedy and A. afra and A. annua plant extracts. S Afr J Bot 74(2):186CrossRefGoogle Scholar
  158. Van Nieuwerburgh FCW, Vande Casteele SRF, Maes L, Goossens A, Inzé D, Van Bocxlaer J, Deforce DLD (2006) Quantitation of artemisinin and its biosynthetic precursors in Artemisia annua L. by high performance liquid chromatography-electrospray quadrupole time-of-flight tandem mass spectrometry. J Chromatogr A 111(2):180CrossRefGoogle Scholar
  159. Verdoes JC, Sandmann G, Visser H, Diaz M, van Mossel M, van Ooyen AJ (2003) Metabolic engineering of the carotenoid biosynthetic pathway in the yeast Xanthophyllomyces dendrorhous (Phaffia rhodozyma). Appl Environ Microbiol 69(7):3728–3738CrossRefGoogle Scholar
  160. Verwaal R, Wang J, Meijnen J-P, Visser H, Sandmann G, van den Berg JA, van Ooyen AJJ (2007) High-level production of β-carotene in Saccharomyces cerevisiae by successive transformation with carotenogenic genes from Xanthophyllomyces dendrorhous. Appl Environ Microbiol 73(13):4342–4350CrossRefGoogle Scholar
  161. Visser H, van Ooyen AJ, Verdoes JC (2003) Metabolic engineering of the astaxanthin-biosynthetic pathway of Xanthophyllomyces dendrorhous. FEMS Yeast Res 4(3):221–231CrossRefGoogle Scholar
  162. Visser H, Sandmann G, Verdoes JC (2005) Xanthophylls in fungi. In: Barredo JL (ed) Methods in biotechnology. Microbial processes and products. Humana, Totowa, p 257CrossRefGoogle Scholar
  163. Walker K, Croteau R (2001) Taxol biosynthetic genes. Phytochemistry 58(1):1–7CrossRefGoogle Scholar
  164. Wallaart TE, Bouwmeester HJ, Hille J, Poppinga L, Maijers NC (2001) Amorpha-4, 11-diene synthase: cloning and functional expression of a key enzyme in the biosynthetic pathway of the novel antimalarial drug artemisinin. Planta 212(3):460–465CrossRefGoogle Scholar
  165. Wang X, Willen R, Wadstrom T (2000) Astaxanthin-rich algal meal and vitamin C inhibit Helicobacter pylori infection in BALB/cA mice. Antimicrob Agents Chemother 44(9):2452–2457CrossRefGoogle Scholar
  166. Wilderman PR, Peters RJ (2007) A single residue switch converts abietadiene synthase into a pimaradiene specific cyclase. J Am Chem Soc 129(51):15736–15737CrossRefGoogle Scholar
  167. Withers ST, Keasling JD (2007) Biosynthesis and engineering of isoprenoid small molecules. Appl Microbiol Biotechnol 73(5):980–990CrossRefGoogle Scholar
  168. Xu M, Wilderman PR, Peters RJ (2007) Following evolution's lead to a single residue switch for diterpene synthase product outcome. Proc Natl Acad Sci 104(18):7397–7401CrossRefGoogle Scholar
  169. Yeum KJ, Russell RM (2002) Carotenoid bioavailability and bioconversion. Annu Rev Nutr 22:483–504CrossRefGoogle Scholar
  170. Yoon SH, Park HM, Kim JE, Lee SH, Choi MS, Kim JY, Oh DK, Keasling JD, Kim SW (2007) Increased β-carotene production in recombinant Escherichia coli harboring an engineered isoprenoid precursor pathway with mevalonate addition. Biotechnol Prog 23(3):599–605CrossRefGoogle Scholar
  171. Yuan LZ, Rouviere PE, Larossa RA, Suh W (2006) Chromosomal promoter replacement of the isoprenoid pathway for enhancing carotenoid production in E. coli. Metab Eng 8(1):79–90CrossRefGoogle Scholar
  172. Yukimune Y, Hara Y, Nomura E, Seto H, Yoshida S (2000) The configuration of methyl jasmonate affects paclitaxel and baccatin III production in Taxus cells. Phytochemistry 54(1):13–17CrossRefGoogle Scholar
  173. Zhang Y, Teoh KH, Reed DW, Maes L, Goossens A, Olson DJ, Ross AR, Covello PS (2008) The molecular cloning of artemisinic aldehyde Delta11(13) reductase and its role in glandular trichome-dependent biosynthesis of artemisinin in Artemisia annua. J Biol Chem 283(31):21501–21508CrossRefGoogle Scholar
  174. Zhao K, Ping W, Zhang L, Liu J, Lin Y, Jin T, Zhou D (2008) Screening and breeding of high taxol producing fungi by genome shuffling. Sci China C Life Sci 51(3):222–231CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Remco Muntendam
    • 1
  • Elena Melillo
    • 1
  • Annamargareta Ryden
    • 1
  • Oliver Kayser
    • 1
    • 2
  1. 1.Department of Pharmaceutical Biology, GUIDEUniversity of GroningenGroningenThe Netherlands
  2. 2.Rijksuniversiteit Groningen, Farmaceutische BiologieGroningenthe Netherlands

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