A Glimpse into the Biosynthesis of Terpenoids
Abstract
Terpenoids represent the largest class of natural products with a diverse array of structures and functions. Many terpenoids have reported therapeutic properties such as antimicrobial, anti-inflammatory, immunomodulatory and chemotherapeutic properties making them of great interest in the medical field. Also, they are widely used in the flavors and fragrances industries, in addition to being a source of biofuels. Terpenoids suffer from low natural yields and complicated chemical synthesis, hence the need for a more sustainable production method. Metabolic engineering provide an excellent opportunity to construct microbial cell factories producing the desired terpenoids. The biosynthetic mevalonate and non-mevalonate pathways involved in the production of terpenoid precursors are fully characterized so exploring methods to improve their flux would be the first step in creating a successful cell factory. The complexity and diversity of terpenoid structures depends mainly on the action of the terpene synthases responsible for their synthesis. These enzymes are classified into different classes and gaining insight into their catalytic mechanism will be useful in designing approaches to improve terpenoid production. This review focuses on the biosynthesis and biodiversity of terpenoids, understanding the terpene synthase enzyme family involved in their synthesis and the engineering efforts to create microbial cell factories for terpenoid production.
References
[1] Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nature Reviews Drug Discovery 2005;4:206–220.
[2] Lahlou M. The success of natural products in drug discovery. Pharmacology & Pharmacy 2013;4:17–31.
[3] Dias DA, Urban S, Roessner U. A Historical overview of natural products in drug discovery. Metabolites 2012;2:303–36.
[4] Harvey AL, Edrada-Ebel R, Quinn RJ. The re-emergence of natural products for drug discovery in the genomics era. Nature Reviews Drug Discovery 2015;14:111–29.
[5] Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. Journal of Natural Products 2012;75:311–35.
[6] Wang G, Tang W, Bidigare RR. Terpenoids as therapeutic drugs and pharmaceutical agents. Natural products: Drug discovery and therapeutic medicine. In: Zhang L, Demain AL (Eds.). Totowa, NJ: Humana Press; 2005. p. 197–227.
[7] Thoppil RJ, Bishayee A. Terpenoids as potential chemopreventive and therapeutic agents in liver cancer. World Journal Hepatology 2011;3:228–249.
[8] Guan Z, Xue D, Abdallah II, Dijkshoorn L, Setroikromo R, Guiyuan L, et al. Metabolic engineering of Bacillus subtilis for terpenoid production. Applied Microbiology and Biotechnology 2015;99:9395–9406.
[9] Ajikumar PK, Tyo K, Carlsen S, Mucha O, Phon TH, Stephanopoulos G. Terpenoids: Opportunities for biosynthesis of natural product drugs using engineered microorganisms. Molecular Pharmaceutics 2008;5:167–190.
[10] Lange BM, Rujan T, Martin W, Croteau R. Isoprenoid biosynthesis: the evolution of two ancient and distinct pathways across genomes. Proceedings of the National Academy of Sciences of USA 2000;97:13172–13177.
[11] Dewick PM. The mevalonate and deoxyxylulose phosphate pathways: terpenoids and steroids. In: Medicinal natural products. John Wiley & Sons, Ltd; 2001. p. 167– 289.
[12] Eisenreich W, Schwarz M, Cartayrade A, Arigoni D, Zenk MH, Bacher A. The deoxyxylulose phosphate pathway of terpenoid biosynthesis in plants and microorganisms. Chemistry and Biology 1998;5:R221–R233.
[13] Tholl D. Terpene synthases and the regulation, diversity and biological roles of terpene metabolism. Current Opinion in Plant Biology 2006;9:297–304.
[14] Pattanaik B, Lindberg P. Terpenoids and their biosynthesis in cyanobacteria. Life 2015;5:269–293.
[15] Loza-Tavera H. Monoterpenes in essential oils. Biosynthesis and properties. Advances in Experimental Medicine and Biology 1999;464:49–62.
[16] Banthorpe DV, Charlwood BV, Francis MJO. Biosynthesis of monoterpenes. Chemical Review 1972;72:115–155.
[17] Cordell GA. Biosynthesis of sesquiterpenes. Chemical Review 1976;76:425–460.
[18] Chadwick M, Trewin H, Gawthrop F, Wagstaff C. Sesquiterpenoids lactones: Benefits to plants and people. International Journal of Molecular Sciences 2013;14:12780– 12805.
[19] Bhat SV, Sivakumar M, Nagasampagi BA. Chemistry of natural products. Berlin: Narosa; 2005.
[20] Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nature Medicine 2011;17:1217–1220.
[21] Lai HC, Singh NP, Sasaki T. Development of artemisinin compounds for cancer treatment. Investigational New Drugs 2013;31:230–246.
[22] Das AK. Anticancer effect of antimalarial artemisinin compounds. Annals of Medical and Health Sciences Research 2015;5:93–102.
[23] Lai H, Sasaki T, Singh NP. Targeted treatment of cancer with artemisinin and artemisinin-tagged iron-carrying compounds. Expert Opinion on Therapeutic Targets 2005;9:995–1007.
[24] Abdallah II, Czepnik M, van Merkerk R, Quax WJ. Insights into the three-dimensional structure of amorpha-4,11-diene synthase and probing of plasticity residues. Journal of Natural Product 2016;79:2455–2463
[25] Priyadarshini K, Keerthi Aparajitha U. Paclitaxel against cancer: A short review Medical Chemistry 2012;2:139–141.
[26] Boghigian BA, Salas D, Ajikumar PK, Stephanopoulos G, Pfeifer BA. Analysis of heterologous taxadiene production in K- and B-derived Escherichia coli. Applied Microbiology and Biotechnology 2012;93:1651–1661.
[27] Hezari M, Croteau R. Taxol biosynthesis: An update. Planta Medica 1997;63:291–295.
[28] Gao Y, Honzatko RB, Peters RJ. Terpenoid synthase structures: A so far incomplete view of complex catalysis. Natural Product Reports 2012;29:1153–1175.
[29] Köksal M, Jin Y, Coates RM, Croteau R, Christianson DW. Taxadiene synthase structure and evolution of modular architecture in terpene biosynthesis. Nature 2011;469:116–120.
[30] Christianson DW. Structural biology and chemistry of the terpenoid cyclases. Chemical Reviews 2006;106:3412–3442.
[31] Noel JP, Dellas N, Faraldos JA, Zhao M, Hess BA, Smentek L, et al. Structural elucidation of cisoid and transoid cyclization pathways of a sesquiterpene synthase using 2-fluorofarnesyl diphosphates. ACS Chemical Biology 2010;5:377–392.
[32] Bloom JD, Meyer MM, Meinhold P, Otey CR, MacMillan D, Arnold FH. Evolving strategies for enzyme engineering. Current Opinion in Structural Biology 2005;15:447–452.
[33] Diaz JE, Lin CS, Kunishiro K, Feld BK, Avrantinis SK, Bronson J, Greaves J, Saven JG,Weiss GA. Computational design and selections for an engineered, thermostable terpene synthase. Protein Science 2011;20:1597–1606.
[34] Christianson DW. Unearthing the roots of the terpenome. Current Opinion in Chemical Biology 2008;12:141–150.
[35] Köksal M, Zimmer I, Schnitzler J-P, Christianson DW. Structure of isoprene synthase illuminates the chemical mechanism of teragram atmospheric carbon emission. Journal of Molecular Biology 2010;402:363–373.
[36] Hyatt DC, Youn B, Zhao Y, Santhamma B, Coates RM, Croteau RB, et al. Structure of limonene synthase, a simple model for terpenoid cyclase catalysis. Proceedings of National Academy of Sciences USA 2007;104:5360–5365.
[37] Kampranis SC, Ioannidis D, Purvis A, Mahrez W, Ninga E, Katerelos NA, et al. Rational conversion of substrate and product specificity in a Salvia monoterpene synthase: structural insights into the evolution of terpene synthase function. Plant Cell 2007;19:1994–2005.
[38] Whittington DA, Wise ML, Urbansky M, Coates RM, Croteau RB, Christianson DW.Bornyl diphosphate synthase: structure and strategy for carbocation manipulation by a terpenoid cyclase. Proceedings of National Academy of Sciences USA 2002;99:15375–15380.
[39] Miller DJ, Allemann RK. Sesquiterpene synthases: Passive catalysts or active players? Natural Product Reports 2012;29:60–71.
[40] Li JX, Fang X, Zhao Q, Ruan JX, Yang CQ, Wang LJ, et al. Rational engineering of plasticity residues of sesquiterpene synthases from Artemisia annua: Product specificity and catalytic efficiency. Biochemical Journal 2013;451:417–426.
[41] Klein-Marcuschamer D, Ajikumar PK, Stephanopoulos G. Engineering microbial cell factories for biosynthesis of isoprenoid molecules: beyond lycopene. Trends in Biotechnology 2007;25:417–424.
[42] Chang MCY, Keasling JD. Production of isoprenoid pharmaceuticals by engineered microbes. Nature Chemical Biology 2006;2:674–681.
[43] Chen X, Zhou L, Tian K, Kumar A, Singh S, Prior BA, Wang Z. Metabolic engineering of Escherichia coli: A sustainable industrial platform for bio-based chemical production. Biotechnology Advances 2013;31:1200–1223.
[44] Martin VJJ, Pitera DJ, Withers ST, Newman JD, Keasling JD. Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nature Biotechnology 2003;21:796–802.
[45] Kampranis SC, Makris AM. Developing a yeast cell factory for the production of terponoids. Computational and Structural Biotechnology Journal 2012;3:1–7.
[46] Xue D, Abdallah II, de Haan IEM, Sibbald MJJB, Quax WJ. Enhanced C30 carotenoid production in Bacillus subtilis by systematic overexpression of MEP pathway genes. Applied Microbiology and Biotechnology 2015;99:5907–5915.
[47] Zhou K, Zou R, Zhang C, Stephanopoulos G, Too HP. Optimization of amorphadiene synthesis in Bacillus subtilis via transcriptional, translational, and media modulation.Biotechnology and Bioengineering 2013;110:2556–2561.
[48] Yoshida K, Ueda S, Maeda I. Carotenoid production in Bacillus subtilis achieved by metabolic engineering. Biotechnology Letters 2009;31:1789–1793.
[49] Ducat DC, Way JC, Silver PA. Engineering cyanobacteria to generate high-value products. Trends Biotechnology 2011;29:95–103.