Metabolic and Enzyme Engineering for the Microbial Production of Anticancer Terpenoids

  • Suresh Chandra Phulara
  • Vikrant Singh Rajput
  • Bidyut Mazumdar
  • Ashish Runthala


Terpene or terpenoid or isoprenoid represents the largest class of secondary metabolites and has a variety of applications in food, fragrance, and pharmaceutical industry. Recent advancements and extensive research analysis on various cell lines and animal models have recognized their anticancer potential. To date plants are the major sources of such terpenoid; however, due to low abundance in these natural resources, their extraction from plant is not cost-effective. In addition, several plant species have been heavily exploited due to the presence of such tremendous molecules and have become endangered. The complex structure of terpenoid also limits their production from chemical routes. Therefore, to overcome the limitations in plant-based extraction and chemical synthesis of terpenoids, several microbial hosts have been exploited for the production of therapeutically important terpenoids including precursors of anticancer terpene, paclitaxel, or Taxol. Here, we summarize the biosynthesis terpenoids in natural system and advances in their production from microbial sources. In silico analysis is done to explore the physicochemical properties of an important enzyme (IspA) of terpenoid biosynthesis pathway, which is responsible for the supply of an isoprenoid precursor, FPP. The enzyme is functionally explored to construct its near-native protein model by comparative modeling. The most and the least conserved residues are lastly traced in this class and structurally localized to delineate the further research.


Terpenoid Anticancer Microbial production Taxol Enzyme design 


  1. 1.
    Ajikumar PK, Tyo K, Carlsen S, Mucha O, Phon TH, Stephanopoulos G (2008) Terpenoids: opportunities for biosynthesis of natural product drugs using engineered microorganisms. Mol Pharm 5:167–190CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Breitmaier E (2006) Terpenes: flavors, fragrances, pharmaca, pheromones. Wiley, WeinheimCrossRefGoogle Scholar
  3. 3.
    George KW, Alonso-Gutierrez J, Keasling JD, Lee TS (2015) Isoprenoid drugs, biofuels, and chemicals-artemisinin, farnesene, and beyond. Adv Biochem Eng Biotechnol:355–389.
  4. 4.
    Hillier SG, Lathe R (2019) Terpenes, hormones, and life: isoprene rule revisited. J Endocrinol 242:R9–R22. Scholar
  5. 5.
    Burke YD, Stark MJ, Roach SL, Sen SE, Crowell PL (1997) Inhibition of pancreatic cancer growth by the dietary isoprenoids farnesol and geraniol. Lipids 32:151–156CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    He L, Mo H, Hadisusilo S, Qureshi AA, Elson CE (1997) Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. J Nutr 127:668–674CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Huang M, Lu JJ, Huang MQ, Bao JL, Chen XP, Wang YT (2012) Terpenoids: natural products for cancer therapy. Expert Opin Investig Drugs 21(12):1801–1818CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ludwiczuk A, Skalicka-Woźniak K, Georgiev MI (2017) Terpenoids. In: Badal S, Delgoda R (eds) Pharmacognosy. Elsevier, pp 233–266.
  9. 9.
    Katsuki H, Bloch K (1967) Studies on the biosynthesis of ergosterol in yeast: formation of methylated intermediates. J Biol Chem 242:222–227PubMedPubMedCentralGoogle Scholar
  10. 10.
    Lynen F (1967) Biosynthetic pathways from acetate to natural products. Pure Appl Chem 14:137–168CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Eisenreich W, Menhard B, Hylands PJ, Zenk MH, Bacher A (1996) Studies on the biosynthesis of Taxol: the taxane carbon skeleton is not of mevalonoid origin. Proc Natl Acad Sci U S A 93:6431–6436CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Rohdich F, Zepeck F, Adam P, Hecht S, Kaiser J, Laupitz R, Grawert T, Amslinger S, Eisenreich W, Bacher A, Arigoni D (2002) The deoxyxylulose phosphate pathway of isoprenoid biosynthesis: studies on the mechanisms of the reactions catalyzed by IspG and IspH protein. Proc Natl Acad Sci U S A 100:1586–1591CrossRefGoogle Scholar
  13. 13.
    Miziorko HM (2011) Enzymes of the mevalonate pathway of isoprenoid biosynthesis. Arch Biochem Biophys 505:131–143. Scholar
  14. 14.
    Ferguson JJ, Rudney H (1959) The biosynthesis of β-hydroxy-β-methylglutaryl coenzyme A in yeast: I. Identification and purification of the hydroxymethylglutaryl coenzyme-condensing enzyme. J Biol Chem 234:1072–1075PubMedPubMedCentralGoogle Scholar
  15. 15.
    Durr IF, Rudney H (1960) The reduction of β-hydroxy-β-methylglutaryl coenzyme A to mevalonic acid. J Biol Chem 235:2572–2578PubMedPubMedCentralGoogle Scholar
  16. 16.
    Tchen TT (1958) Mevalonic kinase: purification and purification. J Biol Chem 233:1100–1103PubMedPubMedCentralGoogle Scholar
  17. 17.
    Helling H, Popjak G (1961) Studies on the biosynthesis of cholesterol: XIII. Phosphomevalonic kinase from liver. J. Lipid Res 2:235–243Google Scholar
  18. 18.
    Bloch K, Chaykin S, Phillips AH, De Waard A (1959) Mevalonic acid pyrophosphate and isopentenyl pyrophosphate. J Biol Chem 234:2595–2604PubMedPubMedCentralGoogle Scholar
  19. 19.
    Wilding EI, Brown JR, Bryant AP, Chalker AF, Holmes DJ, Ingraham KA, Iordanescu S, So CY, Rosenberg M, Gwynn MN (2000) Identification, evolution, and essentiality of the mevalonate pathway for isopentenyl diphosphate biosynthesis in gram-positive cocci. J Bacteriol 182:4319–4327CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hunter WN (2007) The non-mevalonate pathway of isoprenoid precursor biosynthesis. J Biol Chem 282:21573–21577. Scholar
  21. 21.
    Rohdich F, Hecht S, Gärtner 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 U S A 99:1158–1163. Scholar
  22. 22.
    Lange BM, Wildung MR, McCaskill D, Croteau R (1998) A family of transketolases that directs isoprenoid biosynthesis via a mevalonate-independent pathway. Proc Natl Acad Sci U S A 95:2100–2104. Scholar
  23. 23.
    Lange BM, Croteau R (1999) Isoprenoid biosynthesis via a mevalonate-independent pathway in plants: cloning and heterologous expression of 1-deoxy-D-xylulose-5-phosphate reductoisomerase from peppermint. Arch Biochem Biophys 365:170–174CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    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 U S A 96:11758–11763CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    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 U S A 97:1062–1067CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Herz S, Wungsintaweekul J, Schuhr CA, Hecht S, Lüttgen 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 U S A 97:2486–2490CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lesgards JF, Baldovini N, Vidal N, Pietri S (2014) Anticancer activities of essential oils constituents and synergy with conventional therapies: a review. Phytother Res 28(10):1423–1446CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Sun J (2007) D-limonene: safety and clinical applications. Altern Med Rev 12(3):259PubMedPubMedCentralGoogle Scholar
  29. 29.
    Clegg RJ, Middleton B, Bell GD, White DA (1982) The mechanism of cyclic monoterpene inhibition of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase in vivo in the rat. J Biol Chem 257(5):2294–2299PubMedPubMedCentralGoogle Scholar
  30. 30.
    Kawata S, Nagase T, Yamasaki E, Ishiguro H, Matsuzawa Y (1994) Modulation of the mevalonate pathway and cell growth by pravastatin and d-limonene in a human hepatoma cell line (Hep G2). Br J Cancer 69(6):1015CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ji J, Zhang L, Wu YY, Zhu XY, Lv SQ, Sun XZ (2006) Induction of apoptosis by d-limonene is mediated by a caspase-dependent mitochondrial death pathway in human leukemia cells. Leuk Lymphoma 47(12):2617–2624CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Liu D, Chen Z (2009) The effects of cantharidin and cantharidin derivates on tumour cells. Anticancer Agents Med Chem 9(4):392–396CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Chen YN, Chen JC, Yin SC, Wang GS, Tsauer W, Hsu SF, Hsu SL (2002) Effector mechanisms of norcantharidin-induced mitotic arrest and apoptosis in human hepatoma cells. Int J Cancer 100(2):158–165CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Huan SKH, Lee HH, Liu DZ, Wu CC, Wang CC (2006) Cantharidin-induced cytotoxicity and cyclooxygenase 2 expression in human bladder carcinoma cell line. Toxicology 223(1-2):136–143CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Huh JE, Kang KS, Chae C, Kim HM, Ahn KS, Kim SH (2004) Roles of p38 and JNK mitogen-activated protein kinase pathways during cantharidin-induced apoptosis in U937 cells. Biochem Pharmacol 67(10):1811–1818CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Li W, Chen Z, Zong Y, Gong F, Zhu Y, Zhu Y, Lv J, Zhang J, Xie L, Sun Y, Miao Y, Tao M, Han X, Xu Z (2011) PP2A inhibitors induce apoptosis in pancreatic cancer cell line PANC-1 through persistent phosphorylation of IKKα and sustained activation of the NF-κB pathway. Cancer Lett 304(2):117–127CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Li W, Xie L, Chen Z, Zhu Y, Sun Y, Miao Y, Xu Z, Han X (2010) Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. Cancer Sci 101(5):1226–1233CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Chen T, Li M, Zhang R, Wang H (2009) Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy. J Cell Mol Med 13(7):1358–1370CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Hou J, Wang D, Zhang R, Wang H (2008) Experimental therapy of hepatoma with artemisinin and its derivatives: in vitro and in vivo activity, chemosensitization, and mechanisms of action. Clin Cancer Res 14(17):5519–5530CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Buommino E, Baroni A, Canozo N, Petrazzuolo M, Nicoletti R, Vozza A, Tufano MA (2009) Artemisinin reduces human melanoma cell migration by down-regulating αvβ3 integrin and reducing metalloproteinase 2 production. Investig New Drugs 27(5):412–418CrossRefGoogle Scholar
  41. 41.
    Rasheed SAK, Efferth T, Asangani IA, Allgayer H (2010) First evidence that the antimalarial drug artesunate inhibits invasion and in vivo metastasis in lung cancer by targeting essential extracellular proteases. Int J Cancer 127(6):1475–1485CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Zhou L, Zuo Z, Chow MSS (2005) Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol 45(12):1345–1359CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Jiao JW, Wen F (2011) Tanshinone IIA acts via p38 MAPK to induce apoptosis and the down-regulation of ERCC1 and lung-resistance protein in cisplatin-resistant ovarian cancer cells. Oncol Rep 25(3):781–788PubMedPubMedCentralGoogle Scholar
  44. 44.
    Lee DH, Iwanski GB, Thoennissen NH (2010) Cucurbitacin: ancient compound shedding new light on cancer treatment. Sci World J 10:413–418CrossRefGoogle Scholar
  45. 45.
    Lee WY, Cheung CC, Liu KW, Fung KP, Wong J, Lai PB, Yeung JH (2010) Cytotoxic effects of tanshinones from Salvia miltiorrhiza on doxorubicin-resistant human liver cancer cells. J Nat Prod 73(5):854–859CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Leuenroth SJ, Okuhara D, Shotwell JD, Markowitz GS, Yu Z, Somlo S, Crews CM (2007) Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease. Proc Natl Acad Sci 104(11):4389–4394CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    McCallum C, Kwon S, Leavitt P, Shen DM, Liu W, Gurnett A (2007) Triptolide binds covalently to a 90 kDa nuclear protein. Role of epoxides in binding and activity. Immunobiology 212(7):549–556CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Titov DV, Gilman B, He QL, Bhat S, Low WK, Dang Y, Smeaton M, Demain AL, Miller PS, Kugel JF, Goodrich JA (2011) XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat Chem Biol 7(3):182CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Pan DJ, Li ZL, Hu CQ, Chen K, Chang JJ, Lee KH (1990) The cytotoxic principles of Pseudolarix kaempferi: pseudolaric acid-A and-B and related derivatives1. Plantamedica 56(04):383–385Google Scholar
  50. 50.
    Aparicio LMA, Pulido EG, Gallego GA (2012) Vinflunine: a new vision that may translate into antiangiogenic and antimetastatic activity. Anti-Cancer Drugs 23(1):1–11CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lim JCW, Chan TK, Ng DS, Sagineedu SR, Stanslas J, Wong WF (2012) Andrographolide and its analogues: versatile bioactive molecules for combating inflammation and cancer. Clin Exp Pharmacol Physiol 39(3):300–310CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kuttan G, Pratheeshkumar P, Manu KA, Kuttan R (2011) Inhibition of tumor progression by naturally occurring terpenoids. Pharm Biol 49(10):995–1007CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Ikezoe T, Yang Y, Bandobashi K, Saito T, Takemoto S, Machida H, Togitani K, Koeffler HP, Taguchi H (2005) Oridonin, a diterpenoid purified from Rabdosiarubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-κB signal pathways. Mol Cancer Ther 4(4):578–586CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Jin H, Tan X, Liu X, Ding Y (2011) Downregulation of AP-1 gene expression is an initial event in the oridonin-mediated inhibition of colorectal cancer: studies in vitro and in vivo. J Gastroenterol Hepatol 26(4):706–715CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Khanna C, Rosenberg M, Vail DM (2015) A review of paclitaxel and novel formulations including those suitable for use in dogs. J Vet Intern Med 29(4):1006–1012CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Hajek R, Vorlicek J, Slavik M (1996) Paclitaxel (Taxol): a review of its antitumor activity in clinical studies Minireview. Neoplasma 43(3):141–154PubMedPubMedCentralGoogle Scholar
  57. 57.
    Zhao Y, Wang SM, Zhang J (2002) Combination chemotherapy with Taxol and cisplatin for 57 patients with non-small cell lung cancer by intraartery and intravenous infusion. Chinese J Cancer 21(12):1365–1367Google Scholar
  58. 58.
    deMagalhaes-Silverman M, Hammert L, Lembersky B, Lister J, Rybka W, Ball E (1998) High-dose chemotherapy and autologous stem cell support followed by post-transplant doxorubicin and Taxol as initial therapy for metastatic breast cancer: hematopoietic tolerance and efficacy. Bone Marrow Transplant 21(12):1207CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Manfredi JJ, Horwitz SB (1984) Taxol: an antimitotic agent with a new mechanism of action. Pharmacol Ther 25(1):83–125CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Calixto JB, Campos MM, Otuki MF, Santos AR (2004) Anti-inflammatory compounds of plant origin. Part II. Modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. Plantamedica 70(02):93–103Google Scholar
  61. 61.
    Miro M (1995) Cucurbitacins and their pharmacological effects. Phytother Res 9(3):159–168CrossRefGoogle Scholar
  62. 62.
    Hsu HS, Huang PI, Chang YL, Tzao C, Chen YW, Shih HC, Hung SC, Chen YC, Tseng LM, Chiou SH (2011) Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in non-small cell lung cancer-derived CD133-positive cells. Cancer 117(13):2970–2985CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Iwanski GB, Lee DH, En-Gal S, Doan NB, Castor B, Vogt M, Toh M, Bokemeyer C, Said JW, Thoennissen NH, Koeffler HP (2010) Cucurbitacin B, a novel in vivo potentiator of gemcitabine with low toxicity in the treatment of pancreatic cancer. Br J Pharmacol 160(4):998–1007CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Thoennissen NH, Iwanski GB, Doan NB, Okamoto R, Lin P, Abbassi S, Song JH, Yin D, Toh M, Xie WD, Said JW (2009) Cucurbitacin B induces apoptosis by inhibition of the JAK/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic cancer cells. Cancer Res 69(14):5876–5884CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Liu T, Zhang M, Zhang H, Sun C, Yang X, Deng Y, Ji W (2008) Combined antitumor activity of cucurbitacin B and docetaxel in laryngeal cancer. Eur J Pharmacol 587(1-3):78–84CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Giner EM, Máñez S, Recio MC, Giner RM, Cerdá-Nicolás M, Ríos JL (2000) In vivo studies on the anti-inflammatory activity of pachymic and dehydrotumulosic acids. Plantamedica 66(03):221–227Google Scholar
  67. 67.
    Prieto JM, Recio MC, Giner RM, Manez S, Giner-Larza EM, Rios JL (2003) Influence of traditional Chinese anti-inflammatory medicinal plants on leukocyte and platelet functions. J Pharm Pharmacol 55(9):1275–1282CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Ling H, Zhang Y, Ng KY, Chew EH (2011) Pachymic acid impairs breast cancer cell invasion by suppressing nuclear factor-κB-dependent matrix metalloproteinase-9 expression. Breast Cancer Res Treat 126(3):609–620CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Ajikumar PK, Xiao W-H, Tyo KEJ, Wang Y, Simeon F, Leonard E, Mucha O, Phon TH, Pfeifer B, Stephanopoulos G (2010) Isoprenoid pathway optimization for Taxol precursor overproduction in Escherichia coli. Science 330:70–74. Scholar
  70. 70.
    Zhou X, Zhu H, Liu L, Lin J, Tang K (2010) A review: recent advances and future prospects of Taxol-producing endophytic fungi. Appl Microbiol Biotechnol 86:1707–1717. Scholar
  71. 71.
    Thomas P, Farjon A (2011) Taxus wallichiana. IUCN Red List Threat. Species.
  72. 72.
    Li Y, Zhang G, Pfeifer BA (2009) Current and emerging options for Taxol production. In: Schrader J, Bohlmann J (eds) Biotechnology of isoprenoids. Advances in biochemical engineering/biotechnology. Springer, pp 1–35Google Scholar
  73. 73.
    Chandran SS, Kealey JT, Reeves CD (2011) Microbial production of isoprenoids. Process Biochem 46:1703–1710. Scholar
  74. 74.
    Gupta P, Phulara SC (2015) Metabolic engineering for isoprenoid-based biofuel production. J Appl Microbiol 119:605–619. Scholar
  75. 75.
    Tippmann S, Chen Y, Siewers V, Nielsen J (2013) From flavors and pharmaceuticals to advanced biofuels: production of isoprenoids in Saccharomyces cerevisiae. Biotechnol J 8:1435–1444. Scholar
  76. 76.
    Kusari S, Singh S, Jayabaskaran C (2014) Rethinking production of Taxol W (paclitaxel) using endophyte. Trends Biotechnol 32:304–311CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Amrein BA, Runthala A, Kamerlin SCL (2019) In silico-directed evolution using CADEE. Methods Mol Biol 1851:381–415CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Keasling JD (2008) Synthetic biology for synthetic chemistry. ACS Chem Biol 3:64–76CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Phulara SC, Chaturvedi P, Gupta P (2016) Isoprenoid-based biofuels: homologous expression and heterologous expression in prokaryotes. Appl Environ Microbiol 82:5730–5740. Scholar
  80. 80.
    Li Y, Pfeifer BA (2014) Heterologous production of plant-derived isoprenoid products in microbes and the application of metabolic engineering and synthetic biology. Curr Opin Plant Biol 19:8–13. Scholar
  81. 81.
    Wong J, Rios-solis L, Keasling JD (2017) Microbial production of isoprenoids. In: Lee S (ed) Consequences of microbial interactions with hydrocarbons, oils, and lipids: production of fuels and chemicals, Handbook of hydrocarbon and lipid microbiology. Springer, pp 1–24.
  82. 82.
    Engels B, Dahm P, Jennewein S (2008) Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (paclitaxel) production. Metab Eng 10:201–206. Scholar
  83. 83.
    Liu H, Wang Y, Tang Q, Kong W, Chung W-J, Lu T (2014) MEP pathway-mediated isopentenol production in metabolically engineered Escherichia coli. Microb Cell Factories 13:135. Scholar
  84. 84.
    Zhao J, Li Q, Sun T, Zhu X, Xu H, Tang J, Zhang X, Ma Y (2013) Engineering central metabolic modules of Escherichia coli for improving beta-carotene production. Metab Eng 17:42–50. Scholar
  85. 85.
    Sarria S, Wong B, Martín HG, Keasling JD, Peralta-Yahya P (2014) Microbial synthesis of pinene. ACS Synth Biol 3:466–475. Scholar
  86. 86.
    Wang C, Yoon SH, Jang HJ, Chung YR, Kim JY, Choi ES, Kim SW (2011) Metabolic engineering of Escherichia coli for α-farnesene production. Metab Eng 13:648–655. Scholar
  87. 87.
    Zhou D, Sun J, Yu H, Ping W, Zheng X (2001) Nodulisporium, a genus new to China. Mycosystema 20:277–278Google Scholar
  88. 88.
    Croteau R, Ketchum REB, Long RM, Kaspera R, Wildung MR (2006) Taxol biosynthesis and molecular genetics. Phytochem Rev 5:75–97. Scholar
  89. 89.
    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 9:2237–2242. Scholar
  90. 90.
    DeJong JHM, Liu Y, Bollon AP, Long RM, Jennewein S, Williams D, Croteau RB (2006) Genetic engineering of Taxol biosynthetic genes in Saccharomyces cerevisiae. Biotechnol Bioeng 93:212–224. Scholar
  91. 91.
    Boghigian BA, Armando J, Salas D, Pfeifer BA (2012) Computational identification of gene over-expression targets for metabolic engineering of taxadiene production. Appl Microbiol Biotechnol 93:2063–2073. Scholar
  92. 92.
    Kang M-K, Eom J-H, Kim Y, Um Y, Woo HM (2014) Biosynthesis of pinene from glucose using metabolically-engineered Corynebacterium glutamicum. Biotechnol Lett 36:2069–2077. Scholar
  93. 93.
    Peralta-Yahya PP, Ouellet M, Chan R, Mukhopadhyay A, Keasling JD, Lee TS (2011) Identification and microbial production of a terpene-based advanced biofuel. Nat Commun 2:483. Scholar
  94. 94.
    Davies FK, Work VH, Beliaev AS, Posewitz MC (2014) Engineering limonene and bisabolene production in wild type and a glycogen-deficient mutant of Synechococcus sp. PCC 7002. Front Bioeng Biotechnol 2:21. Scholar
  95. 95.
    Halfmann C, Gu L, Gibbons W, Zhou R (2014) Genetically engineering cyanobacteria to convert CO2, water, and light into the long-chain hydrocarbon farnesene. Appl Microbiol Biotechnol 98:9869–9877. Scholar
  96. 96.
    Phelan RM, Sekurova ON, Keasling JD, Zotchev SB (2014) Engineering terpene biosynthesis in Streptomyces for production of the advanced biofuel precursor bisabolene. ACS Synth Biol 4:393–399. Scholar
  97. 97.
    Guan Z, Xue D, Abdallah II, Dijkshoorn L, Setroikromo R, Lv G, Quax WJ (2015) Metabolic engineering of Bacillus subtilis for terpenoid production. Appl Microbiol Biotechnol 99:9395–9406. Scholar
  98. 98.
    Halfmann C, Gu L, Zhou R (2014) Engineering cyanobacteria for the production of a cyclic hydrocarbon fuel from CO2 and H2O. Green Chem 16:3175–3185. Scholar
  99. 99.
    Xue D, Abdallah II, de Haan IEM, Sibbald MJJB, Quax WJ (2015) Enhanced C30 carotenoid production in Bacillus subtilis by systematic overexpression of MEP pathway genes. Appl Microbiol Biotechnol 99:5907–5915. Scholar
  100. 100.
    Xue J, Ahring BK (2011) Enhancing isoprene production by genetic modification of the 1-deoxy-d-xylulose-5-phosphate pathway in Bacillus subtilis. Appl Environ Microbiol 77:2399–2405. Scholar
  101. 101.
    Yoshida K, Ueda S, Maeda I (2009) Carotenoid production in Bacillus subtilis achieved by metabolic engineering. Biotechnol Lett 31:1789–1793. Scholar
  102. 102.
    Fall R, Copley SD (2000) Bacterial sources and sinks of isoprene, a reactive atmospheric hydrocarbon. Environ Microbiol 2:123–130CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Kuzma J, Nemecek-Marshall M, Pollock WH, Fall R (1995) Bacteria produce the volatile hydrocarbon isoprene. Curr Microbiol 30:97–103. Scholar
  104. 104.
    Phulara SC, Chaurasia D, Diwan B, Chaturvedi P, Gupta P (2018) In-situ isopentenol production from Bacillus subtilis through genetic and culture condition modulation. Process Biochem 72:47–54CrossRefGoogle Scholar
  105. 105.
    Dugar D, Stephanopoulos G (2011) Relative potential of biosynthetic pathways for biofuels and bio-based products. Nat Biotechnol 29:1074–1078. Scholar
  106. 106.
    George KW, Thompson MG, Kang A, Baidoo E, Wang G, Chan LJG, Adams PD, Petzold CJ, Keasling JD, Lee TS (2015) Metabolic engineering for the high-yield production of isoprenoid-based C 5 alcohols in E. coli. Sci Rep 5:11128. Scholar
  107. 107.
    Fujisaki S, Hara H, Nishimura Y, Horiuchi K, Nishino T (1990) Cloning and nucleotide sequence of the ispA gene responsible for farnesyl diphosphate synthase activity in Escherichia coli. J Biochem 108:995–1000CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Henke NA, Wichmann J, Baier T, Frohwitter J, Lauersen KJ, Risse JM, Peters-Wendisch P, Kruse O, Wendisch VF (2018) Patchoulol production with metabolically engineered Corynebacterium glutamicum. Genes (Basel).
  109. 109.
    Wang C, Kim JY, Choi ES, Kim SW (2011) Microbial production of farnesol (FOH): current states and beyond. Process Biochem 46:1221–1229. Scholar
  110. 110.
    Thulasiram HV, Erickson HK, Poulter CD (2007) Chimeras of two isoprenoid synthases catalyze all four coupling reactions in isoprenoid biosynthesis. Science 316:73–76. Scholar
  111. 111.
    Wang C, Zhou J, Jang H, Yoon S, Kim J, Lee G, Choi E, Kim S (2013) Engineered heterologous FPP synthases-mediated Z,E-FPP synthesis in E coli. Metab Eng 18:53–59. Scholar
  112. 112.
    Runthala A (2012) Protein structure prediction: challenging targets for CASP10. J Biomol Struct Dyn 30(5):607–615CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Runthala A, Chowdhury S (2016) Unsolved problems of ambient computationally intelligent TBM algorithms. In: Hybrid soft computing approaches: research and applications, pp 75-105Google Scholar
  114. 114.
    Madeira F, Park YM, Lee J, Buso N, Gur T, Madhusoodanan N, Basutkar P, Tivey ARN, Potter SC, Finn RD, Lopez R (2019) The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res 47(W1):W636–W641CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    El-Gebali S, Mistry J, Bateman A, Eddy SR, Luciani A, Potter SC, Qureshi M, Richardson LJ, Salazar GA, Smart A, Sonnhammer ELL, Hirsh L, Paladin L, Piovesan D, Tosatto SCE, Finn RD (2019) The Pfam protein families database in 2019. Nucleic Acids Res 47(D1):D427–D432CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Artimo P, Jonnalagedda M, Arnold K, Baratin D, Csardi G, de Castro E, Duvaud S, Flegel V, Fortier A, Gasteiger E, Grosdidier A, Hernandez C, Ioannidis V, Kuznetsov D, Liechti R, Moretti S, Mostaguir K, Redaschi N, Rossier G, Xenarios I, Stockinger H (2012) ExPASy: SIB bioinformatics resource portal. Nucleic Acids Res 40(W1):W597–W603CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Zimmermann L, Stephens A, Nam SZ, Rau D, Kübler J, Lozajic M, Gabler F, Söding J, Lupas AN, Alva V (2018) A completely reimplemented MPI bioinformatics toolkit with a new HHpred server at its core. J Mol Biol 430(15):2237–2243CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Runthala A, Chowdhury S (2019) Refined template selection and combination algorithm significantly improves template-based modeling accuracy. J Bioinforma Comput Biol 17(2):1950006–1950006CrossRefGoogle Scholar
  119. 119.
    Webb B, Sali A (2016) Comparative protein structure modeling using MODELLER. Curr Protoc Bioinformatics 54:5.6.1–5.6.37CrossRefGoogle Scholar
  120. 120.
    Runthala A, Chowdhury S (2014) Iterative optimal TM_Score and Z_Score guided sampling significantly improves model topology, lecture notes in engineering and computer science: proceedings of the international multiconference of engineers and computer scientists, Hong Kong, 2014, pp 123–128Google Scholar
  121. 121.
    Chen VB, Arendall WB 3rd, Headd JJ, Keedy DA, Immormino RM, Kapral GJ, Murray LW, Richardson JS, Richardson DC (2010) MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr 66(1):12–21CrossRefGoogle Scholar
  122. 122.
    Lovell SC, Davis IW, Arendall WB III, De Bakker PI, Word JM, Prisant MG, Richardson DC (2003) Structure validation by Cα geometry: ϕ, ψ and Cβdeviation. Proteins 50(3):437–450CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Ashkenazy H, Abadi S, Martz E, Chay O, Mayrose I, Pupko T, Ben-Tal N (2016) ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation inmacromolecules. Nucleic Acids Res 44:344–350CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Suresh Chandra Phulara
    • 1
  • Vikrant Singh Rajput
    • 2
  • Bidyut Mazumdar
    • 3
  • Ashish Runthala
    • 1
  1. 1.Department of Biotechnology, Koneru Lakshmaiah Education FoundationGunturIndia
  2. 2.School of Biotechnology, JNUNew DelhiIndia
  3. 3.Department of Chemical EngineeringNational Institute of Technology RaipurRaipurIndia

Personalised recommendations