Advertisement

Acta Physiologiae Plantarum

, 40:165 | Cite as

Effects of lovastin, fosmidomycin and methyl jasmonate on andrographolide biosynthesis in the Andrographis paniculata

  • Rakesh Kumar Sinha
  • Shiv Narayan Sharma
  • Shiv S. Verma
  • Jenu Zha
Original article
  • 58 Downloads

Abstract

Andrographolide is a diterpene secondary metabolite product of Andrographis paniculata. It has been known to be a pharmaceutically important compound synthesized via the cytosolic mevalonate (MVA) and the plastidial 2-C-methyl-d-erythritol-4-phosphate (MEP) pathways. To understand the biosynthetic pathway of andrographolide biosynthesis in Andrographis paniculata, lovastatin, fosmidomycin and methyl jasmonate (MeJA) were used to inhibit the key enzymes 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), and 1-deoxy-d-xylulose-5-phosphate reducto-isomerase (DXR) involved in the synthesis of andrographolide in the MVA and MEP pathways, respectively. The inhibition of andrographolide accumulation was linked with the expression level of the studied regulatory genes, 3-hydroxy-3-methyl glutaryl coenzyme A synthase (hmgs), 3-hydroxy-3-methyl glutaryl coenzyme A reductase (hmgr), 1-deoxyxylulose-5-phosphate synthase (dxs), 1-deoxyxylulose-5-phosphate reductoisomerase (dxr), 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase (hds),1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate reductase (hdr), 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate reductase(isph), isopentenyl diphosphate isomerase (ipp), geranylgeranyl diphosphatesynthase (ggps) of the MVA and MEP pathways. The pathways associated transcript expression level, and andrographolide biosynthesis was significantly modulated by the inhibitors indicating that the andrographolide biosynthesis is strongly responsive at the transcriptional level. The results demonstrated that both pathways can contribute to the biosynthesis of andrographolide in A. paniculata. Both hmgr and dxr played a critical role consistent with some crossover between MVA and MEP pathways in andrographolide biosynthesis.

Keywords

Andrographis paniculata Andrographolide Mevalonate Fosmidomycin Lovastatin Methyl jasmonate 

Abbreviations

DMAPP

Dimethylallyl diphosphate

DXP

1-Deoxy-d-xylulose-5-phosphate

dxr

1-Deoxyxylulose-5-phosphate reductoisomerase

dxs

1-Deoxyxylulose-5-phosphate synthase

GAP

Glyceraldehyde-3-phosphate

GGPP

Geranyl geranyl diphosphate

ggps

Geranylgeranyl diphosphate synthase

hds

1-Hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase

hdr

1-Hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate reductase

E HMBPP

(E)-4-hydroxy-3-methylbut-2-enyl pyrophosphate

hmgr

3-Hydroxy-3-methyl glutaryl coenzyme A reductase

hmgs

3-Hydroxy-3-methyl glutaryl coenzyme A synthase

Ipp

Isopentenyl diphosphate

Isph

1-Hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate reductase

MEP

2-C-methyl-d-erythritol-4-phosphate

MVA

Mevalonic acid

Notes

Acknowledgements

Financial support from Indira Gandhi Krishi Vishwavidyalaya (IGKV), Raipur is gratefully acknowledged. Thanks to Dr. D.K. Sharma, Former Head, Department of Plant Molecular Biology and Biotechnology for arranging funds and facilities. We thank Jordan Pepper for providing an English proof read.

References

  1. Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, Patchett A, Monaghan R, Currie S, Stapley E, Albers-Schonberg G, Hensens O, Hirshfield J, Hoogsteen K, Liesch J, Springer J (1980) Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci USA 77:3957–3961CrossRefPubMedGoogle Scholar
  2. Bochar DA, Stauffacher CV, Rodwell VW (1999) Investigation of the conserved lysines of Syrian hamster 3-hydroxy-3-methylglutaryl coenzyme A reductase. Biochemistry 38:15848–15852CrossRefPubMedGoogle Scholar
  3. Chandrasekaran CV, Thiyagarajan P, Deepak HB, Agarwal A (2011) In vitro modulation of LPS/calcimycin induced inflammatory and allergic mediators by pure compounds of Andrographis paniculata (King of bitters) extract. Int Immunopharmacol 11:79–84CrossRefPubMedGoogle Scholar
  4. Cherukupalli N, Divate M, Mittapelli SR, Khareedu VR, Vudem DR (2016) De novo assembly of leaf transcriptome in the medicinal plant Andrographis paniculata. Front Plant Sci 7:1203–1215CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cheung HY, Cheung SH, Li J, Cheung CS, Lai WP, Fong WF, Leung FM (2005) Andrographolide isolated from Andrographis paniculata induces cell cycle arrest and mitochondrial-mediated apoptosis in human leukemic HL-60 cells. Planta Med 71:1106–1111CrossRefPubMedGoogle Scholar
  6. Eisenreich W, Rohdich F, Bacher A (2001) Deoxyxylulose phosphate pathway to terpenoids. Trends Plant Sci 6:78–84CrossRefPubMedGoogle Scholar
  7. Fang Y, Smith MAL, Pepin MF (1999) Effects of exogenous methyl jasmonate in elicited anthocyanin producing cell cultures of ohelo (Vaccinium pahalae). In Vitro Cell Dev Biol Plant 35:106–113CrossRefGoogle Scholar
  8. Han X, Hu Y, Zhang G, Jiang Y, Chen Z, Yu D (2018) Jasmonate negatively regulates stomatal development in Arabidopsis cotyledons. Plant Physiol.  https://doi.org/10.1104/pp.17.00444 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Hawari AH, Mohamed-Hussein ZA (2010) Simulation of a Petri net-based model of the terpenoid biosynthesis pathway. BMC Bioinform 11:83CrossRefGoogle Scholar
  10. 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 97:2486–2490CrossRefPubMedGoogle Scholar
  11. Hoeffler JF, Hemmerlin A, Grosdemange-Billiard C, Bach TJ, Rohmer M (2002) Isoprenoid biosynthesis in higher plants and in Escherichia coli: on the branching in the methylerythritol phosphate pathway and the independent biosynthesis of isopentenyl diphosphate and dimethylallyl diphosphate. Biochem J 366:573–583CrossRefPubMedPubMedCentralGoogle Scholar
  12. Hu FX, Zhong JJ (2008) Jasmonic acid mediates gene transcription of ginsenoside biosynthesis in cell cultures of Panax notoginseng treated with chemically synthesized 2-hydroxyethyl jasmonate. Process Biochem 43:113–118CrossRefGoogle Scholar
  13. Jiang Y, Ye J, Li S, Niinemets U (2017) Methyl jasmonate-induced emission of biogenic volatiles is biphasic in cucumber: a high-resolution analysis of dose dependence. J Exp Bot 68:4679–4694CrossRefPubMedPubMedCentralGoogle Scholar
  14. Koyama T, Ogura K (1999) Isopentenyl diphosphate isomerase and prenyltransferases. In: Cane DE (eds) Comprehensive natural product chemistry: isoprenoids including carotenoids and steroids, vol 2. Pergamon Press, Oxford, pp 69–96CrossRefGoogle Scholar
  15. Kuzuyama T, Shimizu T, Seto H (1998) Fosmidomycin, a specific inhibitor of 1-deoxy-d-xylulose 5-phosphate reductoisomerase in the nonmevalonate pathway for terpenoid biosynthesis. Proc Natl Acad Sci USA 95:2100–2104CrossRefGoogle Scholar
  16. Laule O, Fürholz 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 100:6866–6871CrossRefPubMedPubMedCentralGoogle Scholar
  17. Lee JC, Tseng CK, Young KC, Sun HY, Wang SW, Chen WC, Lin CK, Wu YH (2014) Andrographolide exerts anti-hepatitis C virus activity by up-regulating haeme oxygenase-1 via the p38 MAPK/Nrf2 pathway in human hepatoma cells. Br J Pharmacol 171:237–252CrossRefPubMedGoogle Scholar
  18. Lichtenthaler HK (1999) The 1-deoxy-d-xylulose-5-phosphate pathway of isoprenoid biosynthesis in plants. Annu Rev Plant Physiol Plant Mol Bio 50:47–65CrossRefGoogle Scholar
  19. Mueller C, Schwender J, Zeidler J, Lichtenthaler HK (2000) Properties and inhibition of the first two enzymes of the non-mevalonate pathway of isoprenoid biosynthesis. Biochem Soc Trans 28:792–793CrossRefPubMedGoogle Scholar
  20. Murashige T, Skoog F (1962) A revised medium for rapid growth and bio-assays with tobacco tissue cultures. Physiol Plant 15:473–497CrossRefGoogle Scholar
  21. Perez-Gil J, Rodriguez-Concepcion M (2013) Metabolic plasticity for isoprenoid biosynthesis in bacteria. Biochem J 452:19–25CrossRefGoogle Scholar
  22. Reymond P, Farmer EE (1998) Jasmonate and salicylate as global signals for defense gene expression. Curr Opin Plant Biol 1:404–411CrossRefPubMedGoogle Scholar
  23. Rodriguez-Concepcion M, Boronat A (2002) Elucidation of the methylerythritol phosphate pathway for isoprenoid biosynthesis in bacteria and plastids. A metabolic milestone achieved through genomics. Plant Physiol 130:1079–1089CrossRefPubMedGoogle Scholar
  24. Rohmer M, Seemann M, Horbach S, Bringer-Meyer S, Sahm H (1996) Glyceraldehyde 3-phosphate and pyruvate as precursors of isoprenic units in an alternative non-mevalonate pathway for terpenoid biosynthesis. J Am Chem Soc 118:2564–2566CrossRefGoogle Scholar
  25. Sareer O, Ahmad S, Umar S (2014) Andrographis paniculata: a critical appraisal of extraction., isolation and quantification of andrographolide and other active constituents. Nat Prod Res 28:2081–2101CrossRefPubMedGoogle Scholar
  26. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protoc 3:1101–1108CrossRefGoogle Scholar
  27. Schwarz M, Arigoni D (1999) Ginkgolide biosynthesis. In: Cane D (ed) Comprehensive natural product chemistry, vol 2. Pergamon, Oxford, pp 367–399CrossRefGoogle Scholar
  28. Sharma SN, Sinha RK, Sharma D, Jha Z (2009) Assessment of intra-specific variability at morphological, molecular and biochemical level of Andrographis paniculata (Kalmegh). Curr Sci 96:402–408Google Scholar
  29. Sharma SN, Jha Z, Sinha RK (2013) Establishment of in vitro adventitious root cultures and analysis of andrographolide in Andrographis paniculata. Nat Prod Commun 8:1045–1047PubMedGoogle Scholar
  30. Sharma SN, Jha Z, Sinha RK, Geda AK (2015) Jasmonate-induced biosynthesis of andrographolide in Andrographis paniculata. Physiol Plant 153:221–229CrossRefPubMedGoogle Scholar
  31. Singh RS, Gara RK, Bhardwaj PK, Kaachra A, Malik S, Kumar R, Sharma M, Ahuja PS, Kumar S (2010) Expression of 3-hydroxy-3-methylglutaryl-CoA reductase, p-hydroxybenzoate-m-geranyltransferase and genes of phenylpropanoid pathway exhibits positive correlation with shikonins content in arnebia [Arnebia euchroma Royle. Johnston]. BMC Mol Biol 11:88CrossRefPubMedPubMedCentralGoogle Scholar
  32. Srivastava N, Akhila A (2010) Biosynthesis of andrographolide in Andrographis paniculata. Phytochem 71:1298–1304CrossRefGoogle Scholar
  33. Suebsasana S, Pongnaratorn P, Sattayasai J, Arkaravichien T, Tiamkao S,.Aromdee C (2009) Analgesic, antipyretic, anti-inflammatory and toxic effects of andrographolide derivatives in experimental animals. Arch Pharm Res 32:1191–1200CrossRefPubMedGoogle Scholar
  34. Tang C, Liu Y, Wang B, Gu G, Yang L, Zheng Y, Qian H, Huang W (2012) Synthesis and biological evaluation of andrographolide derivatives as potent anti-HIV agents. Arch Pharm Weinh 345:647–656CrossRefGoogle Scholar
  35. Tholl D, Lee S (2011) Terpene specialized metabolism in Arabidopsis thaliana. Arabidopsis Book Am Soc Plant Biol 9:e0143CrossRefGoogle Scholar
  36. Vakil MM, Mendhulkar V (2013) Enhanced synthesis of andrographolide by Aspergillus niger and Penicillium expansum elicitors in cell suspension culture of Andrographis paniculata Burm. f. Nees. Bot Stud 54:49CrossRefPubMedPubMedCentralGoogle Scholar
  37. Valdiani A, Talei D, Tan SG, Abdul Kadir M, Maziah M, Rafii MY, Sagineedu SR (2014) A classical genetic solution to enhance the biosynthesis of anticancer phytochemicals in Andrographis paniculata Nees. PloS One 9:e87034CrossRefPubMedPubMedCentralGoogle Scholar
  38. Van der Fits L, Memelink J (2000) ORCA3, a jasmonate responsive transcriptional regulator of plant primary and secondary metabolism. Science 289:295–297CrossRefGoogle Scholar
  39. Vranova E, Coman D, Gruissem W (2013) Network analysis of the MVA and MEP pathways for isoprenoid synthesis. Annu Rev Plant Biol 64:665–700CrossRefGoogle Scholar
  40. Wen L, Xia N, Chen X, Li Y, Hong Y, Liu Y, Wang Z, Liu Y (2014) Activity of antibacterial, antiviral, anti-inflammatory in compounds andrographolide salt. Eur J Pharmacol 740:421–427CrossRefPubMedGoogle Scholar
  41. Wu S, Schalk M, Clark A, Miles RB, Coates R, Chappell J (2006) Redirection of cytosolic or plastidic isoprenoid precursors elevates terpene production in plants. Nat Biotech 24:1441–1447CrossRefGoogle Scholar
  42. Xu J, Li Z, Cao M, Zhang H, Sun J, Zhao J, Zhou Q, Wu Z, Yang L (2012) Synergetic effect of Andrographis paniculata polysaccharide on diabetic nephropathy with andrographolide. Int J Biol Macromol 51:738–742CrossRefPubMedGoogle Scholar
  43. Yamazaki Y, Kitajima M, Arita M, Takayama H, Sudo H, Yamazaki M, Aimi N, Saito K (2004) Biosynthesis of camptothecin. In silico and in vivo tracer study from [1-13C] glucose. Plant Physiol 134:161–170CrossRefPubMedPubMedCentralGoogle Scholar
  44. Yang D, Du X, Liang X, Han R, Liang Z, Liu Y, Liu F, Zhao J (2012) Different roles of the mevalonate and methylerythritol phosphate pathways in cell growth and tanshinone production of Salvia miltiorrhiza hairy roots. PloS one 7:e46797CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Franciszek Górski Institute of Plant Physiology, Polish Academy of Sciences, Kraków 2018

Authors and Affiliations

  • Rakesh Kumar Sinha
    • 1
    • 2
  • Shiv Narayan Sharma
    • 3
  • Shiv S. Verma
    • 4
  • Jenu Zha
    • 3
  1. 1.Faculty of Biology and Environmental ProtectionUniversity of Silesia in KatowiceKatowicePoland
  2. 2.Department of Biophysics and Biochemistry of PlantsInstitute of Plant Molecular Biology, Biology Centre of the ASCRČeské BudějoviceCzechia
  3. 3.Department of Genetics and Plant BreedingIGKVRaipurIndia
  4. 4.Agricultural and Agri-Food CanadaLethbridgeCanada

Personalised recommendations