Skip to main content
SpringerLink
Log in

Phytochemistry and biosynthesis of δ-lactone withanolides

  • Published:
Phytochemistry Reviews Aims and scope Submit manuscript

Abstract

Withanolides are highly oxygenated natural products. These C28 steroids with ergostane-based skeletons functionalized at C-22 and C-26 form six-membered δ-lactone rings. Withanolides containing a δ-lactone side chain often occur in Solanaceae and have a variety of biological activities because of their complicated structures. Characteristic spectroscopic behaviors and biosynthesis of withanolides are conducive to their structural elucidation and “biomimetic synthesis”, respectively. However, the last review to summarize their spectroscopic features and biosynthesis was in 1996. Since then, many withanolides with novel structures have been described by their spectra with biosynthesis investigated with many bioassays. This review surveys δ-lactone withanolides and emphasizes their spectral features, configurations and biosynthetic genes. The period reviewed includes through January 2014. We also include phytochemical species.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

AD:

Alzheimer’s disease

CAS:

Cycloartenol synthase

CD:

Circular dichroism spectroscopy

CID-MS/MS:

Low-energy collision-induced dissociation tandem mass spectrometric

CIP:

Cahn–Lngold–Prelog

CPR:

NADPH-cytochrome P450 reductase

CYPs:

Cytochrome P450s

DMAPP:

Dimethylallyl diphosphate

DOXP:

1-Deoxy-D-xylulose-5-phosphate

EI-MS:

Electron impact mass spectra

ER:

Endoplasmic reticulum

ESI-MS:

Electrospray ionization mass spectrometry

ESI-QqTOF-MS/MS:

Electrospray-ionization quadropole time-of-flight tandem mass spectrometry

FPPS:

Farnesyl diphosphate synthase

GPP:

Geranyl diphosphate

HMG-CoA:

3-Hydroxy-3-methylglutaryl coenzyme A

HMGR:

3-Hydroxy-3-methylglutaryl coenzyme A reductase

LAS:

Lanosterol synthase

LC/IT-MS:

Liquid-chromatography ion-trap mass spectrometry

IPP:

Isopentenyl diphosphate

IR:

Infrared spectroscopy

MEP:

2-C-methyl-D-erythritol-4-phosphate

MS:

Mass spectrometry

MVA:

Mevalonate

NMR:

Nuclear magnetic resonance

ODM:

Obtusifoliol demethylase

OSCs:

Oxidosqualene cyclase

SMT-1:

Sterol methyltransferase

SQE:

Squalene epoxidase

SQS:

Squalene synthase

UV:

Utraviolet spectrum

VDW:

Van der Waals’ force

References

  • Abdeljebbar LH, Humam M, Christen P et al (2007) Withanolides from Withania adpressa. Helv Chim Acta 90:346–352

    Article  CAS  Google Scholar 

  • Abe F, Nagafuji S, Okawa M et al (2006) Trypanocidal constituents in plants 6 minor withanolides from the aerial parts of Physalis angulata. Chem Pharm Bull 54:1226–1228

    Article  CAS  PubMed  Google Scholar 

  • Abe I, Abe T, Lou W et al (2007) Sitedirected mutagenesis of conserved aromatic residues in rat squalene epoxidase. Biochem Biophys Res Commun 352:259–263

    Article  CAS  PubMed  Google Scholar 

  • Abou-Douh AM (2002) New withanolides and other constituents from the fruit of Withania somnifera. Arch Pharm (Weinheim) 335:267–276

    Article  CAS  Google Scholar 

  • Ahmad S, Yasmin R, Malik A (1999a) New withanolide glycosides from Physalis peruviana L. Chem Pharm Bull 47:477–480

    Article  CAS  Google Scholar 

  • Ahmad S, Malik A, Yasmin R et al (1999b) Withanolides from Physalis peruviana. Phytochemistry 50:647–651

    Article  CAS  Google Scholar 

  • Akhtar N, Gupta P, Sangwan NS et al (2013) Cloning and functional characterization of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene from Withania somnifera: an important medicinal plant. Protoplasma 250:613–622

    Article  CAS  PubMed  Google Scholar 

  • Akizuki M, Yamashita H, Uemura K et al (2013) Optineurin suppression causes neuronal cell death via NF-κB pathway. J Neurochem 126:699–704

    Article  CAS  PubMed  Google Scholar 

  • Ali M, Shuaib M, Ansari SH (1997) Withanolides from the stem bark of Withania somnifera. Phytochemistry 44:1163–1168

    Article  CAS  Google Scholar 

  • Almeida-Lafeta RC, Ferreira MJP, Emerenciano VP et al (2010) Withanolides from Aureliana fasciculata var. Fasciculata. Helv Chim Acta 93:2478–2485

    Article  CAS  Google Scholar 

  • Andrade-Pavón D, Sánchez-Sandoval E, Rosales-Acosta B et al (2014) The 3-hydroxy-3-methylglutaryl coenzyme-A reductases from fungi: a proposal as a therapeutic target and as a study model. Rev Iberoam Micol 31:81–85

    Article  PubMed  Google Scholar 

  • Anjaneyyulu ASR, Rao DS, Lequesne PW (1998) Studies in natural products chemistry. In: Atta-ur-Rahman (ed) Elsevier Science, Amsterdam 20:135

  • Atta-ur-Rahman Shabbir M, Yousaf M et al (1999) Three withanolides from Withania coagulans. Phytochemistry 52:1361–1364

    Article  CAS  Google Scholar 

  • Babiychuk E, Bouvier-Navé P, Compagnon V et al (2008) Allelic mutant series reveal distinct functions for Arabidopsis cycloartenol synthase 1 in cell viability and plastid biogenesis. Proc Natl Acad Sci USA 105:3163–3168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baker CH, Matsuda SPT, Liu DR et al (1995) Molecular-cloning of the human gene encoding lanosterol synthase from a liver cDNA library. Biochem Biophy Res Commun 213:154–160

    Article  CAS  Google Scholar 

  • Bellila A, Tremblay C, Pichette A et al (2011) Cytotoxic activity of withanolides isolated from Tunisian Datura metel L. Phytochemistry 72:2031–2036

    Article  CAS  PubMed  Google Scholar 

  • Benjumea D, Martín-Herrera D, Abdala S et al (2009) Withanolides from Whitania aristata and their diuretic activity. J Ethnopharmacol 123:351–355

    Article  CAS  PubMed  Google Scholar 

  • Benveniste I, Lesot A, Hasenfratz MP et al (1991) Multiple forms of NADPH-cytochrome P450 reductase in higher plants. Biochem Bioph Res Commun 177:105–112

    Article  CAS  Google Scholar 

  • Bhat WW, Lattoo SK, Razdan S et al (2012) Molecular cloning, bacterial expression and promoter analysis of squalene synthase from Withania somnifera (L.) Dunal. Gene 499:25–36

    Article  CAS  PubMed  Google Scholar 

  • Bolleddula J, Fitch W, Vareed SK et al (2012) Identification of metabolites in Withania sominfera fruits by liquid chromatography and high-resolution mass spectrometry. Rapid Commun Mass Spectrom 26:1277–1290

    Article  CAS  PubMed  Google Scholar 

  • Bravo JA, Sauvain BM, Gimenez A et al (2001) Trypanocidal withanolides and withanolide glycosides from Dunalia brachyacantha. J Nat Prod 64:720–725

    Article  CAS  Google Scholar 

  • Brunton LS, Lazo JS, Parker KL (2008) Goodman and Gilman’s the pharmacological basis of therapeutics. McGraw-Hill Publication, USA, pp 1225–1242

    Google Scholar 

  • Budhiraja RD, Krishan P, Sudhir S (2000) Biological activity of withanolides. J Sci Ind Res 59:904–911

    CAS  Google Scholar 

  • Cao X, Zong Z, Ju X et al (2010) Molecular cloning, characterization and function analysis of the gene encoding HMG-CoA reductase from Euphorbia pekinensis. Rupr Mol Biol Rep 37:1559–1567

    Article  CAS  PubMed  Google Scholar 

  • Chao CH, Chou KJ, Wen ZH et al (2011) Paraminabeolides A-F, cytotoxic and anti-inflammatory marine withanolides from the soft coral Paraminabea acronocephala. J Nat Prod 74:1132–1141

    Article  CAS  PubMed  Google Scholar 

  • Chappell J (1995) The biochemistry and molecular biology of isoprenoid metabolism. Plant Physiol 107:1–6

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chaurasia ND, Sangwan NS, Sabir F et al (2012) Withanolide biosynthesis recruits both mevalonate and DOXP pathways of isoprenogenesis in Ashwagandha Withania somnifera L. (Dunal). Plant Cell Rep 31:1889–1897

    Article  CAS  Google Scholar 

  • Chaurasiya ND, Sangwan RS, Misra LN et al (2009) Metabolic clustering of a core collection of Indian ginseng Withania somnifera Dunal through DNA, isoenzyme, polypeptide and withanolide profile diversity. Fitoterapia 80:496–505

    Article  CAS  PubMed  Google Scholar 

  • Chen LX, He H, Qiu F (2011) Natural withanolides: an overview. Nat Prod Rep 28:705–740

    Article  CAS  PubMed  Google Scholar 

  • Cheng J, Yang L (2006) Research progresses of cytochrome P450 reductase. Chin Pharm Bull 22:129–133

    CAS  Google Scholar 

  • Choi DW, Jung JD, Ha YI et al (2005) Analysis of transcripts in methyl jasmonate-treated ginseng hairy roots to identify genes involved in the biosynthesis of ginsenosides and other secondary metabolites. Plant Cell Rep 23:557–566

    Article  CAS  PubMed  Google Scholar 

  • Choudhary MI, Yousuf S, Nawaz SA et al (2004) Cholinesterase inhibiting withanolides from Withania somnifera. Chem Pharm Bull (Tokyo) 52:1358–1361

    Article  CAS  Google Scholar 

  • Choudhary MI, Yousaf S, Ahmed S et al (2005) Antileishmanial physalins from Physalis minima. Chem Biodivers 2:1164–1173

    Article  CAS  PubMed  Google Scholar 

  • Choudhary ML, Yousuf S, Atta-ur-Rahman (2013) Withanolides: chemistry and antitumor activity. Nat Prod 3465–3495

  • Cordero CP, Morantes SJ, Páez A et al (2009) Cytotoxicity of withanolides isolated from Acnistus arborescens. Fitoterapia 80:64–368

    Article  CAS  Google Scholar 

  • Corey EJ, Matsuda SPT, Baker CH et al (1996) Molecular cloning of a Schizosaccharomyces pombe cDNA encoding lanosterol synthase and investigation of conserved tryptophan residues. Biochem Biophy Res Commun 219:27–331

    Article  Google Scholar 

  • Dai Z, Cui G, Zhou SF et al (2011) loning and characterization of a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase gene from Salvia miltiorrhiza involved in diterpenoid tanshinone accumulation. J Plant Physiol 168:48–157

    Article  CAS  Google Scholar 

  • Damu AG, Kuo PC, Su CR et al (2007) Isolation, structures, and structure-cytotoxic activity relationships of withanolides and physalins from Physalis angulata. J Nat Prod 70:1146–1152

    Article  CAS  PubMed  Google Scholar 

  • Devarenne TP, Shin DH, Back K et al (1998) Molecular characterization of tobacco squalene synthase and regulation in response to fungal elicitor. Arch Biochem Biophys 349:205–215

    Article  CAS  PubMed  Google Scholar 

  • Dinan LN, Sarker SD, Vladimiršik (1997) 28-Hydroxywithanolide E from Physalis peruviana. Phytochemistry 44:509–512

    Article  CAS  Google Scholar 

  • Eberle D, Ullmann P, Werck-Reichhart D et al (2009) cDNA cloning and functional characterisation of CYP98A14 and NADPH:cytochrome P450 reductase from Coleus blumei involved in rosmarinic acid biosynthesis. Plant Mol Biol 69:239–253

    Article  CAS  PubMed  Google Scholar 

  • Fang ST, Liu JK, Li B (2010) A novel 1,10-seco withanolide from Physalis peruviana. J Asian Nat Prod Res 12:618–622

    Article  CAS  PubMed  Google Scholar 

  • Fang ST, Liu JK, Li B (2012) Ten new withanolides from Physalis peruviana. Steroids 77:36–44

    Article  CAS  PubMed  Google Scholar 

  • Geoffrey DB (1998) The biosynthesis of steroids and triterpenoids. Nat Prod Rep 15:653–696

    Article  Google Scholar 

  • Gil RR, Misico RI, Sotes IR et al (1997) 16-Hydroxylated withanolides from Exodeconus maritimus. J Nat Prod 60:568–572

    Article  CAS  Google Scholar 

  • Glotter E (1991) Withanolides and related ergostane type steroids. Nat Prod Rep 8:415–440

    Article  CAS  PubMed  Google Scholar 

  • Gupta P, Akhtar N, Tewari SK et al (2011) Differential expression of farnesyl diphosphate synthase gene from Withania somnifera in different chemotypes and in response to elicitors. Plant Growth Regul 65:93–100

    Article  CAS  Google Scholar 

  • Gupta P, Agarwal AV, Akhtar N et al (2013) Cloning and characterization of 2-C-methyl-d-erythritol-4-phosphate pathway genes for isoprenoid biosynthesis from Indian Ginseng, Withania somnifera. Protoplasma 250:285–295

    Article  CAS  PubMed  Google Scholar 

  • Haines BE, Wiest O, Stauffacher CV (2013) The increasingly complex mechanism of HMG-CoA reductase. Accounts Chem Res 46:2416–2426

    Article  CAS  Google Scholar 

  • Han JY, In JG, Kwon YS et al (2010) Regulation of ginsenoside and phytosterol biosynthesis by RNA interferences of squalene epoxidase gene in Panax ginseng. Phytochemistry 71:36–46

    Article  CAS  PubMed  Google Scholar 

  • Hayashi H, Hirota A, Hiraoka N et al (1999) Molecular cloning and characterization of two cDNAs for Glycyrrhiza glabra squalene synthase. Biol Pharm Bull 22:947–950

    Article  CAS  PubMed  Google Scholar 

  • He QP, Ma L, Luo JY et al (2007) Cytotoxic withanolides from Physalis angulata L. Chem Biodivers 4:443–449

    Article  CAS  PubMed  Google Scholar 

  • He F, Zhu Y, He M et al (2008) Molecular cloning and characterization of the gene encoding squalene epoxidase in Panax notoginseng. DNA Seq 19:270–273

    Article  CAS  PubMed  Google Scholar 

  • Hsieh PW, Huang ZY, Chen JH et al (2007) Cytotoxic Withanolides from Tubocapsicum anomalum. J Nat Prod 70:747–753

    Article  CAS  PubMed  Google Scholar 

  • Hu FX, Zhong JJ (2008) Jasmonic acid mediates gene transcription of ginsenoside biosynthesis in cell cultures of Panax notoginseng treatedwith chemically synthesized 2-hydroxyethyl jasmonate. Process Biochem 43:113–118

    Article  CAS  Google Scholar 

  • Huang CF, Ma L, Sun LJ et al (2009) Immunosuppressive withanolides from Withania coagulans. Chem Biodivers 6:1415–1426

    Article  CAS  PubMed  Google Scholar 

  • Huang FC, Sung PH, Do YY et al (2012) Differential expression and functional characterization of the NADPH cytochrome P450 reductase genes from Nothapodytes foetida. Plant Sci 190:16–23

    Article  CAS  PubMed  Google Scholar 

  • Ihsan-ul-Haq Youn UJ, Chai X et al (2013) Biologically active withanolides from Withania coagulans. J Nat Prod 76:22–28

    Article  CAS  PubMed  Google Scholar 

  • Iyanagi T, Xia C, Kim JJ (2012) NADPH-cytochrome P450 oxidoreductase: prototypic member of the diflavin reductase family. Arch Biochem Biophys 528:72–89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jahan E, Perveen S, Fatima I et al (2010) Coagulansins A and B, new withanolides from Withania coagulans Dunal. Helv Chim Acta 93:530–535

    Article  CAS  Google Scholar 

  • Jayaprakasam B, Nair MG (2003) Cyclooxygenase-2 enzyme inhibitory withanolides from Withania somnifera leaves. Tetrahedron 59:841–898

    Article  CAS  Google Scholar 

  • Jennewein S, Park H, DeJong JM et al (2005) Coexpression in yeast of Taxus cytochrome P450 reductase with cytochrome P450 oxygenases involved in Taxol biosynthesis. Biotechnol Bioeng 89:588–598

    Article  CAS  PubMed  Google Scholar 

  • Kato-Emori S, Higashi K, Hosoya K et al (2001) Cloning and characterization of the gene encoding 3-hydroxy-3- methylglutaryl coenzyme A reductase in melon (Cucumis melo L. reticulatus). Mol Gen Genom 265:135–142

    Article  CAS  Google Scholar 

  • Khan PM, Malik A, Ahmad S et al (1999a) Withanolides from Ajuga parviflora. J Nat Prod 62:1290–1292

    Article  CAS  PubMed  Google Scholar 

  • Khan PM, Nawaz HR, Ahmad S et al (1999b) Ajugins C and D, new withanolides from Ajuga parviflora. Helv Chim Acta 82:1423–1426

    Article  CAS  Google Scholar 

  • Kim YS, Cho JH, Park S et al (2011) Gene regulation patterns in triterpene biosynthetic pathway driven by overexpression of squalene synthase and methyl jasmonate elicitation in Bupleurum falcatum. Planta 233:343–355

    Article  CAS  PubMed  Google Scholar 

  • Kirson I, Glotter E (1981) Recent developments in naturally occurring ergostane type steroids: a review. J Nat Prod 44:633–647

    Article  CAS  Google Scholar 

  • Kirson I, Lavie D, Subramanian SS et al (1972) Withanicandrin, a Ring-c-substituted Withanolide from Nicandra physaloides (Solanaceae). J Chem Soc Perkin Trans I:2109–2111

    Article  Google Scholar 

  • Kirson I, Abraham A, Sethi PD et al (1976) 4β-hydroxywithanolide E, a new natural steroid with a 17α-oriewied side-chain. Phytochemistry 15:340–342

    Article  CAS  Google Scholar 

  • Kolesnikova MD, Xiong Q, Lodeiro S et al (2006) Lanosterol biosynthesis in plants. Arch Biochem Biophys 447:87–95

    Article  CAS  PubMed  Google Scholar 

  • Koopmann E, Hahlbrock K (1997) Differentially regulated NADPH: cytochrome P450 oxidoreductases in parsley. Proc Nat Acad Sci USA 94:14954–14959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Korth KL, Stemer BA, Bhattacharyya MK et al (1997) HMGCoA reductase gene families that differentially accumulate transcripts in potato tubers are developmentally expressed in floral tissues. Plant Mol Biol 33:545–551

    Article  CAS  PubMed  Google Scholar 

  • Kuang HX, Yang BY, Tang L et al (2009) Baimantuoluosides A-C, three new withanolide glucosides from the flower of Datura metel L. Helv Chim Acta 92:1315–1323

    Article  CAS  Google Scholar 

  • Kuang HX, Yang BY, Xia YG et al (2011) Two new withanolide lactones from Flos Daturae. Molecules 16:5833–5839

    Article  CAS  PubMed  Google Scholar 

  • Kumar A, Ali M, Mir SR (2004) A new withanolide from the roots of Withania somnifera. Indian J Chem, Sect B 43:2001–2003

    Google Scholar 

  • Kuroyanagi M, Shibata K, Umehara K (1999) Cell differentiation inducing steroids from Withania somnifera L. (DUN.). Chem Pharm Bull 47:1646–1649

    Article  CAS  Google Scholar 

  • Kushwaha S, Soni VK, Singh PK et al (2012) Withania somnifera chemotypes NMITLI 101R, NMITLI 118R, NMITLI 128R and withaferin A protect Mastomys coucha from Brugia malayi infection. Parasite Immunol 34:199–209

    Article  CAS  PubMed  Google Scholar 

  • Lal P, Misra L, Sangwan RS et al (2006) New withanolides from fresh berries of Withania somnifera. Z Naturforsch, B: Chem Sci 61:1143–1147

    Article  CAS  Google Scholar 

  • Lan YH, Chang FR, Pan MJ et al (2009) New cytotoxic withanolides from Physalis peruviana. Food Chem 116:462–469

    Article  CAS  Google Scholar 

  • Lavie D, Glotter E, Shvo Y (1965) Constituents of Withania somnifera Dun III. The side chain of withaferin A. J Org Chem 30:1774–1778

    Article  CAS  Google Scholar 

  • Leber R, Landl K, Zinser E et al (1998) Dual localization of squalene epoxidase, Erg1p, in yeast reflects a relationship between the endoplasmic reticulum and lipid particles. Mol Biol Cell 9:375–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JH, Yoon YH, Kim HY et al (2002) Cloning and expression of squalene synthase cDNA from hot pepper (Capsicum annuum L.). Mol Cells 13:436–443

    CAS  PubMed  Google Scholar 

  • Lee MH, Jeong JH, Seo JW et al (2004) Enhanced triterpene and phytosterol biosynthesis in Panax ginseng overexpressing squalene synthase gene. Plant Cell Physiol 45:976–984

    Article  CAS  PubMed  Google Scholar 

  • Lee SW, Pan MH, Chen CM et al (2008) Withangulatin I, a new cytotoxic withanolide from Physalis angulata. Chem Pharm Bull 56:234–236

    Article  CAS  PubMed  Google Scholar 

  • Lee MJ, Schep D, McLaughlin B et al (2014) Structural analysis and identification of PhuS as a heme-degrading enzyme from Pseudomonas aeruginosa. J Mol Biol 426:1936–1946

    Article  CAS  PubMed  Google Scholar 

  • Li YZ, Pan YM, Huang XY et al (2008) Withanolides from Physalis alkekengi var. Francheti. Helv Chim Acta 91:2284–2291

    Article  CAS  Google Scholar 

  • Liao Z, Tan Q, Chai Y et al (2004) Cloning and characterisation of the gene encoding HMG-CoA reductase from Taxus media and its functional identification in yeast. Funct Plant Biol 31:73–81

    Article  CAS  Google Scholar 

  • Lin J, Jin Y, Zhou M et al (2009) Molecular cloning, characterization and functional analysis of a 3-hydroxy-3-methylglutaryl coenzyme A reductase gene from Jatropha curcas. Afr J Biotechnol 8:3455–3462

    CAS  Google Scholar 

  • Liu HY, Ni E, Xie BB et al (2006) Five new withanolides from Tacca plantaginea. Chem Pharm Bull 54:992–995

    Article  CAS  PubMed  Google Scholar 

  • Llanos GG, Araujo LM, Jiménez IA et al (2012) Withaferin A-related steroids from Withania aristata exhibit potent antiproliferative activity by inducing apoptosis in human tumor cells. Eur J Med Chem 54:499–511

    Article  CAS  PubMed  Google Scholar 

  • Ma CY, Williams ID, Che CT (1999) Withanolides from Hyoscyamus niger Seeds. J Nat Prod 62:1445–1447

    Article  CAS  PubMed  Google Scholar 

  • Ma L, Xie CM, Li J et al (2006) Daturametelins H, I, and J: three new withanolide glycosides from Datura metel L. Chem Biodivers 3:180–186

    Article  CAS  PubMed  Google Scholar 

  • Maldonado E, Torres FR, Martínez M et al (2004) 18-Acetoxywithanolides from Physalis chenopodifolia. Planta Med 70:59–64

    Article  CAS  PubMed  Google Scholar 

  • Maldonado E, Alvarado VE, Torres FR et al (2005) Androstane and withanolides from Physalis cinerascens. Planta Med 71:548–553

    Article  CAS  PubMed  Google Scholar 

  • Maldonado E, Amador S, Martínez M et al (2010) Virginols A-C, three new withanolides from Physalis virginiana. Steroids 75:346–349

    Article  CAS  PubMed  Google Scholar 

  • Maldonado E, Gutiérrez R, Pérez-Castorena AL et al (2012) Orizabolide, a new withanolide from Physalis orizabae. J Mex Chem Soc 56:128–130

    CAS  Google Scholar 

  • Maldonado-Mendoza IE, Vincent RM, Nessler CL (1997) Molecular characterization of three differentially expressed members of the Camptotheca acuminata 3-hydroxy-3-methylglutaryl CoA reductase (HMGR) gene family. Plant Mol Biol 34:781–790

    Article  CAS  PubMed  Google Scholar 

  • Manickam M, Awasthi SB, Sinhabagchi A et al (1996) Withanolides from Datura Tatula. Phytochemistry 41:981–983

    Article  CAS  Google Scholar 

  • Matsuda H, Murakami T, Kishi A et al (2001) Structures of withanosides I, II, III, IV, V, VI, and VII, new withanolide glycosides, from the roots of Indian Withania somnifera Dunal. and inhibitory activity for tachyphylaxis to clonidine in isolated guinea-pig ileum. Bioorg Med Chem 9:1499–1507

    Article  CAS  PubMed  Google Scholar 

  • Minguzzi S, Barata LES, Shin YG et al (2002) Cytotoxic withanolides from Acnistus arborescens. Phytochemistry 59:635–641

    Article  CAS  PubMed  Google Scholar 

  • Misico RI, Veleiro AS, Burton G et al (1997) Withanolides from Jaborosa leucotricha. Phytochemistry 45:1045–1048

    Article  CAS  Google Scholar 

  • Misico RI, Gil RR, Oberti JC et al (2000) Withanolides from Vassobia lorentzii. J Nat Prod 63:1329–1332

    Article  CAS  PubMed  Google Scholar 

  • Misico RI, Nicotra VE, Oberti JC et al (2011) Withanolides and related steroids. Prog Chem Org Nat Prod 94:127–229

    CAS  PubMed  Google Scholar 

  • Misra L, Lal P, Sangwan RS et al (2005) Unusually sulfated and oxygenated steroids from Withania somnifera. Phytochemistry 66:2702–2707

    Article  CAS  PubMed  Google Scholar 

  • Misra L, Mishra P, Pandey A et al (2008) Withanolides from Withania somnifera roots. Phytochemistry 69:1000–1004

    Article  CAS  PubMed  Google Scholar 

  • Mizutani M, Ohta D (1998) Two isoforms of NADPH: cytochrome P450 reductase in Arabidopsis thaliana—gene structure, heterologous expression in insect cells, and differential regulation. Plant Physiol 116:357–367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Musharraf SG, Ali A, Ali RA et al (2011) Analysis and development of structure-fragmentation relationships in withanolides using an electrospray ionization quadropole time-of-flight tandem mass spectrometry hybrid instrument. Rapid Commun Mass Spectrom 25:104–114

    Article  CAS  PubMed  Google Scholar 

  • Nagafuji S, Okabe H, Akahane H et al (2004) Trypanocidal constituents in plants 4 withanolides from the aerial parts of Physalis angulata. Biol Pharm Bull 27:193–197

    Article  CAS  PubMed  Google Scholar 

  • Nawaz HR, Malik A, Khan PM et al (1999) Ajugin E and F: two withanolides from Ajuga parviflora. Phytochemistry 52:1357–1360

    Article  CAS  Google Scholar 

  • Nawaz HR, Malik A, Muhammad P et al (2000a) Chemical constituents of Ajuga parviflora. Naturforsch B: Chem Sci 55b:100–103

  • Nawaz HR, Riaz M, Malik A et al (2000b) Withanolides and alkaloid from Ajuga parviflora. Chem Soc Pak 22:138–141

    CAS  Google Scholar 

  • Neogi P, Sahai M, Ray AB (1987) Withaperuvins F and G, two withanolides of Physais peruvana roots. Phytochemistry 26:243–247

    Article  Google Scholar 

  • Nicotra VE, Gil RR, Vaccarini C et al (2003) 15,21-Cyclowithanolides from Jaborosa bergii. J Nat Prod 66:1471–1475

    Article  CAS  PubMed  Google Scholar 

  • Niero R, Silva ITD, Tonial GC et al (2006) Cilistepoxide and cilistadiol, two new withanolides from Solanum sisymbiifolium. Nat Prod Res 20:1164–1168

    Article  CAS  PubMed  Google Scholar 

  • Niu Y, Luo H, Chen S et al (2012) Cloning and bioinformatics analysis of cycloartenol synthase(HcCAS1) gene in Huperzia carinata. Zhongguo Zhong Yao Za Zhi 37:1715–1719

    CAS  PubMed  Google Scholar 

  • Niu Y, Luo H, Sun C et al (2014) Expression profiling of the triterpene saponin biosynthesis genes FPS, SS, SE, and DS in the medicinal plant Panax notoginseng. Gene 533:295–303

    Article  CAS  PubMed  Google Scholar 

  • Nur-e-Alam M, Yousaf M, Qureshi S et al (2003) A novel dimeric podophyllotoxin-type lignan and a new withanolide from Withania coagulans. Helv Chim Acta 86:607–614

    Article  CAS  Google Scholar 

  • Ohyama K, Suzuki M, Kikuchi J et al (2009) Dual biosynthetic pathways to phytosterol via cycloartenol and lanosterol in Arabidopsis. Proc Natl Acad Sci USA 106:725–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pan YH, Wang XC, Hu XM (2007) Cytotoxic withanolides from the flowers of Datura metel. J Nat Prod 70:1127–1132

    Article  CAS  PubMed  Google Scholar 

  • Pérez-Castorena AL, Oropeza RF, Vazquez AR et al (2006) Labdanes and withanolides from Physalis coztomatl. J Nat Prod 69:1029–1033

    Article  PubMed  CAS  Google Scholar 

  • Pramanick S, Roy A, Ghosh S et al (2008) Withanolide Z, a new chlorinated withanolide from Withania somnifera. Planta Med 74:1745–1748

    Article  CAS  PubMed  Google Scholar 

  • Quang TH, Ngan NT, Minh CV et al (2012) Plantagiolides I and J, two new withanolide glucosides from Tacca plantaginea with nuclear factor-kappaB inhibitory and peroxisome proliferator-activated receptor transactivational activities. Chem Pharm Bull (Tokyo) 60:1494–1501

    Article  CAS  Google Scholar 

  • Rahman Atta-ur, Choudhary MI, Yousaf M et al (1998) New Withanolides from Withania coagulans. Chem Pharm Bull 46:1853–1856

    Article  Google Scholar 

  • Ramacciotti NS, Nicotra VE (2007) Withanolides from Jaborosa kurtzii. J Nat Prod 70:1513–1515

    Article  CAS  PubMed  Google Scholar 

  • Rana S, Lattoo SK, Dhar N et al (2013) NADPH-cytochrome P450 reductase: molecular cloning and functional characterization of two paralogs from Withania somnifera (L.) dunal. PLoS ONE 8:e57068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Razdan S, Bhat WW, Rana S et al (2013) Molecular characterization and promoter analysis of squalene epoxidase gene from Withania somnifera (L.) Dunal. Mol Biol Rep 40:905–916

    Article  CAS  PubMed  Google Scholar 

  • Reddy KS, Row LR, Matsuura T (1985) Pubescenol, a new withanolide from Physdis pubescence. J Chem Soc Perkin Trans I 419–420

  • Riaz N, Malik A, Aziz-ur-Rehman et al (2004) Cholinesterase-inhibiting withanolides from Ajuga bracteosa. Chem Biodivers 1:1289–1295

    Article  CAS  PubMed  Google Scholar 

  • Ro DK, Ehlting J, Douglas C (2002) Cloning, functional expression, and subcellular localization of multiple NADPH-cytochrome P450 reductases from hybrid poplar. Plant Physiol 130:1837–1851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosco A, Pauli HH, Priesner W et al (1997) Cloning and heterologous expression of NADPH—cytochrome P450 reductases from the hybrid poplar. Arch Biochem Biophys 348:369–377

    Article  CAS  PubMed  Google Scholar 

  • Sangwan RS, Chaurasiya ND, Misra LN et al (2004) Phytochemical variability in commercial herbal products and preparations of Withania somnifera (Ashwagandha). Curr Sci 86:461–465

    CAS  Google Scholar 

  • Sangwan RS, Chaurasiya ND, Lal P et al (2008) Withanolide A is inherently de novo synthesized with in roots in Ashwagandha (Withania somnifera). Physiol Plantarum 133:278–287

    Article  CAS  Google Scholar 

  • Sawai S, Akashi T, Sakurai N et al (2006) Plant lanosterol synthase: divergence of the sterol and triterpene biosynthetic pathways in eukaryotes. Plant Cell Physiol 47:673–677

    Article  CAS  PubMed  Google Scholar 

  • Schwarz H, Liu B, Peters S et al (2009) Purification, cDNA cloning and functional expression of NADPH-cytochrome P450 reductase from Centaurium erythraea cell cultures. Plant Biol (Stuttg) 11:300–306

    Article  CAS  Google Scholar 

  • Schwarz BH, Driver J, Peacock R et al (2014) Kinetic characterization of an oxidative, cooperative HMG-CoA reductase from Burkholderia cenocepacia. Biochim Biophys Acta 1844:457–464

    Article  CAS  PubMed  Google Scholar 

  • Sehgal N, Gupta A, Valli RK et al (2012) Withania sonimnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci 109:3510–3515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seo JW, Jeong JH, Shin CG et al (2005) Overexpression of squalene synthase in Eleutherococcus senticosus increases phytosterol and triterpene accumulation. Phytochemistry 66:869–877

    Article  CAS  PubMed  Google Scholar 

  • Shen G, Pang Y, Wu W et al (2006) Cloning and characterization of a root-specific expressing gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase from Ginkgo biloba. Mol Biol Rep 33:117–127

    Article  CAS  PubMed  Google Scholar 

  • Shinozaki J, Shibuya M, Masuda K et al (2008) Squalene cyclase and oxidosqualene cyclase from a fern. FEBS Lett 582:310–318

    Article  CAS  PubMed  Google Scholar 

  • Silva GL, Burton G, Obert JC (1999) 18,20-Hemiacetal-type and other withanolides from Dunalia brachyacantha. J Nat Prod 62:949–953

    Article  CAS  PubMed  Google Scholar 

  • Simmons DL, Lalley PA, Kasper CB (1985) Chromosomal assignments of genes coding for components of the mixed-function oxidase system in mice. Genetic localization of the cytochrome P-450PCN and P-450PB gene families and the nadph-cytochrome P-450 oxidoreductase and epoxide hydratase genes. J Biol Chem 260:515–521

    CAS  PubMed  Google Scholar 

  • Su BN, Misico R, Park EJ et al (2002) Isolation and characterization of bioactive principles of the leaves and stems of Physalis philadelphica. Tetrahedron 58:3453–3466

    Article  CAS  Google Scholar 

  • Su BN, Park EJ, Nikolic D et al (2003) Isolation and characterization of miscellaneous secondary metabolites of deprea subtriflora. J Nat Prod 66:1089–1093

    Article  CAS  PubMed  Google Scholar 

  • Suleiman RK, Zarga MA, Sabri SS et al (2010) New withanolides from Mandragora officinarum: first report of withanolides from the Genus Mandragora. Fitoterapia 81:864–868

    Article  CAS  PubMed  Google Scholar 

  • Suzuki H, Achnine L, Xu R et al (2002) A genomics approach to the early stages of triterpene saponin biosynthesis in Medicago truncatula. Plant J 32:1033–1048

    Article  CAS  PubMed  Google Scholar 

  • Suzuki M, Xiang T, Ohyama K et al (2006) Lanosterol synthase in dicotyledonous plants. Plant Cell Physiol 47:565–571

    Article  CAS  PubMed  Google Scholar 

  • Tettamanzi MC, Veleiro AS, de la Fuente JR et al (2001) Withanolides from Salpichroa origanifolia. J Nat Prod 64:783–786

    Article  CAS  PubMed  Google Scholar 

  • Thaker SJ, Mehta DS, Shah HA et al (2013) A comparative randomized open label study to evaluate efficacy, safety and cost effectiveness between topical 2% sertaconazole and topical 1% butenafine in tinea infections of skin. Indian J Dermatol Ve 58:451–456

    Article  Google Scholar 

  • Tong X, Zhang H, Timmermann BN et al (2011) Chlorinated withanolides from Withania somnifera. Phytochem Lett 4:411–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uchida H, Sugiyama R, Nakayachi O et al (2007) Expression of the gene for sterol-biosynthesis enzyme squalene epoxidase in parenchyma cells of the oil plant Euphorbia tirucalli. Planta 226:1109–1115

    Article  CAS  PubMed  Google Scholar 

  • Vankar PS, Srivastava J, Molčanov K et al (2009) Withanolide A series steroidal lactones from Eucalyptus globulus bark. Phytochem Lett 2:67–71

    Article  CAS  Google Scholar 

  • Vasina OE, Abdullaev ND, Abubakirov NK (1990) Withasteroids of Physalis. IX. Physangulide-The first natural 22S-withasteroid. Chem Nat Compd 26:304–307

    Article  Google Scholar 

  • Veleiro AS, Burton G, Gros EG (1985) 2,3-dihydrojaborosalactone A, a witanolide from Acnistus bre viflorus. Phytochemistry 24:1799–1802

    Article  CAS  Google Scholar 

  • Veleiro AS, Cirigliano AM, Oberti JC et al (1999) 7-Hydroxywithanolides from datura ferox. J Nat Prod 62:1010–1012

    Article  CAS  PubMed  Google Scholar 

  • Vermillion K, Holguin FO, Berhow MA et al (2011) Dinoxin B, a withanolide from Datura inoxia leaves with specific cytotoxic activities. J Nat Prod 74:267–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang M, Roberts DL, Paschke R et al (1997) Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes. Proc Natl Acad Sci USA 94:8411–8416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Guo B, Zhang F et al (2007) Molecular cloning and functional analysis of the gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase from hazel (Corylus avellana L. Gasaway). J Biochem Mol Biol 40:861–869

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Yeats T, Han H et al (2010) Cloning and characterization of oxidosqualene cyclases from Kalanchoe daigremontiana: enzymes catalyzing up to 10 rearrangement steps yielding friedelin and other triterpenoids. J Biol Chem 285:29703–29712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wube AA, Wenzig EM, Gibbons S et al (2008) Constituents of the stem bark of Discopodium penninervium and their LTB4 and COX-1 and -2 inhibitory activities. Phytochemistry 69:982–987

    Article  CAS  PubMed  Google Scholar 

  • Xia CW, Panda SP, Marohnic CC et al (2011) Structural basis for human NADPH-cytochrome P450 oxidoreductase deficiency. Proc Natl Acad Sci USA 108:13486–13491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang BY, Kuang HX (2005) Studies on chemical constituents & pharmacological action of effective parts for psoriasis in Flos Datuare. Heilongjiang University of Chinese Medicine, Harbin, pp 45–153

  • Yang BY, Wang QH, Xia YG et al (2007) Withanolide compounds from the flower of Datura metel L. Helv Chim Acta 90:1522–1528

    Article  CAS  Google Scholar 

  • Yang BY, Wang QH, Xia YG et al (2008) Baimantuoluolines D-F, three new withanolides from the flower of Datura metel L. Helv Chim Acta 91:964–971

    Article  CAS  Google Scholar 

  • Yang BY, Xia YG, Wang QH et al (2010a) Baimantuoluosides D-G, four new withanolide glucosides from the flower of Datura metel L. Arch Pharm Res 33:1143–1148

    Article  CAS  PubMed  Google Scholar 

  • Yang CQ, Lu S, Mao YB et al (2010b) Characterization of two NADPH: cytochrome P450 reductases from cotton (Gossypium hirsutum). Phytochemistry 71:27–35

    Article  CAS  PubMed  Google Scholar 

  • Yang JY, Chen CX, Zhao RH et al (2011) Plantagiolide F, a minor withanolide from Tacca plantaginea. Nat Prod Res 25:40–44

    Article  PubMed  CAS  Google Scholar 

  • Yang BY, Xia YG, Liu Y (2014) New antiproliferative and immunosuppressive withanolides from the seeds of Datura metel. Phytochem Lett 8:92–96

    Article  CAS  Google Scholar 

  • Yokosuka A, Mimaki Y, Sashida Y (2003) Chantriolides A and B, two new withanolide glucosides from the rhizomes of Tacca chantrieri. J Nat Prod 66:876–878

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Liu JY, Xu LZ et al (2009) Chantriolide C, a new withanolide glucoside and a new spirostanol saponin from the rhizomes of Tacca chantrieri. Chem Pharm Bull 57:1126–1128

    Article  CAS  PubMed  Google Scholar 

  • Zhang HP, Samadi AK, Gallagher RJ et al (2011) Cytotoxic withanolide constituents of Physalis longifolia. J Nat Prod 74:2532–2544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Bazzill J, Gallagher RJ et al (2013) Antiproliferative withanolides from Datura wrightii. J Nat Prod 76:445–449

    Article  CAS  PubMed  Google Scholar 

  • Zhao J, Nakamura N, Hattori M et al (2002) Withanolide derivatives from the roots of Withania somnifera and their neurite outgrowth activities. Chem Pharm Bull (Tokyo) 50:760–765

    Article  CAS  Google Scholar 

  • Zhu XH, Ando J, Takagi M et al (2001a) Six new withanolide-type steroids from the leaves of Solanum cilistum. Chem Pharm Bull 49:161–164

    Article  CAS  PubMed  Google Scholar 

  • Zhu XH, Takagi M, Ikeda T et al (2001b) Withanolide-type steroids from Solanum cilistum. Phytochemistry 6:741–745

    Article  Google Scholar 

Download references

Acknowledgments

We thank the authors of all the references cited herein for their valuable contributions. This work was financially sponsored by the Chang Jiang Scholar Candidates Program for Provincial Universities in Heilongjiang (2013CJHB006).

Author information

Author notes

    Authors and Affiliations

    1. Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China

      Bing-You Yang, Yong-Gang Xia, Juan Pan, Yan Liu, Qiu-Hong Wang & Hai-Xue Kuang

    Authors
    1. Bing-You Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Yong-Gang Xia
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Juan Pan
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yan Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Qiu-Hong Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Hai-Xue Kuang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Hai-Xue Kuang.

    Additional information

    Bing-You Yang and Yong-Gang Xia have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOC 3343 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Yang, BY., Xia, YG., Pan, J. et al. Phytochemistry and biosynthesis of δ-lactone withanolides. Phytochem Rev 15, 771–797 (2016). https://doi.org/10.1007/s11101-015-9420-6

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11101-015-9420-6

    Keywords

    Search

    Navigation