Skip to main content
SpringerLink
Log in

Design of high energy intermediate analogues to study sterol biosynthesis in higher plants

  • Papers from the H. W. Kircher Memorial Symposium on Chemistry Biosynthesis and Function of Sterols Presented at the 76th AOCS Annual Meeting in Philadelphia, Pennsylvania, May 1985
  • Published:
Lipids

Abstract

Several enzymes of plant sterol biosynthesis involve during their catalysis postulated or demonstrated carbocationic high energy intermediates (HEI). The aim of this study was to interfere with plant sterol biosynthesis by means of rationally designed species able to mimic these carbocationic HEI. It has been demonstrated previously that the design of transition state (TS) or HEI analogues could lead to powerful and specific inhibitors of enzymes. We applied this approach to the following target enzymes: 2,3-epoxy-2,3-dihydroqualene cyclase, AdoMet-cycloartenol-C-24-methyltransferase (AdoMet CMT), cycloeucalenol-obtusifoliol isomerase (COI) and Δ8-Δ7-sterol isomerase. Very potent inhibitors have been obtained in the four cases. As an example, analogues of cycloartenol substituted at C-25 by a charged heteroatom (N, As, S) have been synthesized and shown to be able to mimic the C-25 carbocationic HEI involved in the reaction catalyzed by the AdoMet CMT. These compounds were shown to be very potent and specific inhibitors of this enzyme both in vitro (Ki=2.10−8 M, Ki/Km=10−3) and in vivo. The potent inhibitors described are powerful tools to control in vivo the sterol profile of plant cells and therefore to study the structural and functional roles of sterols in cell membranes. Moreover, these compounds constitute leader molecules of a new class of rationally designed inhibitors which could be of value in plant protection.

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

Similar content being viewed by others

Abbreviations

tridemorph (52):

4-(1,5,9-trimethyldecyl)-2,6-dimethyl morpholine

fenpropimorph (51):

4-|3-|4-tert-butylphenyl|-2-methyl| propyl-2,6-dimethylmorpholine

zymosterol (12):

5α-cholesta-8,24-dien-3β-ol

episterol (41):

5αergosta-7,24(28)-dien-3β-ol

fecosterol (42):

5α-ergosta-8,24(28)-dien-3βol

fucosterol (38):

stigmasta-5,E-24(28)-dien-3β-ol

isofucosterol (38a):

stigmasta-5-Z-24(28)-dien-3βol. Other steroids cited in the text have been drawn in Figure 1

References

  1. Goodwin, T.W. (1981) inBiosynthesis of Isoprenoid Compounds (Porter, J.W., and Spurgeon, S.L., eds.), pp. 447–480, John Wiley & Sons, New York.

    Google Scholar 

  2. Colbeau, A., Nachbaur, J., and Vignais, P.M. (1971)Biochim. Biophys. Acta 249, 462–492.

    Article  PubMed  CAS  Google Scholar 

  3. Demel, R.A., and De Kruyff, F. (1976)Biochim. Biophys. Acta 457, 109–132.

    PubMed  CAS  Google Scholar 

  4. Bloch, K.E. (1983)CRC Crit. Rev. Biochem. 242, 5802–5806.

    Google Scholar 

  5. Clark, A.J., and Bloch, K. (1959)J. Biol. Chem. 234, 2583–2588.

    CAS  Google Scholar 

  6. Svoboda, J.A., Thomson, M.J., Robbins, W.E., and Kaplanis, J.N. (1978)Lipids 13, 742–753.

    Article  CAS  Google Scholar 

  7. McMorris, T.C. (1978)Lipids 13, 716–722.

    Article  CAS  Google Scholar 

  8. Maugh, T.M. (1981)Science 212, 33–34.

    Article  PubMed  Google Scholar 

  9. Pauling, L. (1946)Chem. Eng. News 24, 1375–1377.

    CAS  Google Scholar 

  10. Douglas, K.T. (1983)Chem. Ind. (London), 311–315.

  11. Bartlett, P.A., and Marlowe, C.K. (1983)Biochemistry 22, 4618–4624.

    Article  PubMed  CAS  Google Scholar 

  12. Wolfenden, R. (1976)Annu. Rev. Biophys. 5, 271–306.

    Article  CAS  Google Scholar 

  13. Schowen, R.L. (1978) inTransition States of Biochemical Processes (Gandour, R.D., and Schowen, R.L., eds.), pp. 77–114, Plenum Press, New York.

    Google Scholar 

  14. Schmitt, P., and Benveniste, P. (1979)Phytochemistry 18, 445–450.

    Article  CAS  Google Scholar 

  15. Bladocha, M., and Benveniste, P. (1983)Plant Physiol. 41, 756–762.

    Article  Google Scholar 

  16. Rahier, A., Genot, J.C., Schuber, F., Benveniste, P., and Narula, A.S. (1984)J. Biol. Chem. 259, 15215–15223.

    PubMed  CAS  Google Scholar 

  17. Rahier, A., Cattel, L., and Benveniste, P. (1977)Phytochemistry 16, 1187–1192.

    Article  CAS  Google Scholar 

  18. Delprino, L., Balliano, G., Cattel, L., Benveniste, P., and Bouvier, P. (1983)J. Chem. Soc. Chem. Commun. 381–382.

  19. Duriatti, A. Bouvier-Navé, P., Benveniste, P., Schuber, F., Delprino, L., Balliano, G., and Cattel, L. (1985)Biochem. Pharmacol. 15, 2765–2777.

    Article  Google Scholar 

  20. Heintz, R., and Benveniste, P. (1974)J. Biol. Chem. 249, 4267–4274.

    PubMed  CAS  Google Scholar 

  21. Rahier, A., Taton, M., Schmitt, P., Benveniste, P., Place, P., and Anding, C. (1985)Phytochemistry 26, 1223–1232.

    Article  Google Scholar 

  22. Schmitt, P., Benveniste, P., and Leroux, P. (1981)Phytochemistry 20, 2153–2159.

    Article  CAS  Google Scholar 

  23. Schmitt, P., Narula, A.S., Benveniste, P., and Rahier, A. (1981)Phytochemistry 20, 197–201.

    Article  CAS  Google Scholar 

  24. Cattel, L., Ceruti, M., Viola, F., Delprino, L., Balliano, G., Duriatti, A., and Bouvier-Navé, P. (1986)Lipids 21, 31–38.

    PubMed  CAS  Google Scholar 

  25. Dean, P.D.G. (1971)Steroidologia 2, 143–157.

    PubMed  CAS  Google Scholar 

  26. Van Tamelen, E.E. (1977)J. Am. Chem. Soc. 99, 950–952.

    Article  Google Scholar 

  27. Cerutti, M., Delprino, L., Cattel, L., Benveniste, P., Schuber, F., and Bouvier-Navé, P. (1985)J. Chem. Soc. Chem. Commun. 1054–1055.

  28. Linton, E.P. (1940)J. Am. Chem. Soc. 62, 1945–1948.

    Article  CAS  Google Scholar 

  29. Wojciechowski, L.J., Goad, L.J., and Goodwin, T.W. (1973)Biochem. J. 136, 405–412.

    PubMed  CAS  Google Scholar 

  30. Avruch, L., Fischer, S., Pierce, H.D. Jr. and Oehlschlager, A.C. (1976)Can. J. Biochem. 54, 657–665.

    Article  PubMed  CAS  Google Scholar 

  31. Mihailovic, M.M. (1984) Ph.D. Dissertation, Eidgenosische Technische, Hochschule, Zurich, Switzerland.

  32. Arigoni, D. (1978)Ciba Found. Symp. 60, 243–261.

    CAS  Google Scholar 

  33. Lederer, E. (1969)Q. Rev. Chem. Soc. Lond., 23, 453–481.

    Article  CAS  Google Scholar 

  34. Goad, L.J., and Goodwin, T.W. (1972)Progress Phytochem. 3, 113–198.

    CAS  Google Scholar 

  35. Oehlschlager, A.C., Angus, R.H., Pierce, A.M., Pierce, H.D. Jr., and Srinavasan, R. (1984)Biochemistry 23, 3582–3589.

    Article  PubMed  CAS  Google Scholar 

  36. Malhotra, H.C., and Nes, W.R. (1971)J. Biol. Chem. 246, 4931–4937.

    Google Scholar 

  37. Frieden, C., Kurz, L.C., and Gilbert, M.R. (1980)Biochemistry 19, 5303–5309.

    Article  PubMed  CAS  Google Scholar 

  38. Schloss, J.V., and Cleland, W.W. (1982)Biochemistry 21, 4420–4427.

    Article  PubMed  CAS  Google Scholar 

  39. Fonteneau, P., Hartmann-Bouillon, M.A., and Benveniste, P. (1977)Plant Sci. Lett. 10, 147–155.

    Article  CAS  Google Scholar 

  40. Lin, H.-K., and Knoche, H.W. (1976)Phytochemistry 15, 683-XXX.

    Article  CAS  Google Scholar 

  41. Schmitt, P., Narula, A.S., Benveniste, P., and Rahier, A. (1981)Phytochemistry 20, 197–201.

    Article  CAS  Google Scholar 

  42. Rahier, A., Narula, A.S., Benveniste, P., and Schmitt, P. (1980)Biochem. Biophys. Res. Commun. 92, 20–25.

    Article  PubMed  CAS  Google Scholar 

  43. Olah, G.A. (1979)Top. Curr. Chem. 80, 19–88.

    Article  CAS  Google Scholar 

  44. Port, G.N.J., and Pullmann, A. (1973)Theor. Chim. Acta 31, 231–237.

    Article  CAS  Google Scholar 

  45. Wilton, D.C., Rahimtula, A.D., and Akhtar, M. (1969)Biochim. J. 114, 71–73.

    CAS  Google Scholar 

  46. Caspi, E., and Ramm, P.J. (1969)Tetrahedron Lett., 181.

  47. Yabusaki, Y., Nishima, T., Ariga, N., and Katsuki, H. (1979)J. Biochem. 85, 1531–1537.

    PubMed  CAS  Google Scholar 

  48. Bimpson, T., Goad, L.J., and Goodwin, T.W. (1969)J. Chem. Soc. Chem. Commun., 297–298.

  49. Goad, L.J., and Goodwin, T.W. (1972)Progr. Phytochem. 3, 113–198.

    CAS  Google Scholar 

  50. Rahier, A. (1980) Thèse de Doctorat d'Etat, University of Strasbourg, Strasbourg, France.

  51. Rahier, A., Schmitt, P., and Benveniste, P. (1982)Phytochemistry 21, 1969–1974.

    Article  CAS  Google Scholar 

  52. Chou, T. (1974)Mol. Pharmacol. 10, 235–243.

    PubMed  CAS  Google Scholar 

  53. Schwinn, F.J. (1983)Pestic. Sci. 15, 40–47.

    Article  Google Scholar 

  54. Bohnen, K., Siegle, M., and Löcher, F. (1979)Proc. Br. Insectic. Fungic. Conf. 10th 2, 541–548.

    Google Scholar 

  55. Himmele, W., and Pommer, E.H. (1980)Angew. Chem. Int. Ed. Engl. 19, 184–189.

    Article  Google Scholar 

  56. König, K.H., Pommer, E.H., and Sanne, W. (1965)Angew. Chem. Int. Ed. Engl. 4, 336–341.

    Article  Google Scholar 

  57. Kato, T., Shoami, M., and Kawase, Y. (1980)J. Pestic. Sci. 5, 69–70.

    CAS  Google Scholar 

  58. Leroux, P., and Gredt, M. (1983)Agronomie 3, 123–130.

    Google Scholar 

  59. Kerkenaar, A., Van Rossum, J.M., Versluis, G.G., and Marsman, J.A. (1984)Pestic. Sci. 15, 177–187.

    Article  CAS  Google Scholar 

  60. Shapiro, S.H. (1971) inKirk-Othmer Encyclopedia of Chemical Technology (Standen, A., ed.) 2nd Ed. (suppl.), pp. 32–40, John Wiley and Sons, New York.

    Google Scholar 

  61. Hosokawa, G., Patterson, G.W., and Lusby, W.R. (1984)Lipids 19, 449–456.

    CAS  Google Scholar 

  62. Sandifer, R.M., Thompson, M.D., Gaughan, R.G., and Poulter, C.D. (1982)J. Am. Chem. Soc. 104, 7376–7378.

    Article  CAS  Google Scholar 

  63. Whittaker, J.W., and Lipscomb, J.D. (1984)J. Biol. Chem. 259, 4476–4486.

    PubMed  CAS  Google Scholar 

  64. Leroux, P., and Gredt, M. (1984)Pestic. Sci. 15, 85–89.

    Article  CAS  Google Scholar 

  65. Serrano, R. (1983)Arch. Biochem. Biophys. 227, 1–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, Paul M. Gross Chemical Laboratory, Duke University, 27707, Durham, NC

    Acharan S. Narula

  2. Istituto di Chimica Farmaceutica Applicata, Torino, Italy

    Luigi Cattel

  3. Rhone-Poulenc Agrochimie, Lyon, France

    Claude Anding & Pierre Place

  4. Laboratoire de Biochimie Végétale et de Chimie Enzymatique, UA 570 du CNRS, Institut de Botanique, 28, rue Goethe, 67083, Strasbourg, France

    Alain Rahier, Maryse Taton, Pierrette Bouvier-Navé, Paulette Schmitt, Pierre Benveniste & Francis Schuber

Authors
  1. Alain Rahier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maryse Taton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierrette Bouvier-Navé
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paulette Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pierre Benveniste
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francis Schuber
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Acharan S. Narula
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luigi Cattel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Claude Anding
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pierre Place
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Rahier, A., Taton, M., Bouvier-Navé, P. et al. Design of high energy intermediate analogues to study sterol biosynthesis in higher plants. Lipids 21, 52–62 (1986). https://doi.org/10.1007/BF02534303

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02534303

Keywords

Search

Navigation