Skip to main content
SpringerLink
Log in

Application of Isotopic Methods to Secondary Metabolic Pathways

  • Chapter
  • First Online:
Biosynthesis

Part of the book series: Topics in Current Chemistry ((4143,volume 195))

Abstract

The application of stable isotope labelling methods to the study of biosynthetic pathways of secondary metabolites is illustrated by describing studies on the biosynthesis of polyketide and terpenoid metabolites of fungal origins. The use of doubly 13C-labelled precursors provides information on the mode of assembly, cyclisation and rearrangements of polyketide and terpenoid carbon skeletons. More detailed information on the oxidation levels of biosynthetic intermediates and oxidative and reductive modifications occurring during later stages of the pathway can be obtained by the use of precursors labelled with 13C in conjunction with 2H and 18O. These methods are illustrated with reference to studies on the mechanistic and stereochemical details of polyketide chain assembly and on compounds of mixed polyketide-terpenoid (meroterpenoid) origins. Fluorine labelled precursors can provide information on key steps as well as producing interesting analogues of the natural metabolites. Application of 15N labelling in conjunction with other isotopes, e.g. 13C and 18O, is illustrated by studies on the formation of 3-nitropropanoic acid. Recent work on the enzymes of polyketide biosynthesis also makes use of multiple stable isotope labelling to assist in the elucidation of 3D protein structure and to obtain information on the mode of action of some of these enzymes.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 16.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Simpson TJ (1975) Chem Soc Rev 4:497

    Article  CAS  Google Scholar 

  2. Garson MJ, Staunton J (1979) Chem Soc Rev 8:539

    Article  CAS  Google Scholar 

  3. Abell C (1986) The use of NMR spectroscopy to follow deuterium in studies of fungal metabolism. In:Linskens HF, Jackson JF (eds) Modern methods of plant analysis vol 2. Springer, Berlin Heidelberg New York, p 60

    Google Scholar 

  4. Simpson TJ (1986) 13C NMR in metabolic studies. In: Linskens HF, Jackson JF (eds) Modern methods of plant analysis vol 2. Springer, Berlin Heidelberg New York, p 1

    Google Scholar 

  5. Simpson TJ (1987) Chem Soc Rev 16:123

    Article  CAS  Google Scholar 

  6. Simpson TJ (1991) Application of stable isotope labelling and multinuclear NMR to biosynthetic studies. In:Buncel E, Jones JR (eds) Isotopes in the physical and medical sciences. Elsevier, Amsterdam, p 431

    Google Scholar 

  7. Simpson TJ (1995) Chem Ind 1995:407

    Google Scholar 

  8. Simpson TJ (1979) J Chem Soc Perkin Trans 1 1979:1233

    Article  Google Scholar 

  9. Overton KH, Picken DJ (1976) J Chem Soc Chem Comm 1976:105

    Google Scholar 

  10. Sadler IH, Simpson TJ (1992) Magn Reson Chem 30:518

    Article  Google Scholar 

  11. Simpson TJ, (1994) J Chem Soc Perkin Trans 1 1994:3055

    Article  Google Scholar 

  12. Kaneda M, Takahashi R, Iitaka Y, Shubata S (1972) Tetrahedron Lett 1972:4008

    Google Scholar 

  13. Birch AJ, Baldas J, Hlubucek JR, Simpson TJ, Westerman PW (1976) J Chem Soc Perkin Trans 1 1976:898

    Article  Google Scholar 

  14. Bardshiri E, Simpson TJ (1981) J Chem Soc Chem Commun 1981:195

    Google Scholar 

  15. Ahmed SA, Bardshiri E, McIntyre CR, Simpson TJ (1992) Austral J Chem 45:249

    Article  CAS  Google Scholar 

  16. Arnone A, Nasini G, Merlini L, Ragg E, Assante G (1993) J Chem Soc Perkin Trans 1 1993:145

    Article  Google Scholar 

  17. Tabata N, Tomoda H, Matsuzaki K, Omura S (1993) J Am Chem Soc 115:8558

    Article  CAS  Google Scholar 

  18. Pachler KGR, Steyn PS, Vleggaar R, Wessels PL, Scott De B (1976) J Chem Soc Perkin Trans 1976:1182

    Google Scholar 

  19. Chandler IM, McIntyre CR, Simpson TJ (1992) J Chem Soc Perkin Trans 1 1992:2285

    Article  Google Scholar 

  20. Ayer WA, Jiminez LD (1994) Can J Chem 72:2326

    Article  CAS  Google Scholar 

  21. Chandler IM, McIntyre CR, Simpson TJ (1992) J Chem Soc Perkin Trans 1 1992:2271

    Article  Google Scholar 

  22. Gudgeon JA, Holker JSE, Simpson TJ (1974) J Chem Soc Chem Commun 1974:636

    Google Scholar 

  23. Gudgeon JA, Holker JSE, Simpson TJ, Young K (1979) Bioorganic Chemistry 8:311

    Article  CAS  Google Scholar 

  24. Holker JSE, O’Brien E, Moore RN, Vederas JC (1983) J Chem Soc Perkin Trans 1 1983:192

    Google Scholar 

  25. Simpson TJ, Holker JSE (1975) Tetrahedron Lett 1975:4693

    Google Scholar 

  26. Nakajima H, Fukuyama K, Fujimoto H, Baba T, Hamasaki T (1994) J Chem Soc Perkin Trans 1 1994:1865

    Article  Google Scholar 

  27. MacMillan J, Lunnon MW (1976) J Chem Soc Perkin Trans 1 1976:584

    Google Scholar 

  28. Simpson TJ, Stevenson GI (1985) J Chem Soc Chem Commun 1985:1822

    Google Scholar 

  29. Simpson TJ, Stenzel DJ (1982) J Chem Soc Chem Commun 1982:1074

    Google Scholar 

  30. Leeper FJ, Staunton J (1982) J Chem Soc Chem Commun 1982:911

    Google Scholar 

  31. O’Neill JA, Simpson TJ, Willis CL (1993) J Chem Soc Chem Commun 1993:738

    Google Scholar 

  32. O’Neill JA, Simpson TJ, Willis CL (1994) J Chem Soc Perkin Trans 1 (1994):2493

    Google Scholar 

  33. O’Neill JA, Lindell SD, Simpson TJ, Willis CL (1996) J Chem Soc Perkin Trans 1 1996:632

    Google Scholar 

  34. Ahmed SA, Simpson TJ, Staunton J, Sutkowski AC, Trimble LA, Vederas JC (1985) J Chem Soc Chem Commun 1985:1685

    Google Scholar 

  35. Staunton J, Sutkowski AC (1991) J Chem Soc Chem Commun 1991:1106; Laue ED, Pollard KOB, Skilling J, Staunton J, Sutkowski AC (1987) J Mag Res 72:493

    Google Scholar 

  36. Staunton J, Sutkowski AC (1991) J Chem Soc Chem Commun 1991:1108

    Google Scholar 

  37. Staunton J, Sutkowski AC (1991) J Chem Soc Chem Commun 1991:1110

    Google Scholar 

  38. Jacobs A, Staunton J, Sutkowski AC (1991) J Chem Soc Chem Commun 1991:1113

    Google Scholar 

  39. Jacobs A, Hill A, Staunton J (1995) J Chem Soc Chem Commun 1995:859

    Google Scholar 

  40. Hill A, Staunton J (1995) J Chem Soc Chem Commun 1995:861

    Google Scholar 

  41. Jacobs A, Staunton J (1995) J Chem Soc Chem Commun 1995:863

    Google Scholar 

  42. Cane D, Yang CC (1987) J Am Chem Soc 109:1255

    Article  CAS  Google Scholar 

  43. Hutchinson CR, Yue S, Duncan JS, Yamamoto Y (1987) J Am Chem Soc 109:1253

    Article  Google Scholar 

  44. Yoshizawa Y, Li Z, Reese PB, Vederas, JC (1990) J Am Chem Soc 112:212

    Article  Google Scholar 

  45. Li Z, Martin FM, Vederas J (1992) J Am Chem Soc 114:1531

    Article  CAS  Google Scholar 

  46. Scott FE, Simpson TJ, Trimble LA, Vederas JC (1984) J Chem Soc Chem Commun 1984:756

    Google Scholar 

  47. McNicholas C, Simpson TJ, Willett NJ (1996) Tetrahedron Lett 37:8053

    Article  CAS  Google Scholar 

  48. Rawlings BJ, Reese PB, Ramer SE, Vederas JC (1989) J Am Chem Soc 111:3382

    Article  CAS  Google Scholar 

  49. Arai K, Rawlings BJ, Yoshizawa Y, Vederas JC (1989) J Am Chem Soc 111:3391

    Article  CAS  Google Scholar 

  50. Townsend CA, Brobst SW, Ramer SE, Vederas JC (1988) J Am Chem Soc 110:318

    Article  CAS  Google Scholar 

  51. Brobst SW, Townsend CA (1994) Can J Chem 72:200

    CAS  Google Scholar 

  52. Watanabe CMH, Wilson D, Linz JE, Townsend CA (1996) Chemistry and Biology 3:463

    Article  CAS  Google Scholar 

  53. Abraham EP, Pang, CP, White RL, Crout DHG, Mutstorf L, Morgan PJ, Derome AE (1983) J Chem Soc Chem Commun 1983:723

    Google Scholar 

  54. Evans JNS, Fagerness PE, Mackenzie NE, Scott AI (1984) J Am Chem Soc 106:5738

    Article  CAS  Google Scholar 

  55. Hayes MA (1991) PhD thesis, University of Bristol

    Google Scholar 

  56. Abell C, Staunton J (1984) J Chem Soc Chem Commun 1984:1005

    Google Scholar 

  57. Jordan PM, Spencer JB (1990) J Chem Soc Chem Commun 1990:238

    Google Scholar 

  58. Jordan PM, Spencer JB (1990) J Chem Soc Chem Commun 1990:1704

    Google Scholar 

  59. Spencer JB, Jordan PM (1992) J Chem Soc Chem Commun 1992:646

    Google Scholar 

  60. Woo E-R, Fujii I, Ehizuka E, Sankawa U, Kamaguchi A, Huang S, Beale JM, Shibuya M, Mocek U, Floss HG (1989) J Am Chem Soc 111:5498

    Article  CAS  Google Scholar 

  61. Thiericke R, Rohr J (1993) Nat Prod Rep 10:265

    Article  CAS  Google Scholar 

  62. Harper DB, O’Hagan D (1994) Nat Prod Rep 11:123

    Article  CAS  Google Scholar 

  63. Jones CA, Sidebottom PJ, Cannell RJP, Noble D, Rudd, BAM (1992) J Antibiotics 45:1492

    CAS  Google Scholar 

  64. Cannell RJP, Dawson MJ, Hale RS, Hall RM, Noble D, Lynn S, Taylor NL (1993) J Antibiotics 46:1381

    CAS  Google Scholar 

  65. Less SL, Handa S, Millburn K, Leadlay PF, Dutton CJ, Staunton J (1996) Tetrahedron Lett 37:3515

    Article  CAS  Google Scholar 

  66. Less SL, Leadlay PF, Dutton CJD, Staunton J (1996) Tetrahedron Lett 37:3519

    Article  CAS  Google Scholar 

  67. Less SL, Handa S, Leadlay PF, Dutton CJD, Staunton J (1996) Tetrahedron Lett 37:3511

    Article  CAS  Google Scholar 

  68. McKeown DSJ, McNicholas C, Simpson TJ, Willett NJ (1996) J Chem Soc Chem Commun 1996:301

    Google Scholar 

  69. Simpson TJ (1979) J Chem Soc Perkin Trans 1 1979:2118

    Article  Google Scholar 

  70. Simpson TJ, Walkinshaw MD (1981) J Chem Soc Chem Commun 1981:914

    Google Scholar 

  71. Holker JSE, Simpson TJ (1978) J Chem Soc Chem Commun 1978:626

    Google Scholar 

  72. Chexal KK, Springer JP, Clardy J, Cole RJ, Kirksey TW, Dorner JW, Cutler HG, Strawter WJ (1976) J Am Chem Soc 98:6748

    Article  CAS  Google Scholar 

  73. Springer JW, Corner JW, Cole RJ, Cox RH (1979) J Org Chem 44:4852

    Article  CAS  Google Scholar 

  74. Bartlett AJ, Holker JSE, O’Brien E, Simpson TJ (1983) J Chem Soc Perkin Trans 1 1983:667

    Article  Google Scholar 

  75. Bartlett AJ, Holker JSE, O’Brien E, Simpson TJ (1981) J Chem Soc Chem Commun 1981:1198

    Google Scholar 

  76. Ahmed S, Scott FE, Simpson TJ, Trimble LA, Vederas JC (1989) J Chem Soc Perkin Trans 1 1989:807

    Article  Google Scholar 

  77. McIntyre CR, Scott FE, Simpson TJ, Trimble LA, Vederas JC, (1989) Tetrahedron 45:2307

    Article  CAS  Google Scholar 

  78. McIntyre CR, Simpson TJ, Moore RN, Trimble LA, Vederas JC (1984) J Chem Soc Chem Commun 1984:1498

    Google Scholar 

  79. McIntyre CR, Scott FE, Simpson TJ, Trimble LA, Vederas JC (1986) J Chem Soc Chem Commun 1986:501

    Google Scholar 

  80. Scott FE, Simpson TJ, Trimble LA, Vederas JC (1986) J Chem Soc Chem Commun 1986:214

    Google Scholar 

  81. Simpson TJ, Ahmed SA, McIntyre CR, Scott FE, Sadler IH (1997) Tetrahedron 53:4013

    Article  CAS  Google Scholar 

  82. Simpson TJ, Stenzel DJ, Bartlett AJ, O’Brien E, Holker JSE (1982) J Chem Soc Perkin Trans 1 1982:2687

    Article  Google Scholar 

  83. Maebayashi Y, Okuyama M, Yamakazi M, Katsube Y (1982) Chem Pharm Bull 30:1911

    CAS  Google Scholar 

  84. Okuyuma E, Yamasaki M, Katsube Y (1984) Tetrahedron Lett 25:3233

    Article  Google Scholar 

  85. Okuyama M, Yamasaki M, Kobayashi K, Sakuvai T (1983) 24:3113

    Google Scholar 

  86. Kosemura S, Matsunaga K, Yamamuro S (1991) Chemistry Lett 1991:811

    Google Scholar 

  87. Shiomi K, Uchida R, Inokoshi J, Tanaka H, Iwai T, Omura S (1996) Tetrahedron Lett 37:1265

    Article  CAS  Google Scholar 

  88. Kosemura S, Miyata H, Yamamura S, Albone K, Simpson TJ (1994) J Chem Soc Perkin Trans 1 1994:135

    Article  Google Scholar 

  89. Baxter RL, Abbot EM, Greenwood SL, MacFarlane IJ (1985) J Chem Soc Chem Commun 1985:564

    Google Scholar 

  90. Baxter RL, Greenwood SL (1986) J Chem Soc Chem Commun 1986:175

    Google Scholar 

  91. Baxter RL, Hanley AB, Chan HW-S (1988) J Chem Soc Chem Commun 1988:757

    Google Scholar 

  92. Baxter RL, Hanley AB, Chan HW-S, Greenwood SL, Abbot EM, MacFarlane IJ, Milne K (1992) J Chem Soc Perkin Trans 1 1992:2495

    Article  Google Scholar 

  93. Crosby J, Sherman DH, Bibb M, Simpson TJ, Hopwood DA, (1995) Biochim Biophys Acta 1251:32

    Google Scholar 

  94. Crump MP, Crosby J, Dempsey CE, Murray M, Simpson TJ, Hopwood DA (1996) FEBS Letters 391:302

    Article  CAS  Google Scholar 

  95. Crump MP, Crosby C, Dempsey CE, Parkinson JA, Murray M, Hopwood, DA, Simpson TJ (1997) Biochemistry 36:6000

    Article  CAS  Google Scholar 

  96. Kelly NM, Reid RG, Willis CL, Winton P (1995) Tetrahedron Lett 36:8315

    CAS  Google Scholar 

  97. Simpson TJ, Willis CL (1996) Enzymatic and chemical methods for the enantioselective synthesis of isotopically labelled amino acids and metabolic intermediates. Proceedings of the Chiral Europe’ 96 Symposium, Strasbourg, p 49

    Google Scholar 

  98. Gehring AM, Lambalot RM, Vogel KW, Drueckammer DG, Walsh CT (1997) Chemistry& Biology 4:17

    Article  CAS  Google Scholar 

  99. Cox RJ, Hitchman TS, Byrom KJ, Findlow ISC, Tanner JA, Crosby J, Simpson TJ (1997) FEBS Letters 405:267

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, Great Britain

    Thomas J. Simpson

Authors
  1. Thomas J. Simpson
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, Great Britain

    Finian J. Leeper

  2. Department of Chemistry, University of Alberta, E3-44 Chemistry Building, Edmonton, T6G 2G2, Canada

    John C. Vederas

Rights and permissions

Reprints and permissions

Copyright information

© 1998 Springer Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Simpson, T.J. (1998). Application of Isotopic Methods to Secondary Metabolic Pathways. In: Leeper, F.J., Vederas, J.C. (eds) Biosynthesis. Topics in Current Chemistry, vol 195. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-69542-7_1

Download citation

  • DOI: https://doi.org/10.1007/3-540-69542-7_1

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-63418-8

  • Online ISBN: 978-3-540-69542-4

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation