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.
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References
Simpson TJ (1975) Chem Soc Rev 4:497
Garson MJ, Staunton J (1979) Chem Soc Rev 8:539
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
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
Simpson TJ (1987) Chem Soc Rev 16:123
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
Simpson TJ (1995) Chem Ind 1995:407
Simpson TJ (1979) J Chem Soc Perkin Trans 1 1979:1233
Overton KH, Picken DJ (1976) J Chem Soc Chem Comm 1976:105
Sadler IH, Simpson TJ (1992) Magn Reson Chem 30:518
Simpson TJ, (1994) J Chem Soc Perkin Trans 1 1994:3055
Kaneda M, Takahashi R, Iitaka Y, Shubata S (1972) Tetrahedron Lett 1972:4008
Birch AJ, Baldas J, Hlubucek JR, Simpson TJ, Westerman PW (1976) J Chem Soc Perkin Trans 1 1976:898
Bardshiri E, Simpson TJ (1981) J Chem Soc Chem Commun 1981:195
Ahmed SA, Bardshiri E, McIntyre CR, Simpson TJ (1992) Austral J Chem 45:249
Arnone A, Nasini G, Merlini L, Ragg E, Assante G (1993) J Chem Soc Perkin Trans 1 1993:145
Tabata N, Tomoda H, Matsuzaki K, Omura S (1993) J Am Chem Soc 115:8558
Pachler KGR, Steyn PS, Vleggaar R, Wessels PL, Scott De B (1976) J Chem Soc Perkin Trans 1976:1182
Chandler IM, McIntyre CR, Simpson TJ (1992) J Chem Soc Perkin Trans 1 1992:2285
Ayer WA, Jiminez LD (1994) Can J Chem 72:2326
Chandler IM, McIntyre CR, Simpson TJ (1992) J Chem Soc Perkin Trans 1 1992:2271
Gudgeon JA, Holker JSE, Simpson TJ (1974) J Chem Soc Chem Commun 1974:636
Gudgeon JA, Holker JSE, Simpson TJ, Young K (1979) Bioorganic Chemistry 8:311
Holker JSE, O’Brien E, Moore RN, Vederas JC (1983) J Chem Soc Perkin Trans 1 1983:192
Simpson TJ, Holker JSE (1975) Tetrahedron Lett 1975:4693
Nakajima H, Fukuyama K, Fujimoto H, Baba T, Hamasaki T (1994) J Chem Soc Perkin Trans 1 1994:1865
MacMillan J, Lunnon MW (1976) J Chem Soc Perkin Trans 1 1976:584
Simpson TJ, Stevenson GI (1985) J Chem Soc Chem Commun 1985:1822
Simpson TJ, Stenzel DJ (1982) J Chem Soc Chem Commun 1982:1074
Leeper FJ, Staunton J (1982) J Chem Soc Chem Commun 1982:911
O’Neill JA, Simpson TJ, Willis CL (1993) J Chem Soc Chem Commun 1993:738
O’Neill JA, Simpson TJ, Willis CL (1994) J Chem Soc Perkin Trans 1 (1994):2493
O’Neill JA, Lindell SD, Simpson TJ, Willis CL (1996) J Chem Soc Perkin Trans 1 1996:632
Ahmed SA, Simpson TJ, Staunton J, Sutkowski AC, Trimble LA, Vederas JC (1985) J Chem Soc Chem Commun 1985:1685
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
Staunton J, Sutkowski AC (1991) J Chem Soc Chem Commun 1991:1108
Staunton J, Sutkowski AC (1991) J Chem Soc Chem Commun 1991:1110
Jacobs A, Staunton J, Sutkowski AC (1991) J Chem Soc Chem Commun 1991:1113
Jacobs A, Hill A, Staunton J (1995) J Chem Soc Chem Commun 1995:859
Hill A, Staunton J (1995) J Chem Soc Chem Commun 1995:861
Jacobs A, Staunton J (1995) J Chem Soc Chem Commun 1995:863
Cane D, Yang CC (1987) J Am Chem Soc 109:1255
Hutchinson CR, Yue S, Duncan JS, Yamamoto Y (1987) J Am Chem Soc 109:1253
Yoshizawa Y, Li Z, Reese PB, Vederas, JC (1990) J Am Chem Soc 112:212
Li Z, Martin FM, Vederas J (1992) J Am Chem Soc 114:1531
Scott FE, Simpson TJ, Trimble LA, Vederas JC (1984) J Chem Soc Chem Commun 1984:756
McNicholas C, Simpson TJ, Willett NJ (1996) Tetrahedron Lett 37:8053
Rawlings BJ, Reese PB, Ramer SE, Vederas JC (1989) J Am Chem Soc 111:3382
Arai K, Rawlings BJ, Yoshizawa Y, Vederas JC (1989) J Am Chem Soc 111:3391
Townsend CA, Brobst SW, Ramer SE, Vederas JC (1988) J Am Chem Soc 110:318
Brobst SW, Townsend CA (1994) Can J Chem 72:200
Watanabe CMH, Wilson D, Linz JE, Townsend CA (1996) Chemistry and Biology 3:463
Abraham EP, Pang, CP, White RL, Crout DHG, Mutstorf L, Morgan PJ, Derome AE (1983) J Chem Soc Chem Commun 1983:723
Evans JNS, Fagerness PE, Mackenzie NE, Scott AI (1984) J Am Chem Soc 106:5738
Hayes MA (1991) PhD thesis, University of Bristol
Abell C, Staunton J (1984) J Chem Soc Chem Commun 1984:1005
Jordan PM, Spencer JB (1990) J Chem Soc Chem Commun 1990:238
Jordan PM, Spencer JB (1990) J Chem Soc Chem Commun 1990:1704
Spencer JB, Jordan PM (1992) J Chem Soc Chem Commun 1992:646
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
Thiericke R, Rohr J (1993) Nat Prod Rep 10:265
Harper DB, O’Hagan D (1994) Nat Prod Rep 11:123
Jones CA, Sidebottom PJ, Cannell RJP, Noble D, Rudd, BAM (1992) J Antibiotics 45:1492
Cannell RJP, Dawson MJ, Hale RS, Hall RM, Noble D, Lynn S, Taylor NL (1993) J Antibiotics 46:1381
Less SL, Handa S, Millburn K, Leadlay PF, Dutton CJ, Staunton J (1996) Tetrahedron Lett 37:3515
Less SL, Leadlay PF, Dutton CJD, Staunton J (1996) Tetrahedron Lett 37:3519
Less SL, Handa S, Leadlay PF, Dutton CJD, Staunton J (1996) Tetrahedron Lett 37:3511
McKeown DSJ, McNicholas C, Simpson TJ, Willett NJ (1996) J Chem Soc Chem Commun 1996:301
Simpson TJ (1979) J Chem Soc Perkin Trans 1 1979:2118
Simpson TJ, Walkinshaw MD (1981) J Chem Soc Chem Commun 1981:914
Holker JSE, Simpson TJ (1978) J Chem Soc Chem Commun 1978:626
Chexal KK, Springer JP, Clardy J, Cole RJ, Kirksey TW, Dorner JW, Cutler HG, Strawter WJ (1976) J Am Chem Soc 98:6748
Springer JW, Corner JW, Cole RJ, Cox RH (1979) J Org Chem 44:4852
Bartlett AJ, Holker JSE, O’Brien E, Simpson TJ (1983) J Chem Soc Perkin Trans 1 1983:667
Bartlett AJ, Holker JSE, O’Brien E, Simpson TJ (1981) J Chem Soc Chem Commun 1981:1198
Ahmed S, Scott FE, Simpson TJ, Trimble LA, Vederas JC (1989) J Chem Soc Perkin Trans 1 1989:807
McIntyre CR, Scott FE, Simpson TJ, Trimble LA, Vederas JC, (1989) Tetrahedron 45:2307
McIntyre CR, Simpson TJ, Moore RN, Trimble LA, Vederas JC (1984) J Chem Soc Chem Commun 1984:1498
McIntyre CR, Scott FE, Simpson TJ, Trimble LA, Vederas JC (1986) J Chem Soc Chem Commun 1986:501
Scott FE, Simpson TJ, Trimble LA, Vederas JC (1986) J Chem Soc Chem Commun 1986:214
Simpson TJ, Ahmed SA, McIntyre CR, Scott FE, Sadler IH (1997) Tetrahedron 53:4013
Simpson TJ, Stenzel DJ, Bartlett AJ, O’Brien E, Holker JSE (1982) J Chem Soc Perkin Trans 1 1982:2687
Maebayashi Y, Okuyama M, Yamakazi M, Katsube Y (1982) Chem Pharm Bull 30:1911
Okuyuma E, Yamasaki M, Katsube Y (1984) Tetrahedron Lett 25:3233
Okuyama M, Yamasaki M, Kobayashi K, Sakuvai T (1983) 24:3113
Kosemura S, Matsunaga K, Yamamuro S (1991) Chemistry Lett 1991:811
Shiomi K, Uchida R, Inokoshi J, Tanaka H, Iwai T, Omura S (1996) Tetrahedron Lett 37:1265
Kosemura S, Miyata H, Yamamura S, Albone K, Simpson TJ (1994) J Chem Soc Perkin Trans 1 1994:135
Baxter RL, Abbot EM, Greenwood SL, MacFarlane IJ (1985) J Chem Soc Chem Commun 1985:564
Baxter RL, Greenwood SL (1986) J Chem Soc Chem Commun 1986:175
Baxter RL, Hanley AB, Chan HW-S (1988) J Chem Soc Chem Commun 1988:757
Baxter RL, Hanley AB, Chan HW-S, Greenwood SL, Abbot EM, MacFarlane IJ, Milne K (1992) J Chem Soc Perkin Trans 1 1992:2495
Crosby J, Sherman DH, Bibb M, Simpson TJ, Hopwood DA, (1995) Biochim Biophys Acta 1251:32
Crump MP, Crosby J, Dempsey CE, Murray M, Simpson TJ, Hopwood DA (1996) FEBS Letters 391:302
Crump MP, Crosby C, Dempsey CE, Parkinson JA, Murray M, Hopwood, DA, Simpson TJ (1997) Biochemistry 36:6000
Kelly NM, Reid RG, Willis CL, Winton P (1995) Tetrahedron Lett 36:8315
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
Gehring AM, Lambalot RM, Vogel KW, Drueckammer DG, Walsh CT (1997) Chemistry& Biology 4:17
Cox RJ, Hitchman TS, Byrom KJ, Findlow ISC, Tanner JA, Crosby J, Simpson TJ (1997) FEBS Letters 405:267
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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
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DOI: https://doi.org/10.1007/3-540-69542-7_1
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