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The Biosynthesis of Ochratoxin a and Other Structurally Related Polyketides by Aspergillus Ochraceus

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The Biosynthesis of Ochratoxin a and Other Structurally Related Polyketides by Aspergillus Ochraceus The biosynthesis of ochratoxin A and other structurally related polyketides by Aspergillus ochraceus. A thesis submitted in fulfilment of the requirements for the degree of Ph.D. of the University of London. by Jonathan Peter Harris 1996 Department of Biochemistry Imperial College of Science, Technology and Medicine London, SW7 2AY Abstract. This study has revealed new information on the pathway and the dynamics of the biosynthesis of the important mycotoxin ochratoxin A by a particular isolate of Aspergillus ochraceus in the context of the production of other structurally related polyketides including ochratoxins B, a, and 13, mellein, diaporthin and orthosporin. Orthosporin and diaporthin had never been previously found as A. ochraceus metabolites and the metabolic oiigin of diaporthin was found to be from both acetate and methionine. New physico-chemical data were obtained for diaporthin, ochratoxins a and 13, 0-methyl, methylochratoxins A and a, 0-methylochratoxin A and mellein. [ 14C] Labelled primary metabolite precursors and the methylation inhibitor ethionine were used in feeding studies to shaken liquid cultures of A. ochraceus to reveal a distinct early phase of ochratoxin A biosynthesis principally involving acetate. Further isotopic labelling experiments using [ 14C] mellein, [1O- 14C] ochratoxins a and 13 and [1O-14C, phenylalanyl-3H] ochratoxins A and B, all prepared biosynthetically, showed that i) ochratoxin 13 was incorporated into both ochratoxins A and B, ii) ochratoxin a was incorporated only into ochratoxin A, iii) mellein may not be an advanced intermediate in either ochratoxins A or B biosynthesis (which questions the accuracy of proposed biosynthetic schemes) and iv) there was detectable inter-conversion between ochratoxins A and B, albeit non-specifically and at a low rate. Optimised shaken shredded wheat cultures of A. ochraceus yielded astonishing amounts of ochratoxins A and B (up to 12 and 3 mg/g substrate, respectively). This finding led to the development of this unusual fermentation system to facilitate the use of this technique in the above biosynthetic studies. A pilot study on the mycobiota of fine green coffee beans from the major producing regions revealed a low incidence of A. ochraceus and, of those isolated, none was ocbratoxinogenic. However, an apparently novel metabolite (C31H27N0), produced by all A. ochraceus strains isolated from coffee beans was partially charactensed. II To Barbara and Khan, my special little family. 111 Table of contents. Title page 1 Abstract. 11 Dedication. 111 Table of contents. iv List of figures. ix List of tables. xvi Acknowledgements. xix 1: Introduction. 1 1.1: The ochratoiins. 1 1.2: Polyketides. 4 1.3: Polyketide biosynthesis. 4 1.4: The biosynthesis of the ochratoxins. 12 1.5: The melleins. 17 1.6: The biosynthesis of the melleins. 20 1.7: Diaporthin and orthosporin. 28 1.8: The biosynthesis of diaporthin and orthosponn. 29 2: Dynamics of the biosynthesis of Aspergillus ochraceus D2306 polyketide metabolites in liquid and solid substrate fermentations. 32 2.1: Introduction. 32 2.2: Materials and methods. 34 2.2.1: Dynamics of the biosynthesis of Aspergillus ochraceus D2306 polyketide metabolites in liquid substrate fermentations. 34 2.2.2: Intra- and extracellular polyketide concentrations versus time for Aspergillus ochraceus D2306 on either potato dextrose broth or yeast extract-sucrose. 36 2.2.3: Aspergillus ochraceus D2306 solid substrate fermentations. 39 iv 2.2.4: Dynamics of the biosynthesis of Aspergillus ochraceus D2306 polyketide metabolites in solid substrate fermentations. 41 2.2.5: Effectiveness of shaken shredded wheat culture for other ochratoxinogenic fungi. 42 2.3: Results and discussion. 45 2.3.1: Dynamics of the biosynthesis of Aspergillus ochraceus D2306 polyketide metabolites in liquid substrate fermentations. 45 2.3.2: Intra- and extracellular polyketide concentrations versus time for Aspergillus ochraceus D23 06 on either potato dextrose broth or yeast extract-sucrose. 47 2.3.3: Aspergillus ochraceus D2306 solid substrate fermentations. 51 2.3.4: Dynamics of the biosynthesis of Aspergillus ochraceus D2306 polyketide metabolites in solid substrate fermentations. 55 2.3.5: Effectiveness of shaken shredded wheat culture for other ochratoxinogenic fungi. 58 3: Isolation and identification of Aspergillus ochraceus D2306 polyketide and other, metabolites. 59 3.1: Introduction. 59 3.2: Materials and methods. 59 3.2.1: Ochratoxin A. 59 3.2.2: Ochratoxin B. 60 3.2.3: Ochratoxin cx. 60 3.2.4: Ochratoxin 3. 61 3.2.5: 0-methyl, methylochratoxin A. 61 3.2.6: Diaporthin. 61 3.2.7: Orthosponn. 64 3.2.8: Mellein. 65 3.2.9: Hydroxymellein. 65 3.2.10: Cycloechinulin. 66 v 3.2.11: Aspergillic acids. 66 3.3: Results and Discussion. 67 3.3.1: The A. ochraceus polyketide UV absorption spectra. 67 3.3.2: Ochratoxins A and B. 67 3.3.3: Ochratoxin a. 70 3.3.4: Ocliratoxin . 74 3.3.5: 0-methyl, methylochratoxin A. 78 3.3.6:Diaporthin. 78 3.3.7: Orthosponn. 88 3.3.8: Mellein. 91 3.3.9: Hydroxymellein. 91 3.3.10: Cycloechinulin. 99 3.3.11: Aspergillic acids. 99 4: Feeding radiolabelled precursors of polyketide biosynthesis to, and the effect of ethionine on, Aspergillus ochraceus D2306 potato dextrose broth fermentations. 108 4.1: Introduction. 108 4.2: Materials and methods. 108 4.3: Results and discussion. 109 5: Feeding [14C1 mellein, u1O-14CJ ochratoxins a or 13 or I1O-14C, phenylalanyl-3H1 ochratoxins A and B to Aspergillus ochraceus D2306 fermentations. 117 5.1: Introduction. 117 5.2: Materials and methods. 117 5.2.1: Feeding [ 14C] mellein to an Aspergillus ochraceus D2306 potato dextrose broth fermentation. 117 5.2.2: The course of intra- and extraceilular accumulation of mellein in an Aspergi/lus ochraceus KBf potato dextrose broth fermentation. 118 5.2.3: Rate of incorporation of [1-' 4C] acetate into [14C] mellein in v an Aspergillus ochraceus KBf potato dextrose broth fermentation. 119 5.2.4: Producing [14C] mellein of a higher specific radioactivity. 120 5.2.5: Establishing the optimal time of advanced intermediate addition to an Aspergillus ochraceus D2306 solid substrate fermentation. 120 5.2.6: Feeding [ 14C] mellein or [1O- 14C] ochratoxins a or 13 to an Aspergillus ochraceus D2306 solid substrate fermentation. 121 of 5.2.7: The interconversion10- 14C, phenylalanyl-3H1 ochratoxins A and B into ochratoxins A and B. 122 5.3: Results and discussion. 123 5.3.1: Feeding [ 14C] mellein to an Aspergillus ochraceus D2306 potato dextrose broth fermentation. 123 5.3.2: The course of intra- and extracellular accumulation of mellein in an Aspergillus ochraceus KBf potato dextrose broth fermentation. 126 5.3.3: Rate of incorporation of[1- 14C] acetate into [ 14C] mellein in an Aspergillus ochraceus KBf potato dextrose broth fermentation. 126 5.3.4: Producing [14C] mellein of a higher specific radioactivity. 127 5.3.5: Establishing the optimal time of advanced intermediate addition to an Aspergillus ochraceus D2306 solid substrate fermentation. 127 5.3.6: Feeding [ 14C] mellein or [10-14C] ochratoxins a or 13 to an Aspergillus ochraceus D2306 solid substrate fermentation. 132 of 5.3.7: The interconversionA[10l4C, phenylalanyl-3H] ochratoxins A and B into ochratoxins A and B. 136 6: The chemical degradation of ochratoxin A. 141 6.1: Introduction. 141 6.2: Materials and methods. 144 6.2.1: Experiments involving ochratoxin A and its derivatives. 144 6.2.2: Experiments involving ochratoxin a and its derivatives. 145 6.3: Results and discussion. 145 6.3.1: Experiments involving ochratoxin A and its derivatives. 145 vu 6.2.2: Experiments involving ochratoxin a and its derivatives. 151 7: Feeding I'4C1 diaporthin, diaporthin and orthosporin to Penicillium citrinum lEa potato dextrose broth fermentations. 155 7.1: Introduction. 155 7.2: Materials and Methods. 155 7.3: Results and discussion. 158 8: Isolation and characterisation of fungi from unroasted coffee beans. 168 8.1: Introduction. 168 8.2: Materials and methods. 170 8.2.1: Mycological analysis. 170 8.2.2: Ochratoxins A and B analysis. 172 8.3: Results and discussion. 174 8.3.1: Mycological analysis. 174 8.3.2: Ochratoxins A and B analysis. 177 9: Isolation and characterisation of metabolite "429" of an Aspergilus ochraceus isolate from green coffee beans. 180 9.1: Introduction. 180 9.2: Materials and methods. 180 9.3: Results and discussion. 183 10: Summary. 196 Appendices. I: DAD-HPLC calibration details of ochratoxin A. 202 II: DAD-HPLC calibration details of ochratoxin B. 203 ifi: DAD-HPLC calibration details of orthosporin. 204 IV: DAD-HPLC calibration details of diaporthin. 205 V: DAD-HPLC calibration details of mellein. 206 VI: DAD-HPLC calibration details of ergosterol. 207 VII: DAD-HPLC calibration details of citrinin. 208 VIII: DAD-HPLC calibration details of "429". 209 viii IX: The biosynthesis of citrinin. 210 References. 221 List of figures. Figure 1.1: The structures of ochratoxin A (I), ochratoxin B (II), ochratoxin A methyl ester (1111), ochratoxin B methyl ester (IV), ochratoxin A ethyl ester (V), ochratoxin B ethyl ester (Vi) and 4-hydroxyochratoxin A (VII). 2 Figure 1.2: Decarboxylative condensation of a malonyl thioester with an acetyl thioester to form an acetoacetyl thioester, CO 2 and a free thiol. 5 Figure 1.3: A schematic diagram of fatty acid biosynthesis. 5 Figure 1.4: Palmitic acid (VIII). 8 Figure 1.5: Monensin A (IX). 8 Figure 1.6: Erythromycin A (X). 8 Figure 1.7: 6-Deoxyerythronolide B (XI). 10 Figure 1.8: The organisation of the genes and enzymes of the erythromycin producing PKS in S. erythraea. 10 Figure 1.9: 6-Methylsalicylic acid (XII). 11 Figure 1.10: Hypothetical scheme of the 6-methylsalicylic acid reaction sequence (Beck eta!., 1990 from Dimroth eta!., 1970). 11 Figure 1.11: The folding pattern of the pentaketide fonning ochratoxin A.
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