Metabolic studies on the transformation of trichodiene to trichothecene mycotoxins
Trichodiene and [14C]trichodiene have been produced in high yields by treatment of Fusarium culmorum CMI 14764 cultures with the furanocoumarin xanthotoxin. Smaller amounts of isotrichodermin (ITD) and the unsubstituted trichothecene 12,13-epoxytrichothec-9-ene (EPT) were obtained in the same way. E...
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| Format: | Thesis (University of Nottingham only) |
| Language: | English |
| Published: |
1991
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| Online Access: | https://eprints.nottingham.ac.uk/12521/ |
| _version_ | 1848791517907386368 |
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| author | Hesketh, Andrew R. |
| author_facet | Hesketh, Andrew R. |
| author_sort | Hesketh, Andrew R. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Trichodiene and [14C]trichodiene have been produced in high yields by treatment of Fusarium culmorum CMI 14764 cultures with the furanocoumarin xanthotoxin. Smaller amounts of isotrichodermin (ITD) and the unsubstituted trichothecene 12,13-epoxytrichothec-9-ene (EPT) were obtained in the same way. EPT was also produced by semi-synthesis from ITD.
Trichodiene (TDN) was shown to be a precursor of the trichothecene mycotoxins in F. culmorum, including EPT, ITD, calonectrin (CAL), 7a-hydroxycalonectrin (7-hydroxyCAL), 15-deacetylcalonectrin, 3-acetyldeoxynivalenol (3-AcDON) and 7,8-dihydroxycalonectrin (DHC). When large amounts of TDN were supplied, a new trichodiene metabolite was found to accumulate which was fully characterised as 12,13-epoxy-2a, 11 adihydroxytrichodiene, and given the trivial name isotrichodiol. A method for the production of 14C-labelled isotrichodiol (ITdiol) was developed, and the incorporation of ["C]ITdiol into 3-AcDON, DHC and 7-hydroxyCAL was demonstrated. Slow, acid-catalysed cyclisation of ITdiol to EPT and pre-sambucoin was demonstrated, and allylic isomerisation to both 9a- and 9p-trichodiol was also detected. Labelled pre-sambucoin was incorporated into sambucoin by F. culmorwn, and ITdiol is thus proposed as a precursor to both sambucoin and sambucinol, aswel as to the trichothecenes.
A range of semi-synthetic derivatives of TDN were prepared and tested as possible inhibitors of the post-TDN biosynthesic pathway to trichothecenes in F. culmorum. In whole-cell systems all the derivatives inhibited the incorporation of labelled TDN into trichothecenes, and also initiated the production of ITdiol. One derivative, 9P, 10ß-epoxytrichodiene, was shown to be biotransformed by the fungus, undergoing 12,13-epoxidation with subsequent hydroxylation at C-3 producing 3a-hydroxy-9(3,10(3; 12,13-diepoxytrichodiene.
9ß-Trichodiol was isolated from Trichothecium roseum, and its slow, acidcatalysed cyclisation to EPT was demonstrated. 9a-Trichotriol, 9ß-trichotriol and isotrichotriol were isolated from F. culmorum for the first time, and literature assignments for the stereochemistry of the C-9 hydroxyl in trichodiol and trichotriol are reassessed. The incorporation of [`4C]ITdiol into trichothecenes in F. culmorum was found to be approximately 5 times greater than the incorporation of [14C]-913-trichotriol, and was shown to be inhibited by isotrichotriol but not by 9ß-trichodiol and 9ß-trichotriol. It is proposed that trichodiol and trichotriol are not biosynthetic intermediates in the pathway to the trichothecenes, and that they are non-enzymic metabolites produced from ITdiol and isotrichotriol, respectively, by acid-catalysed isomerisations. A new scheme for the biosynthesis of trichothecenes is proposed in which ITdiol and isotrichotriol are intermediates in the production of isotrichodermol from TDN.
Two novel compounds, 15-deacetyl-7,8-dihydroxycalonectrin (15-deacetylDHC) and 8a-hydroxyisotrichodiol were isolated from F. culmorum, and 15-deacetylDHC and DHC were shown to be precursors to 3-AcDON. It is proposed that the post-cyclisation biosynthesis of 3-AcDON involves sequential oxygenation of isotrichodermol at C-15, C-7 and C-8 producing DHC, which then undergoes deacylation to 15-deacetylDHC followed by oxidation at C-8 to 3-AcDON. |
| first_indexed | 2025-11-14T18:29:46Z |
| format | Thesis (University of Nottingham only) |
| id | nottingham-12521 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T18:29:46Z |
| publishDate | 1991 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-125212025-02-28T11:19:43Z https://eprints.nottingham.ac.uk/12521/ Metabolic studies on the transformation of trichodiene to trichothecene mycotoxins Hesketh, Andrew R. Trichodiene and [14C]trichodiene have been produced in high yields by treatment of Fusarium culmorum CMI 14764 cultures with the furanocoumarin xanthotoxin. Smaller amounts of isotrichodermin (ITD) and the unsubstituted trichothecene 12,13-epoxytrichothec-9-ene (EPT) were obtained in the same way. EPT was also produced by semi-synthesis from ITD. Trichodiene (TDN) was shown to be a precursor of the trichothecene mycotoxins in F. culmorum, including EPT, ITD, calonectrin (CAL), 7a-hydroxycalonectrin (7-hydroxyCAL), 15-deacetylcalonectrin, 3-acetyldeoxynivalenol (3-AcDON) and 7,8-dihydroxycalonectrin (DHC). When large amounts of TDN were supplied, a new trichodiene metabolite was found to accumulate which was fully characterised as 12,13-epoxy-2a, 11 adihydroxytrichodiene, and given the trivial name isotrichodiol. A method for the production of 14C-labelled isotrichodiol (ITdiol) was developed, and the incorporation of ["C]ITdiol into 3-AcDON, DHC and 7-hydroxyCAL was demonstrated. Slow, acid-catalysed cyclisation of ITdiol to EPT and pre-sambucoin was demonstrated, and allylic isomerisation to both 9a- and 9p-trichodiol was also detected. Labelled pre-sambucoin was incorporated into sambucoin by F. culmorwn, and ITdiol is thus proposed as a precursor to both sambucoin and sambucinol, aswel as to the trichothecenes. A range of semi-synthetic derivatives of TDN were prepared and tested as possible inhibitors of the post-TDN biosynthesic pathway to trichothecenes in F. culmorum. In whole-cell systems all the derivatives inhibited the incorporation of labelled TDN into trichothecenes, and also initiated the production of ITdiol. One derivative, 9P, 10ß-epoxytrichodiene, was shown to be biotransformed by the fungus, undergoing 12,13-epoxidation with subsequent hydroxylation at C-3 producing 3a-hydroxy-9(3,10(3; 12,13-diepoxytrichodiene. 9ß-Trichodiol was isolated from Trichothecium roseum, and its slow, acidcatalysed cyclisation to EPT was demonstrated. 9a-Trichotriol, 9ß-trichotriol and isotrichotriol were isolated from F. culmorum for the first time, and literature assignments for the stereochemistry of the C-9 hydroxyl in trichodiol and trichotriol are reassessed. The incorporation of [`4C]ITdiol into trichothecenes in F. culmorum was found to be approximately 5 times greater than the incorporation of [14C]-913-trichotriol, and was shown to be inhibited by isotrichotriol but not by 9ß-trichodiol and 9ß-trichotriol. It is proposed that trichodiol and trichotriol are not biosynthetic intermediates in the pathway to the trichothecenes, and that they are non-enzymic metabolites produced from ITdiol and isotrichotriol, respectively, by acid-catalysed isomerisations. A new scheme for the biosynthesis of trichothecenes is proposed in which ITdiol and isotrichotriol are intermediates in the production of isotrichodermol from TDN. Two novel compounds, 15-deacetyl-7,8-dihydroxycalonectrin (15-deacetylDHC) and 8a-hydroxyisotrichodiol were isolated from F. culmorum, and 15-deacetylDHC and DHC were shown to be precursors to 3-AcDON. It is proposed that the post-cyclisation biosynthesis of 3-AcDON involves sequential oxygenation of isotrichodermol at C-15, C-7 and C-8 producing DHC, which then undergoes deacylation to 15-deacetylDHC followed by oxidation at C-8 to 3-AcDON. 1991 Thesis (University of Nottingham only) NonPeerReviewed application/pdf en arr https://eprints.nottingham.ac.uk/12521/1/335285.pdf Hesketh, Andrew R. (1991) Metabolic studies on the transformation of trichodiene to trichothecene mycotoxins. PhD thesis, University of Nottingham. |
| spellingShingle | Hesketh, Andrew R. Metabolic studies on the transformation of trichodiene to trichothecene mycotoxins |
| title | Metabolic studies on the transformation of trichodiene to trichothecene mycotoxins |
| title_full | Metabolic studies on the transformation of trichodiene to trichothecene mycotoxins |
| title_fullStr | Metabolic studies on the transformation of trichodiene to trichothecene mycotoxins |
| title_full_unstemmed | Metabolic studies on the transformation of trichodiene to trichothecene mycotoxins |
| title_short | Metabolic studies on the transformation of trichodiene to trichothecene mycotoxins |
| title_sort | metabolic studies on the transformation of trichodiene to trichothecene mycotoxins |
| url | https://eprints.nottingham.ac.uk/12521/ |