An intermediary role for the tremorgenic mycotoxin TR-2 in the biosynthesis of verruculogen

Willingale, Julia; Perera, K.P.W.C.; Mantle, Peter G.

doi:10.1042/bj2140991

Cited by 18 publications

(9 citation statements)

References 8 publications

(10 reference statements)

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“…These alkaloids are verruculogen 5 isolated from Penicillium verruculosum (Cole et al, 1972;Cole and Kirksey, 1973;Fayos et al, 1974), Penicillium paraherquei (Yoshizawa et al, 1976), Penicillium piscarium (Gallagher and Latch, 1977), Penicillium janthinellum (Lanigan et al, 1979), Penicillium estinogenum (Day et al, 1980), and Aspergillus fumigatus (Kosalec et al, 2005), and fumitremorgin A 6 and fumitremorgin B 7, from A. fumigatus (Yamazaki et al, 1971;Liu et al, 1996;dos Santos et al, 2003), Aspergillus caespitosus (Schroeder et al, 1975), P. piscarium (Gallagher and Latch, 1977), P. janthinellum (Lanigan et al, 1979), and Neosartoria fischeri (Nielsen et al, 1988). The polycyclic core of these three alkaloids was seen to biosynthetically derive from proline, tryptophan and methionine, while the isopentenyl unit was shown to originate from the mevalonate pathway (Day and Mantle, 1982;Willingale et al, 1983;Mantle and Shipston, 1987;Vleggaar et al, 1993). Verruculogen 5 was found to inhibit the cell cycle progression of mouse tsFT210 cells in the M phase with an MIC value of 12.2 lM (Cui et al, 1996).…”

Section: Indole Alkaloidsmentioning

confidence: 96%

Chemistry and biological activity of azoprenylated secondary metabolites

2009

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Section: Indole Alkaloidsmentioning

confidence: 96%

Chemistry and biological activity of azoprenylated secondary metabolites

2009

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“…The A. fumigatus fumigaclavine biosynthetic cluster has been extensively studied (20,27,48,53,56); however, a number of undefined reactions persist, as do cluster-encoded genes with unknown functions. The A. fumigatus EA cluster is not reported to contain NRP synthetase genes, in contrast to other EA producing fungi (11,52).…”

Section: Discussionmentioning

confidence: 99%

Nonribosomal Peptide Synthetase Genes pesL and pes1 Are Essential for Fumigaclavine C Production in Aspergillus fumigatus

O’Hanlon

Gallagher

Schrettl

et al. 2012

Appl Environ Microbiol

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ABSTRACTThe identity of metabolites encoded by the majority of nonribosomal peptide synthetases in the opportunistic pathogen,Aspergillus fumigatus, remains outstanding. We found that the nonribosomal peptide (NRP) synthetases PesL and Pes1 were essential for fumigaclavine C biosynthesis, the end product of the complex ergot alkaloid (EA) pathway inA. fumigatus. Deletion of eitherpesL(ΔpesL) orpes1(Δpes1) resulted in complete loss of fumigaclavine C biosynthesis, relatively increased production of fumitremorgins such as TR-2, fumitremorgin C and verruculogen, increased sensitivity to H2O2, and increased sensitivity to the antifungals, voriconazole, and amphotericin B. Deletion ofpesLresulted in severely reduced virulence in an invertebrate infection model (P< 0.001). These findings indicate that NRP synthesis plays an essential role in mediating the final prenylation step of the EA pathway, despite the apparent absence of NRP synthetases in the proposed EA biosynthetic cluster forA. fumigatus. Liquid chromatography/diode array detection/mass spectrometry analysis also revealed the presence of fumiquinazolines A to F in bothA. fumigatuswild-type and ΔpesLstrains. This observation suggests that alternative NRP synthetases can also function in fumiquinazoline biosynthesis, since PesL has been shown to mediate fumiquinazoline biosynthesisin vitro. Furthermore, we provide here the first direct link between EA biosynthesis and virulence, in agreement with the observed toxicity associated with EA exposure. Finally, we demonstrate a possible cluster cross-talk phenomenon, a theme which is beginning to emerge in the literature.

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“…These mycotoxins are similar in structure, and it is very likely that fumitremorgin C is converted into verruculogen, which then is partly converted to fumitremorgin A. Additional studies need to be done to determine whether this conversion series is in fact the biosynthetic pathway, since only the conversion of fumitremorgin TR-2 to verruculogen has been confirmed (32). Assuming that this conversion series is the biosynthetic pathway to fumitremorgin A, the data can be more easily explained.…”

Section: Cmentioning

confidence: 99%

Growth of and fumitremorgin production by Neosartorya fischeri as affected by temperature, light, and water activity

Nielsen

Beuchat

Frisvad

1988

Appl Environ Microbiol

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The effects of temperature, light, and water activity (aw) on the growth and fumitremorgin production of a heat-resistant mold, Neosartoryafischeri, cultured on Czapek Yeast Autolysate agar (CYA) were studied for incubation periods of up to 74 days. Colonies were examined visually, and extracts of mycelia and CYA on which the mold was cultured were analyzed for mycotoxin content by high-performance liquid chromatography. Growth always resulted in the production of the tremorgenic mycotoxins verruculogen and fumitremorgins A and C. The optimum temperatures for the production of verruculogen and fumitremorgins A and C on CYA at pH 7.0 were 25, 30, and 37°C, respectively. The production of fumitremorgin C by N. fischeri has not been previously reported. Fumitremorgin production was retarded at 15°C, but an extension of the incubation period resulted in concentrations approaching those observed at 25°C. Light clearly enhanced fumitremorgin production on CYA (pH 7.0, 25°C), but not as dramatically as did the addition of glucose, fructose, or sucrose to CYA growth medium (pH 3.5, 25°C). Growth and fumitremorgin production was greatest at aw of 0.980 on CYA supplemented with glucose or fructose and at aw of 0.990 on CYA supplemented with sucrose. Growth and fumitremorgin production were observed at aw as low as 0.925 on glucose-supplemented CYA but not at aw lower than 0.970 on CYA supplemented with sucrose. Verruculogen was produced in the highest amount on all test media, followed by fumitremorgin A and fumitremorgin C.

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An intermediary role for the tremorgenic mycotoxin TR-2 in the biosynthesis of verruculogen

Cited by 18 publications

References 8 publications

Chemistry and biological activity of azoprenylated secondary metabolites

Chemistry and biological activity of azoprenylated secondary metabolites

Nonribosomal Peptide Synthetase Genes pesL and pes1 Are Essential for Fumigaclavine C Production in Aspergillus fumigatus

Growth of and fumitremorgin production by Neosartorya fischeri as affected by temperature, light, and water activity

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