Aflastatin A

Aflastatin A, a novel inhibitor of aflatoxin production by aflatoxigenic fungi.[Pubmed:9099219]

J Antibiot (Tokyo). 1997 Feb;50(2):111-8.

Aflastatin A, a novel inhibitor of the production of aflatoxin by aflatoxigenic fungi, has been isolated from the solvent extract of mycelial cake of Streptomyces sp. and its molecular formula was determined as C62H115NO24. Aflastatin A completely inhibited aflatoxin production by Aspergillus parasiticus NRRL 2999 in liquid medium or on agar plate at a concentration of 0.5 microgram/ml. The mycelial growth of this fungus was not affected in the liquid medium at the same concentration, while the hyphal extension rate was reduced on the plate together with some morphological changes. The growth of the fungus was not completely inhibited even at a concentration of 100 micrograms/ml. Aflastatin A exhibits antimicrobial activity against some bacteria, yeasts and fungi as well as antitumor activity.

Absolute configuration of aflastatin A, a specific inhibitor of aflatoxin production by Aspergillus parasiticus.[Pubmed:10813953]

J Org Chem. 2000 Jan 28;65(2):438-44.

Aflastatin A (1) is a specific inhibitor of aflatoxin production by Aspergillus parasiticus. It has the novel structure of a tetramic acid derivative with a long alkyl side chain. The absolute configurations of 29 chiral centers contained in 1 were chemically elucidated in this study. First, four small fragment molecules were prepared from 1 or its methyl ether (2), and their absolute structures were assigned as N-methyl-D-alanine, (2S,4R)-2, 4-dimethyl-1,6-hexanediol dibenzoate, (R)-3-hydroxydodecanoic acid, and (R)-1,2,4-butanetriol tribenzoate. Next, an acyclic fragment molecule 3 with 13 chiral centers was obtained from 1 by NaIO(4) oxidation, and its relative stereochemistry was elucidated by J-based configuration analysis. By analyzing coupling constants of (3)J(H,H) and (2,3)J(C,H) and ROE data, the relative configuration of 3 was verified. Finally, by further J-based configuration analysis using a fragment molecule 7 prepared from 2 with 28 chiral carbons, all relative configurations in the alkyl side chain of 1 were clarified. By connecting these relative configurations with the absolute configurations of first four fragment molecules, the absolute stereochemistry of 1 was fully determined.

Inhibitory effect of aflastatin A on melanin biosynthesis by Colletotrichum lagenarium.[Pubmed:11535802]

Microbiology. 2001 Sep;147(Pt 9):2623-8.

The effect of Aflastatin A (AsA), a novel inhibitor of aflatoxin production, on melanin biosynthesis of Colletotrichum lagenarium was examined. Addition of a low concentration of AsA (0.5 microg ml(-1)) to the culture medium almost completely inhibited the melanin production of this organism. AsA also inhibited the production of scytalone, an early intermediate of melanin biosynthesis. Melanin production was restored by addition of exogenous scytalone in the presence of AsA, suggesting that the late steps after the synthesis of scytalone were not significantly affected by AsA. This was confirmed by the results from RT-PCR analysis of the expression of genes encoding melanin biosynthetic enzymes (SCD1, THR1) and a regulatory gene (CMR1). By contrast, expression of PKS1 was severely impaired by AsA, although catalytic activity of a polyketide synthase (PKS1) was not inhibited by AsA. These results indicate that AsA inhibits an early step in melanin production, which suppresses the expression of PKS1.

Effects of aflastatin A, an inhibitor of aflatoxin production, on aflatoxin biosynthetic pathway and glucose metabolism in Aspergillus parasiticus.[Pubmed:11592501]

J Antibiot (Tokyo). 2001 Aug;54(8):650-7.

Aflastatin A inhibits aflatoxin production by Aspergillus parasiticus via an unknown mechanism. We found that Aflastatin A clearly inhibited production of norsolorinic acid, an early biosynthetic intermediate of aflatoxin, at a concentration of 0.25 microg/ml. Reverse-transcriptase polymerase chain reaction (RT-PCR), and real-time quantitative PCR (TaqMan PCR) experiments indicated that the transcription of genes encoding aflatoxin biosynthetic enzymes (pksA, ver-1, and omtA) and a gene encoding a regulatory protein for expression of the biosynthetic enzymes (aflR) were significantly reduced by the addition of Aflastatin A. We also found that Aflastatin A elevated the glucose consumption and ethanol accumulation by A. parasiticus, and repressed transcription of genes involved in ethanol utilization. These results suggest that Aflastatin A inhibits a very early step in aflatoxin biosynthesis prior to the transcription of aflR and can influence glucose metabolism in the fungus.