Yoshinari Tomoya, Akiyama Tetsuo, Nakamura Keita, Kondo Tatsuhiko, Takahashi Yoshikazu, Muraoka Yasuhiko, Nonomura Yoshiaki, Nagasawa Hiromichi, Sakuda Shohei
Department of Applied Biological Chemistry, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Microbial Chemistry Research Center, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan.
Microbiology (Reading). 2007 Aug;153(Pt 8):2774-2780. doi: 10.1099/mic.0.2006/005629-0.
Dioctatin A (DotA), a metabolite of Streptomyces, is known to be an inhibitor of human dipeptidyl aminopeptidase II. Here, it was found that DotA strongly inhibited aflatoxin production by Aspergillus parasiticus, with an IC50 value of 4.0 microM. The mycelial growth of the fungus was not affected by the addition of DotA at a concentration of 50 microM, but inhibition of conidiation was observed at the same concentration. DotA inhibited production of norsolorinic acid, an early biosynthetic intermediate of aflatoxin, and it strongly reduced the mRNA levels of genes encoding aflatoxin biosynthetic enzymes, and significantly decreased the mRNA level of aflR, which encodes a key regulatory protein for aflatoxin biosynthesis. In addition to these genes, the mRNA level of brlA, which encodes a conidiation-specific transcription factor, was also reduced by the addition of DotA. It was also found that DotA dramatically enhanced kojic acid production by the fungus. Furthermore, DotA inhibited production of sterigmatocystin, which is a toxic aflatoxin biosynthetic intermediate, and it also inhibited conidiation in Aspergillus nidulans. These results indicate that DotA has pleiotropic effects on regulatory mechanisms of fungal secondary metabolite production and differentiation, leading to inhibition of aflatoxin production.
双辛他汀A（DotA）是链霉菌的一种代谢产物，已知它是人类二肽基氨基肽酶II的抑制剂。在此研究中，发现DotA能强烈抑制寄生曲霉产生黄曲霉毒素，其IC50值为4.0微摩尔。在50微摩尔浓度下添加DotA不会影响该真菌的菌丝生长，但在相同浓度下观察到产孢受到抑制。DotA抑制了黄曲霉毒素生物合成早期中间体诺索洛林酸的产生，它还大幅降低了编码黄曲霉毒素生物合成酶的基因的mRNA水平，并显著降低了编码黄曲霉毒素生物合成关键调节蛋白的aflR的mRNA水平。除了这些基因外，添加DotA还降低了编码产孢特异性转录因子的brlA的mRNA水平。还发现DotA显著提高了该真菌的曲酸产量。此外，DotA抑制了作为有毒黄曲霉毒素生物合成中间体的柄曲霉素的产生，并且它也抑制了构巢曲霉的产孢。这些结果表明，DotA对真菌次级代谢产物产生和分化的调节机制具有多效性作用，从而导致黄曲霉毒素产生受到抑制。
