Shigemoto Ryosuke, Matsumoto Takara, Masuo Shunsuke, Takaya Naoki
Faculty of Life and Environmental Sciences, University of Tsukuba.
J Gen Appl Microbiol. 2018 Nov 9;64(5):240-247. doi: 10.2323/jgam.2018.01.001. Epub 2018 May 23.
Sirtuin is an NAD-dependent histone deacetylase that is highly conserved among prokaryotes and eukaryotes. Sirtuin deacetylates histones and non-histone proteins, and it is involved in fungal growth and secondary metabolite production. Here, we screened 579 fungal culture extracts that inhibited the histone deacetylase activity of Sirtuin A (SirA), produced by the fungus Aspergillus nidulans. Eight fungal strains containing three Ascomycota, two Basidiomycota and three Deuteromycetes produced SirA inhibitors. We purified the SirA inhibitor from the culture broth of Didymobotryum rigidum JCM 8837, and identified it as 5-methylmellein-a known polyketide. This polyketide and its structurally-related compound, mellein, inhibited SirA activity with IC of 120 and 160 μM, respectively. Adding 5-methylmellein to A. nidulans cultures increased secondary metabolite production in the medium. The metabolite profiles were different from those obtained by adding other sirtuin inhibitors nicotinamide and sirtinol to the culture. These results indicated that 5-methylmellein modulates fungal secondary metabolism, and is a potential tool for screening novel compounds derived from fungi.
沉默调节蛋白是一种依赖烟酰胺腺嘌呤二核苷酸（NAD）的组蛋白脱乙酰酶，在原核生物和真核生物中高度保守。沉默调节蛋白使组蛋白和非组蛋白脱乙酰化，并参与真菌生长和次级代谢产物的产生。在此，我们筛选了579种真菌培养提取物，这些提取物抑制构巢曲霉产生的沉默调节蛋白A（SirA）的组蛋白脱乙酰酶活性。含有三个子囊菌门、两个担子菌门和三个半知菌类的八个真菌菌株产生了SirA抑制剂。我们从硬壁葡萄穗霉JCM 8837的培养液中纯化了SirA抑制剂，并将其鉴定为5-甲基水曲霉毒素——一种已知的聚酮化合物。这种聚酮化合物及其结构相关化合物水曲霉毒素分别以120和160μM的半数抑制浓度（IC）抑制SirA活性。向构巢曲霉培养物中添加5-甲基水曲霉毒素可增加培养基中次级代谢产物的产量。代谢产物谱与向培养物中添加其他沉默调节蛋白抑制剂烟酰胺和西托辛醇所获得的谱不同。这些结果表明，5-甲基水曲霉毒素调节真菌次级代谢，是筛选源自真菌的新型化合物的潜在工具。
