Large-scale metabolomics reveals a complex response of Aspergillus nidulans to epigenetic perturbation.
Large-scale metabolomics reveals a complex response of Aspergillus nidulans to epigenetic perturbation.
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DOI：
10.1021/acschembio.5b00025
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发表时间：
2015-06-19
影响因子：
4
通讯作者：
Kelleher, Neil L.
中科院分区：
文献类型：
--
作者：
Albright, Jessica C.;Henke, Matthew T.;Soukup, Alexandra A.;McClure, Ryan A.;Thomson, Regan J.;Keller, Nancy P.;Kelleher, Neil L.
微生物世界为那些能够从中筛选的人提供了丰富的生物活性化合物来源。能够定量检测天然产物同时识别已知化合物的技术将加快寻找新的药物线索。先前的努力已经针对真菌中的组蛋白脱乙酰酶来全面激活新的次级代谢产物的产生，但没有研究直接评估其在代谢组学水平上具有最小偏倚的影响。使用非靶向代谢组学，我们监测了在组蛋白脱乙酰酶活性（HDACi）的遗传或化学降低后，从模型真菌构巢曲霉分泌的>1000个小分子的变化。通过定量、差异分析，我们发现几乎相同数量的化合物上调和下调了>100倍。我们检测了已知和未知生物合成途径的产物，发现A。nidulans能够产生非鲁酰胺，其表达在HDACi时被诱导约100倍或更高的蛋白酶体抑制剂。这项工作为“组学”驱动的天然产物研究的复苏增添了动力，直接检测取代生物活性作为新药效团的主要筛选。
The microbial world offers a rich source of bioactive compounds for those able to sift through it. Technologies capable of quantitatively detecting natural products while simultaneously identifying known compounds would expedite the search for new pharmaceutical leads. Prior efforts have targeted histone deacetylases in fungi to globally activate the production of new secondary metabolites, yet no study has directly assessed its effects with minimal bias at the metabolomic level. Using untargeted metabolomics, we monitored changes in >1000 small molecules secreted from the model fungus, Aspergillus nidulans, following genetic or chemical reductions in histone deacetylase activity (HDACi). Through quantitative, differential analyses, we found nearly equal numbers of compounds were up- and down-regulated by >100 fold. We detected products from both known and unknown biosynthetic pathways and discovered that A. nidulans is capable of producing fellutamides, proteasome inhibitors whose expression was induced by ~100 fold or greater upon HDACi. This work adds momentum to an ‘omics’-driven resurgence in natural products research, where direct detection replaces bioactivity as the primary screen for new pharmacophores.
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影响因子：
5.1
作者：
El-Elimat T;Figueroa M;Ehrmann BM;Cech NB;Pearce CJ;Oberlies NH
通讯作者：
Oberlies NH
影响因子：
--
作者：
Lim, Fang Yun;Sanchez, James F.;Wang, Clay C. C.;Keller, Nancy P.
通讯作者：
Keller, Nancy P.
DOI：
10.1073/pnas.1205532110
发表时间：
2013-01-02
影响因子：
11.1
作者：
Andersen, Mikael R.;Nielsen, Jakob B.;Mortensen, Uffe H.
通讯作者：
Mortensen, Uffe H.
影响因子：
4.4
作者：
Bergmann, Sebastian;Funk, Alexander N.;Brakhage, Axel A.
通讯作者：
Brakhage, Axel A.
影响因子：
4.4
作者：
Giles, Steve S.;Soukup, Alexandra A.;Keller, Nancy P.
通讯作者：
Keller, Nancy P.