期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 135, 期 36, 页码 13446-13455出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja405128k
关键词
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资金
- Japan Society for the Promotion of Science (JSPS) through the Funding Program for Next Generation World-Leading Researchers
- Council for Science and Technology Policy [LS103]
- Industrial Technology Research Grant Program from New Energy and Industrial Technology Development Organization (NEDO) of Japan [09C46001a]
- Uehara Memorial Foundation
- Takeda Science Foundation
- Sumitomo Foundation
- JSPS
- Institution for Fermentation, Osaka
- Grants-in-Aid for Scientific Research [25242067, 23406031] Funding Source: KAKEN
Postgenomic analysis revealed that many microorganisms carry numerous secondary metabolite biosynthetic genes on their genome. However, activities of those putative genes are not clearly reflected in the metabolic profile of the microorganisms, especially in fungi. A recent genome mining effort is promising in discovering new natural products. However, many fungi and other organisms are not amenable to molecular genetics manipulations, making the study difficult. Here we report successful engineering of Chaetomium globosum, a known producer of various valuable natural products, that allows its genetic manipulation via targeted homologous recombination. This strain permitted us to abolish transcriptional regulators associated with epigenetic silencing of secondary metabolite biosynthetic pathways, leading to the identification of the products generated by different gene clusters and isolation of novel secondary metabolites. We were able to identify six gene clusters that are responsible for the biosynthesis of 11 natural products previously known to be produced by C. globosum, including one cytochalasan and six azaphilone-type compounds. In addition, we isolated two new compounds, mollipilin A and B, that were only recently identified in a related Chaetomium species. Furthermore, our investigation into the mechanism of biosynthesis of those natural products in C. globosum also led to the discovery of a secondary metabolite, aureonitol, that acts like a transcriptional regulator for the biosynthesis of other secondary metabolites. Similar approaches should facilitate exploration of the untapped potential of fungal biosynthetic capability and identification of various unique biological functions that those secondary metabolites possess.
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