| Autor: |
Huang X; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha 410013, China., Li D; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha 410013, China., Long B; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha 410013, China., Li H; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha 410013, China., Li J; Xiangya Hospital of Central South University, Central South University, Changsha, Hunan 410008, China., Wang W; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha 410013, China., Xu K; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha 410013, China., Yu X; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha 410013, China. |
| Abstrakt: |
Fungal azaphilones have attracted widespread attention due to their significant potential as sources of food pigments and pharmaceuticals. Genome mining and gene cluster activation represent powerful tools and strategies for discovering novel natural products and bioactive molecules. Here, a putative azaphilone biosynthetic gene cluster lut from the endophytic fungus Talaromyces sp. was identified through genome mining. By overexpressing the pathway-specific transcription factor LutB, five new sclerotiorin-type azaphilones ( 1 , 6 , 8 , and 10 - 11 ) together with seven known analogues ( 2 - 5 , 7 , 9 , 12 ) were successfully produced. Compounds 8 and 9 exhibited antibacterial activity against Bacillus subtilis with MIC values of 64 and 16 μg/mL, respectively. Compound 11 showed cytotoxic activity against HCT116 and GES-1 with IC 50 values of 10.9 and 4.9 μM, respectively, while 1 , 4 , 5 , and 7 - 10 showed no obvious cytotoxic activity. Gene inactivation experiments confirmed the role of the lut cluster in the production of compounds 1 - 12 . Subsequent feeding experiments unveiled the novel functional diversity of the dual megasynthase system. Furthermore, a LutC-LutD binary oxidoreductase system was discovered, and in combination with DFT calculations, the basic biosynthetic pathway of the sclerotiorin-type azaphilones was characterized. This study provided a good example for the discovery of new azaphilones and further uncovered the biosynthesis of these compounds. |
