Deciphering the Thiolactonization Mechanism in Thiolactomycin Biosynthesis.
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| Auteurs principaux: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Langue: | en |
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Journal of the American Chemical Society
2025
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| _version_ | 1868266188992151553 |
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| author | Guo, Jiawei Zhang, Qiaoyu Shen, Yang Cheng, Fangyuan Sang, Moli Wang, Xuan Pan, Yunjun Liu, Mingyu Yu, Hao-Bing Hu, Bo Wang, Sheng Zheng, Liangzhen Geng, Ce Yang, Chaofan Luo, Lianzhong Zhang, Gang Du, Lei Li, Yuanning Zhang, Wei Zhang, Yandong Wang, Binju Li, Shengying Zhang, Xingwang |
| author_facet | Guo, Jiawei Zhang, Qiaoyu Shen, Yang Cheng, Fangyuan Sang, Moli Wang, Xuan Pan, Yunjun Liu, Mingyu Yu, Hao-Bing Hu, Bo Wang, Sheng Zheng, Liangzhen Geng, Ce Yang, Chaofan Luo, Lianzhong Zhang, Gang Du, Lei Li, Yuanning Zhang, Wei Zhang, Yandong Wang, Binju Li, Shengying Zhang, Xingwang Guo, Jiawei Zhang, Qiaoyu Shen, Yang Cheng, Fangyuan Sang, Moli Wang, Xuan Pan, Yunjun Liu, Mingyu Yu, Hao-Bing Hu, Bo Wang, Sheng Zheng, Liangzhen Geng, Ce Yang, Chaofan Luo, Lianzhong Zhang, Gang Du, Lei Li, Yuanning Zhang, Wei Zhang, Yandong Wang, Binju Li, Shengying Zhang, Xingwang |
| collection | PubMed - marine biology |
| contents | Deciphering the Thiolactonization Mechanism in Thiolactomycin Biosynthesis. Guo, Jiawei Zhang, Qiaoyu Shen, Yang Cheng, Fangyuan Sang, Moli Wang, Xuan Pan, Yunjun Liu, Mingyu Yu, Hao-Bing Hu, Bo Wang, Sheng Zheng, Liangzhen Geng, Ce Yang, Chaofan Luo, Lianzhong Zhang, Gang Du, Lei Li, Yuanning Zhang, Wei Zhang, Yandong Wang, Binju Li, Shengying Zhang, Xingwang Peptide Synthases Cytochrome P-450 Enzyme System Cyclization Thiophenes Thiolactomycin (), which features a unique γ-thiolactone ring, is a promising antibiotic candidate that specifically targets bacterial type II fatty acid synthase. Despite extensive studies on its pharmacological activities, modes of action, and chemical synthesis, the enzymatic processes responsible for forming the activity-determining γ-thiolactone ring have remained largely unknown. Here, we resolve this problem by revealing that the condensation and heterocyclization (Cy) domain of the nonribosomal peptide synthetase (NRPS) TlnC (TlnC), along with the cytochrome P450 enzyme TlnA, cooperatively enable the γ-thiolactone assembly. TlnC mediates an unusual sulfurtransfer reaction to sulfurate the polyketide intermediate, generating a thiocarboxylate intermediate. Subsequently, TlnA acts as a γ-thiolactone synthase, converting the linear thiocarboxylate intermediate into via a distal radical-based cyclization mechanism. These findings not only expand the functional and catalytic repertoires of NRPS Cy domains and P450 enzymes but also highlight a special enzymatic strategy for γ-thiolactone biosynthesis in nature. |
| format | Artículo científico |
| id | pubmed_40537968 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Journal of the American Chemical Society |
| record_format | pubmed |
| spellingShingle | Deciphering the Thiolactonization Mechanism in Thiolactomycin Biosynthesis. Guo, Jiawei Zhang, Qiaoyu Shen, Yang Cheng, Fangyuan Sang, Moli Wang, Xuan Pan, Yunjun Liu, Mingyu Yu, Hao-Bing Hu, Bo Wang, Sheng Zheng, Liangzhen Geng, Ce Yang, Chaofan Luo, Lianzhong Zhang, Gang Du, Lei Li, Yuanning Zhang, Wei Zhang, Yandong Wang, Binju Li, Shengying Zhang, Xingwang Peptide Synthases Cytochrome P-450 Enzyme System Cyclization Thiophenes Deciphering the Thiolactonization Mechanism in Thiolactomycin Biosynthesis. Guo, Jiawei Zhang, Qiaoyu Shen, Yang Cheng, Fangyuan Sang, Moli Wang, Xuan Pan, Yunjun Liu, Mingyu Yu, Hao-Bing Hu, Bo Wang, Sheng Zheng, Liangzhen Geng, Ce Yang, Chaofan Luo, Lianzhong Zhang, Gang Du, Lei Li, Yuanning Zhang, Wei Zhang, Yandong Wang, Binju Li, Shengying Zhang, Xingwang Peptide Synthases Cytochrome P-450 Enzyme System Cyclization Thiophenes Thiolactomycin (), which features a unique γ-thiolactone ring, is a promising antibiotic candidate that specifically targets bacterial type II fatty acid synthase. Despite extensive studies on its pharmacological activities, modes of action, and chemical synthesis, the enzymatic processes responsible for forming the activity-determining γ-thiolactone ring have remained largely unknown. Here, we resolve this problem by revealing that the condensation and heterocyclization (Cy) domain of the nonribosomal peptide synthetase (NRPS) TlnC (TlnC), along with the cytochrome P450 enzyme TlnA, cooperatively enable the γ-thiolactone assembly. TlnC mediates an unusual sulfurtransfer reaction to sulfurate the polyketide intermediate, generating a thiocarboxylate intermediate. Subsequently, TlnA acts as a γ-thiolactone synthase, converting the linear thiocarboxylate intermediate into via a distal radical-based cyclization mechanism. These findings not only expand the functional and catalytic repertoires of NRPS Cy domains and P450 enzymes but also highlight a special enzymatic strategy for γ-thiolactone biosynthesis in nature. |
| title | Deciphering the Thiolactonization Mechanism in Thiolactomycin Biosynthesis. |
| topic | Peptide Synthases Cytochrome P-450 Enzyme System Cyclization Thiophenes |
| url | https://pubmed.ncbi.nlm.nih.gov/40537968/ |