Deciphering the Thiolactonization Mechanism in Thiolactomycin Biosynthesis

  • J Am Chem Soc. 2025 Jul 2;147(26):22368-22386. doi: 10.1021/jacs.4c14296.
Jiawei Guo  1  2 ,  Qiaoyu Zhang  3 ,  Yang Shen  4 ,  Fangyuan Cheng  1  5 ,  Moli Sang  1 ,  Xuan Wang  1 ,  Yunjun Pan  1 ,  Mingyu Liu  1 ,  Hao-Bing Yu  6 ,  Bo Hu  6 ,  Sheng Wang  7 ,  Liangzhen Zheng  7 ,  Ce Geng  8 ,  Chaofan Yang  1 ,  Lianzhong Luo  9 ,  Gang Zhang  9 ,  Lei Du  1 ,  Yuanning Li  1 ,  Wei Zhang  1 ,  Yandong Zhang  4 ,  Binju Wang  3 ,  Shengying Li  1  5 ,  Xingwang Zhang  1  2
Affiliations
  • 1. State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China.
  • 2. Shandong Research Institute of Industrial Technology, Jinan, Shandong 250101, China.
  • 3. State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China.
  • 4. State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, iCHEM, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China.
  • 5. Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, Shandong 266237, China.
  • 6. Department of Marine Biomedicine and Polar Medicine, Naval Medical Center, Naval Medical University, Shanghai 200433, China.
  • 7. Shanghai Zelixir Biotech Company Ltd., Shanghai 200030, China.
  • 8. Shandong Provincial Key Laboratory of Synthetic Biology, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao, Shandong 266101, China.
  • 9. Xiamen Key Laboratory of Marine Natural Product Resources, Xiamen Medical College, Xiamen, Fujian 361023, China.
PMID: 40537968 DOI: 10.1021/jacs.4c14296
Abstract

Thiolactomycin (1), 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 (TlnCCy), along with the Cytochrome P450 enzyme TlnA, cooperatively enable the γ-thiolactone assembly. TlnCCy 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 1 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.

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