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Aryl C-H iodination: are there actual flavin-dependent iodinases in nature?

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Abstract

Flavin-dependent halogenases (FDHs) are well known to introduce carbon halide bonds (mainly C-Cl and C-Br) into natural products with the assistance of a partner protein flavin reductase to generate reduced flavin (FADH2 or FMNH2). Compared with the common chloride- and bromide-containing natural products (approximately 5,000 compounds), iodinated natural products (approximately 100 compounds) are very limited. Specific iodinases have also rarely been identified in nature to date. This study discovered a novel relationship between iodination and flavin reductases for the first time. Through mechanistic studies, it was identified that peroxide (H2O2) was released from the uncoupling reaction of flavin reductases and then reacted with iodide ions (I−) to produce hypoiodous acid (IOH) for the final iodination. Furthermore, this study also unintentionally verified that the recently reported flavin-dependent iodinase VirX1 from the marine virus and its two homologs (MBG and NCV) did not catalyze iodination in the in vitro biochemical system but likely belonged to a new phylogenetic clade in the tryptophan halogenase superfamily. As a consequence, actual flavin-dependent iodinases in nature remain to be discovered by the scientific community in the future.

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Acknowledgements

The authors thank Mrs. B. Dai and J. Wu at the Instrumental Analysis Center of Shanghai Jiao Tong University for making NMR experiments. This work was supported by the National Natural Science Foundation of China (21632007, 21661140002 for S. Lin; 81903525 for Y. Zhang), Research Fund for High-level Talents of Xinxiang Medical University (300-505272), and Open Funding Project of State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University (MMLKF20-11).

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Authors and Affiliations

  1. Synthetic Biology Engineering Lab of Henan Province, School of Life Science and Biotechnology, Xinxiang Medical University, Xinxiang, 453003, China

    Yuyang Zhang, Hongping Chen & Yan Wang

  2. State Key Laboratory of Microbial Metabolism, Joint International Laboratory on Metabolic & Developmental Sciences, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China

    Lin Chen, Tingting Huang, Qing Shi, Xiaozheng Wang, Man-Cheng Tang, Ning-Yi Zhou & Shuangjun Lin

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  1. Yuyang Zhang
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  2. Lin Chen
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  3. Hongping Chen
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  5. Qing Shi
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  6. Xiaozheng Wang
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  7. Yan Wang
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  10. Shuangjun Lin
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Correspondence to Yuyang Zhang or Shuangjun Lin.

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Zhang, Y., Chen, L., Chen, H. et al. Aryl C-H iodination: are there actual flavin-dependent iodinases in nature?. Sci. China Chem. 64, 1730–1735 (2021). https://doi.org/10.1007/s11426-021-1018-0

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  • DOI: https://doi.org/10.1007/s11426-021-1018-0

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