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| Main Authors: | , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Journal of the American Chemical Society
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/39818795/ |
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Table of Contents:
- Selective Synthesis of Cyclopeptides with a 2-Oxindole or 3a-Hydroxy-hexahydropyrrolo-[2,3-]indole Structure by Cytochrome P450 Enzymes. Li, Chao Ma, Junying Guo, Lu Xu, Chao Zhong, Zijian Li, Pengwei Tang, Yue Wang, Wenzhao Li, Defeng Ye, Tao Guo, Zhengyan Chen, Yihua Cytochrome P-450 Enzyme System Indoles Peptides, Cyclic Oxindoles Molecular Structure The structural groups of 2-oxindole and tricyclic 3a-hydroxy-hexahydropyrrolo-[2,3-]indole (HO-HPI) are important pharmacophores. Chemical synthesis of complex alkaloids containing a 2-oxindole or HO-HPI moiety, especially the latter one, has been a long-standing challenge. Herein, we characterized the P450 enzyme AfnD, and its homologue proteins, HmtT, ClpD, KtzM, and LtzR, as cyclopeptide 2-oxindole and HO-HPI monooxygenases (cpOPMOs) that could introduce a 2-oxindole or HO-HPI moiety into the tryptophan-containing cyclopeptides in a pH-dependent manner. A universal catalytic mechanism was proposed for the five cpOPMOs, in which two conserved residues, Asp and Ser (Thr for LtzR), were proposed to divergently open the epoxide intermediates, thereby forming a 2-oxindole or HO-HPI moiety. Based on this, we constructed ten Asp or Ser/Thr mutants of cpOPMOs, which could synthesize cyclopeptides with an HO-HPI or 2-oxindole structure, selectively, under appropriate reaction conditions. All of the ten cpOPMO mutants exhibited high substrate promiscuities and usually performed well with cyclopeptides that are structurally similar to their native substrates. Overall, our work discovers a group of intriguing P450 enzymes, the cpOPMOs, and provides a powerful enzymatic toolkit for the selective synthesis of HO-HPI- or 2-oxindole-containing cyclopeptides.