An enzymatic [4+2] cyclization cascade creates the pentacyclic core of pyrroindomycins

Zhenhua Tian, Peng Sun, Yan Yan, Zhuhua Wu, Qingfei Zheng, Shuaixiang Zhou, Hua Zhang, Futao Yu, Xinying Jia, Dandan Chen, Attila Mándi, Tibor Kurtán, Wen Liu

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

The [4+2] cycloaddition remains one of the most intriguing transformations in synthetic and natural products chemistry. In nature, however, there are remarkably few enzymes known to have this activity. We herein report an unprecedented enzymatic [4+2] cyclization cascade that has a central role in the biosynthesis of pyrroindomycins, which are pentacyclic spirotetramate natural products. Beginning with a linear intermediate that contains two pairs of 1,3-diene and alkene groups, the dedicated cyclases PyrE3 and PyrI4 act in tandem to catalyze the formation of two cyclohexene rings in the dialkyldecalin system and the tetramate spiro-conjugate of the molecules. The two cyclizations are completely enzyme dependent and proceed in a regio- and stereoselective manner to establish the enantiomerically pure pentacyclic core. Analysis of a related spirotetronate pathway confirms that homologs are functionally exchangeable, establishing the generality of these findings and explaining how nature creates diverse active molecules with similar rigid scaffolds.

Original languageEnglish
Pages (from-to)259-265
Number of pages7
JournalNature Chemical Biology
Volume11
Issue number4
DOIs
Publication statusPublished - Apr 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Tian, Z., Sun, P., Yan, Y., Wu, Z., Zheng, Q., Zhou, S., Zhang, H., Yu, F., Jia, X., Chen, D., Mándi, A., Kurtán, T., & Liu, W. (2015). An enzymatic [4+2] cyclization cascade creates the pentacyclic core of pyrroindomycins. Nature Chemical Biology, 11(4), 259-265. https://doi.org/10.1038/nchembio.1769