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<p>Dimeric cyclotryptamine alkaloids are structurally intricate natural products characterized by two cyclotryptamine units linked through sterically hindered vicinal all-carbon quaternary stereocentres. Their complex architecture has long challenged asymmetric synthesis and has inspired decades of chemical innovation, yet the enzymatic basis of their enantioselective assembly in plants has remained unknown. Here we report the biosynthetic pathway of four dimeric cyclotryptamine alkaloids—(−)-chimonanthine, <i>meso</i>-chimonanthine, (−)-folicanthine and (+)-sinodamine B—in Calycanthaceae plants, revealing that two cytochrome P450 enzymes (P450s) catalyse enantioselective oxidative dimerization of tryptamine into (−)-chimonanthine and <i>meso</i>-chimonanthine skeletons, respectively. Furthermore, four <i>N</i>-methyltransferases (NMTs) were identified to mediate regio- and enantioselective methylation, generating all four alkaloids. Structural and mutagenesis analysis reveals the molecular basis of P450 and NMT selectivity. By reconstructing the entire pathway in yeast, de novo production of these alkaloids can be achieved. These findings provide insight into the enzymatic machinery of cyclotryptamine alkaloid biosynthesis and a platform for future bioengineering and synthetic applications.</p><p></p>

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Enzymatic control of enantioselective dimeric cyclotryptamine alkaloid biosynthesis in Calycanthaceae plants

  • 期刊论文

  • 发表日期：

    2026年4月23日

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  • Anan Zhang,
  • Yunfeng Luo,
  • Qi Ding,
  • Benke Hong

摘要

Dimeric cyclotryptamine alkaloids are structurally intricate natural products characterized by two cyclotryptamine units linked through sterically hindered vicinal all-carbon quaternary stereocentres. Their complex architecture has long challenged asymmetric synthesis and has inspired decades of chemical innovation, yet the enzymatic basis of their enantioselective assembly in plants has remained unknown. Here we report the biosynthetic pathway of four dimeric cyclotryptamine alkaloids—(−)-chimonanthine, meso-chimonanthine, (−)-folicanthine and (+)-sinodamine B—in Calycanthaceae plants, revealing that two cytochrome P450 enzymes (P450s) catalyse enantioselective oxidative dimerization of tryptamine into (−)-chimonanthine and meso-chimonanthine skeletons, respectively. Furthermore, four N-methyltransferases (NMTs) were identified to mediate regio- and enantioselective methylation, generating all four alkaloids. Structural and mutagenesis analysis reveals the molecular basis of P450 and NMT selectivity. By reconstructing the entire pathway in yeast, de novo production of these alkaloids can be achieved. These findings provide insight into the enzymatic machinery of cyclotryptamine alkaloid biosynthesis and a platform for future bioengineering and synthetic applications.