Hapalindole alkaloids are a structurally diverse class of cyanobacterial natural products defined by their varied polycyclic ring systems and diverse biological activities. These complex metabolites are generated from a common biosynthetic intermediate by the Stig cyclases in three mechanistic steps: a rare Cope rearrangement, 6-exo-trig cyclization, and electrophilic aromatic substitution. Here we report the structure of HpiC1, a Stig cyclase that catalyzes the formation of 12-epi-hapalindole U in vitro. The 1.5-Å structure revealed a dimeric assembly with two calcium ions per monomer and with the active sites located at the distal ends of the protein dimer. Mutational analysis and computational methods uncovered key residues for an acid-catalyzed [3,3]-sigmatropic rearrangement, as well as specific determinants that control the position of terminal electrophilic aromatic substitution, leading to a switch from hapalindole to fischerindole alkaloids.

中文翻译：

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hapalindole 生物发生中 Cope 重排和环化的结构基础。


哈帕吲哚生物碱是一类结构多样的蓝藻天然产物，由其不同的多环系统和不同的生物活性定义。这些复杂的代谢物是由 Stig 环化酶通过三个机械步骤从常见的生物合成中间体产生的：罕见的 Cope 重排、6-exo-trig 环化和亲电芳香取代。在这里，我们报道了 HpiC1 的结构，HpiC1 是一种 Stig 环化酶，可在体外催化 12-epi-hapalindole U 的形成。 1.5-Å 结构揭示了每个单体有两个钙离子的二聚体组装，活性位点位于蛋白质二聚体的远端。突变分析和计算方法揭示了酸催化的[3,3]-σ重排的关键残基，以及控制末端亲电芳香取代位置的特定决定因素，导致从hapalindole转变为fischerindole生物碱。