State Key Laboratory of Phytochemistry and Plant Resources in West China, and CAS Center for Excellence in Molecular Plant Sciences, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an, 710119, China.
Nat Commun. 2022 Aug 25;13(1):4994. doi: 10.1038/s41467-022-32776-1.
Tropane alkaloids such as hyoscyamine and cocaine are of importance in medicinal uses. Only recently has the hyoscyamine biosynthetic machinery become complete. However, the cocaine biosynthesis pathway remains only partially elucidated. Here we characterize polyketide synthases required for generating 3-oxo-glutaric acid from malonyl-CoA in cocaine biosynthetic route. Structural analysis shows that these two polyketide synthases adopt distinctly different active site architecture to catalyze the same reaction as pyrrolidine ketide synthase in hyoscyamine biosynthesis, revealing an unusual parallel/convergent evolution of biochemical function in homologous enzymes. Further phylogenetic analysis suggests lineage-specific acquisition of polyketide synthases required for tropane alkaloid biosynthesis in Erythroxylaceae and Solanaceae species, respectively. Overall, our work elucidates not only a key unknown step in cocaine biosynthesis pathway but also, more importantly, structural and biochemical basis for independent recruitment of polyketide synthases in tropane alkaloid biosynthesis, thus broadening the understanding of conservation and innovation of biosynthetic catalysts.
托烷生物碱如莨菪碱和可卡因在医学用途中很重要。莨菪碱的生物合成机制最近才变得完整。然而，可卡因的生物合成途径仍然只是部分阐明。在这里，我们描述了在可卡因生物合成途径中从丙二酰辅酶 A 生成 3-氧代戊二酸所需的聚酮合酶。结构分析表明，这两种聚酮合酶采用截然不同的活性位点结构来催化与莨菪碱生物合成中的吡咯烷酮酮合酶相同的反应，揭示了同源酶中生化功能的不寻常平行/趋同进化。进一步的系统发育分析表明，在藜科和茄科物种中，分别获得了托烷生物碱生物合成所需的聚酮合酶的谱系特异性。总的来说，我们的工作不仅阐明了可卡因生物合成途径中的一个关键未知步骤，而且更重要的是，阐明了聚酮合酶在托烷生物碱生物合成中的独立招募的结构和生化基础，从而拓宽了对生物合成催化剂的保守性和创新性的理解。
