School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
Marine Laboratory, University of Guam, UOG Station, Mangilao 96923, Guam.
ACS Chem Biol. 2020 Aug 21;15(8):2185-2194. doi: 10.1021/acschembio.0c00375. Epub 2020 Jul 29.
Pyrrole-imidazole alkaloids are natural products isolated from marine sponges, holobiont metazoans that are associated with symbiotic microbiomes. Pyrrole-imidazole alkaloids have attracted attention due to their chemical complexity and their favorable pharmacological properties. However, insights into how these molecules are biosynthesized within the sponge holobionts are scarce. Here, we provide a multiomic profiling of the microbiome and metabolomic architectures of three sponge genera that are prolific producers of pyrrole-imidazole alkaloids. Using a retrobiosynthetic scheme as a guide, we mine the metabolomes of these sponges to detect intermediates in pyrrole-imidazole alkaloid biosynthesis. Our findings reveal that the nonproteinogenic amino acid homoarginine is a critical branch point that connects primary metabolite lysine to the production of pyrrole-imidazole alkaloids. These insights are derived from the polar metabolomes of these sponges which additionally reveal the presence of zwitterionic betaines that may serve important ecological roles in marine habitats. We also establish that metabolomic richness does not correlate with microbial diversity of the sponge holobiont for neither the polar nor the nonpolar metabolomes. Our findings now provide the biochemical foundation for genomic interrogation of the sponge holobiont to establish biogenetic routes for pyrrole-imidazole alkaloid production.
吡咯并咪唑生物碱是从海洋海绵中分离出来的天然产物，是与共生微生物组相关的后生动物整体生物。吡咯并咪唑生物碱因其化学复杂性和良好的药理特性而受到关注。然而，对于这些分子在海绵整体生物中是如何生物合成的，我们的了解还很有限。在这里，我们对三种盛产吡咯并咪唑生物碱的海绵属的微生物组和代谢组学结构进行了多组学分析。我们使用回溯生物合成方案作为指导，对这些海绵的代谢组进行挖掘，以检测吡咯并咪唑生物碱生物合成中的中间产物。我们的研究结果表明，非蛋白氨基酸同型精氨酸是一个关键的分支点，它将初级代谢物赖氨酸连接到吡咯并咪唑生物碱的生产上。这些发现源于这些海绵的极性代谢组，其中还存在两性离子甜菜碱，它们可能在海洋生境中发挥着重要的生态作用。我们还发现，极性和非极性代谢组的代谢组丰富度都与海绵整体生物的微生物多样性无关。我们的研究结果为海绵整体生物的基因组研究提供了生化基础，以建立吡咯并咪唑生物碱生产的生物发生途径。
