细菌源吡咯里西啶类生物碱的发现及生物合成研究进展

Discovery and biosynthesis of bacterial pyrrolizidine alkaloids

摘要:

吡咯里西啶类生物碱（Pyrrolizidine Alkaloids，PAs）在高等植物中分布广泛，目前超过6 000种植物产生了650余个PAs。源于细菌的PAs发现较少，其中clazamycin A和clazamycin B由Umezawa等在1979年报道。近年来在微生物基因组和合成生物学发展的驱动下，细菌源PAs的发现和生物合成的研究方兴未艾。截至目前，已发现12类（60余个）源于细菌的PAs，包括波米西亚胺、Azetidomonamides和Brabantamides，以及含有PAs结构单元的多烯大环内酰胺ciromicins和Heronamides。对这些结构多样、活性优异的细菌源PAs的研究发现，多数PAs依赖于一对独特的非核糖体多肽合成酶（Non-Ribosomal Peptide Synthetases，NRPSs）/拜耳-维利格单加氧酶（Bayer-Villiger Monooxygenase）生物合成其吡咯双烷基本骨架；而含有β-氨基酸的多烯大环内酰胺中吡咯双烷的形成则可能通过一个高度非对映选择性的电子重排反应途径。微生物基因组挖掘揭示了细菌中有大量沉默的PAs生物合成基因簇，说明细菌PAs在细菌进化和其环境/宿主的适应性中起着重要作用。

Abstract:

Pyrrolizidine alkaloids (PAs) are widely distributed among higher plants, with over 650 PAs produced by more than 6 000 plants. Only a limited number of PAs of bacterial origins are discovered. For example, clazamycin A and B, reported by Umezawa in 1979 were among the firstly discovered bacterial PAs. In recent years, driven by microbial genomics and synthetic biology, the discovery and study of bacterial PAs and their biosynthetic mechanisms have made impressive progresses. To date, 12 types of PAs (~60) derived from bacteria have been identified, including bohemamines, azetidomonamides, and brabantamides, as well as polyene macrolactam ciromicins and heronamides containing PA structural units. The biosynthetic study of several PAs results in the identification of a unique pair of non-ribosomal peptide synthetase/Bayer-Villiger monooxygenase responsible for the formation of the pyrrolizidine skeleton. In contrast, the formation of the pyrrolizidine unit in β-amino acids polyene macrolactams might involve a highly diastereoselective electrocyclization process. Further, microbial genome mining reveals a lot of silent PAs biosynthetic gene clusters in bacteria, indicating that PAs play an important role in bacterial evolution and adaptation of their environment/hosts.