Generate a bioactive natural product library by mining bacterial cytochrome P450 patterns

Abstract

The increased number of annotated bacterial genomes provides a vast resource for genome mining. Several bacterial natural products with epoxide groups have been identified as pre-mRNA spliceosome inhibitors and antitumor compounds through genome mining. These epoxide-containing natural products feature a common biosynthetic characteristic that cytochrome P450s (CYPs) and its patterns such as epoxidases are employed in the tailoring reactions. The tailoring enzyme patterns are essential to both biological activities and structural diversity of natural products, and can be used for enzyme pattern-based genome mining. Recent development of direct cloning, heterologous expression, manipulation of the biosynthetic pathways and the CRISPR-CAS9 system have provided molecular biology tools to turn on or pull out nascent biosynthetic gene clusters to generate a microbial natural product library. This review focuses on a library of epoxide-containing natural products and their associated CYPs, with the intention to provide strategies on diversifying the structures of CYP-catalyzed bioactive natural products. It is conceivable that a library of diversified bioactive natural products will be created by pattern-based genome mining, direct cloning and heterologous expression as well as the genomic manipulation.