Insights into Secondary Metabolism from a Global Analysis of Prokaryotic Biosynthetic Gene Clusters

•The ClusterFinder algorithm detects BGCs of both known and unknown classes•There exist large and widely distributed BGC families with no characterized members•We show that the most prominent family encodes the biosynthesis of aryl polyenes•The aryl polyene clusters constitute the largest known family of BGCs

SummaryAlthough biosynthetic gene clusters (BGCs) have been discovered for hundreds of bacterial metabolites, our knowledge of their diversity remains limited. Here, we used a novel algorithm to systematically identify BGCs in the extensive extant microbial sequencing data. Network analysis of the predicted BGCs revealed large gene cluster families, the vast majority uncharacterized. We experimentally characterized the most prominent family, consisting of two subfamilies of hundreds of BGCs distributed throughout the Proteobacteria; their products are aryl polyenes, lipids with an aryl head group conjugated to a polyene tail. We identified a distant relationship to a third subfamily of aryl polyene BGCs, and together the three subfamilies represent the largest known family of biosynthetic gene clusters, with more than 1,000 members. Although these clusters are widely divergent in sequence, their small molecule products are remarkably conserved, indicating for the first time the important roles these compounds play in Gram-negative cell biology.

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