Discovery of epoxyketone proteasome inhibitors using metagenome mining

This poster describes how short natural product sequence tags derived from conserved biosynthetic motifs can be used profile biosynthetic diversity in the environment and then guide the recovery of gene-clusters from metagenomic libraries. The results of a computational search for epoxyketone proteasome inhibitors within 185 globally distributed soil metagenomes are presented. This screen led to the identification of 99 unique epoxyketone sequence tags that were used to guide the recovery of nine epoxyketone encoding biosynthetic gene-clusters. Seven potent epoxyketone proteasome inhibitors, clarepoxcins A-E (1-5) and landepoxcins A and B (6 and 7), were produced by heterologous expression of two of these pathways.