The natural product co-evolved pyrroloquinoline quinone gene enhances their production when heterologously expressed in a variety of Streptomycetes

<title>Abstract</title> <italic>Streptomyces</italic> has the largest repertoire of natural product biosynthetic gene clusters (BGCs), yet developing a universal engineering paradigm for different <italic>Streptomyces</italic> strains is challenging. That some bacteria and fungi are more adept than others at synthesizing natural products implies the existence of key genes co-evolved with the BGCs for high productivity, which may provide a potential universal strategy for <italic>Streptomyces</italic> to produce more target products. We show here that genes co-evolved with natural product BGCs in <italic>Streptomyces</italic> can be identified by pan-genomic analysis. Among the 598 genes that co-evolved with polyketide BGCs was the gene cluster encoding for the co-factor pyrroloquinoline quinone (PQQ). When the PQQ gene cluster was engineered into 11 <italic>Streptomyces</italic> strains it enhanced production of naturally-produced polyketides with up to 40 fold and activated silent gene clusters. This study provides a new engineering paradigm for improving polyketide production and discovering new biosynthetic gene clusters and potential therapies.