Identification and Analysis of the Paulomycin Biosynthetic Gene Cluster and Titer Improvement of the Paulomycins in <i>Streptomyces paulus</i> NRRL 8115

<div><p>The paulomycins are a group of glycosylated compounds featuring a unique paulic acid moiety. To locate their biosynthetic gene clusters, the genomes of two paulomycin producers, <i>Streptomyces paulus</i> NRRL 8115 and <i>Streptomyces sp</i>. YN86, were sequenced. The paulomycin biosynthetic gene clusters were defined by comparative analyses of the two genomes together with the genome of the third paulomycin producer <i>Streptomyces albus</i> J1074. Subsequently, the identity of the paulomycin biosynthetic gene cluster was confirmed by inactivation of two genes involved in biosynthesis of the paulomycose branched chain (<i>pau11</i>) and the ring A moiety (<i>pau18</i>) in <i>Streptomyces paulus</i> NRRL 8115. After determining the gene cluster boundaries, a convergent biosynthetic model was proposed for paulomycin based on the deduced functions of the <i>pau</i> genes. Finally, a paulomycin high-producing strain was constructed by expressing an activator-encoding gene (<i>pau13</i>) in <i>S</i>. <i>paulus</i>, setting the stage for future investigations.</p>