Production of branched-chain alkylprodiginines in S. coelicolor by replacement of the 3-ketoacyl ACP synthase III initiation enzyme, RedP.

The enzyme RedP is thought to initiate the biosynthesis of the undecylpyrolle component of the antibiotic undecylprodiginine produced by Streptomyces coelicolor. RedP has homology to FabH, which initiates fatty acid biosynthesis by condensing the appropriate acyl-CoA starter unit with malonyl ACP. We have generated a redP-deletion mutant of S. coelicolor M511 (SJM1) and shown that it produces reduced levels of prodiginines and two new analogs, methylundecylprodiginine and methyldodecylprodiginine. Incorporation studies with perdeuterated valine were consistent with these being generated using methylbutyryl-CoA and isobutyryl-CoA as starter units, respectively. Plasmid-based expression of a streptomycete fabH in the SJM1 mutant led to restoration of overall prodiginine titers but the same overall ratio of undecylprodiginines and novel prodiginines. Thus, the redP FabH can be replaced by FabH enzymes with different substrate specificities and provides a method for generating novel prodiginines.