Abstract
Phosphopantetheinyltransferase (PPTase) enzymes fulfil essential roles in primary and secondary metabolism in prokaryotes, archaea and eukaryotes. PPTase enzymes catalyse the essential modification of the carrier protein domain of fatty acid synthases, polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs). In bacteria and fungi, NRPS and PKS enzymes are often responsible for the biosynthesis of secondary metabolites with clinically relevant properties; these secondary metabolites include a variety of antimicrobial peptides. We have previously shown that in the Gram-negative bacterium Serratia marcescens Db10, the PPTase enzyme PswP is essential for the biosynthesis of an NRPS-PKS dependent antibiotic called althiomycin. In this work we utilize bioinformatic analyses to classify PswP as belonging to the F/KES subfamily of Sfp type PPTases and to putatively identify additional NRPS substrates of PswP, in addition to the althiomycin NRPS-PKS, in Ser. marcescens Db10. We show that PswP is required for the production of three diffusible metabolites by this organism, each possessing antimicrobial activity against Staphylococcus aureus. Genetic analyses identify the three metabolites as althiomycin, serrawettin W2 and an as-yet-uncharacterized siderophore, which may be related to enterobactin. Our results highlight the use of an individual PPTase enzyme in multiple biosynthetic pathways, each contributing to the ability of Ser. marcescens to inhibit competitor bacteria by the production of antimicrobial secondary metabolites.
Highlights
Phosphopantetheinyltransferase (PPTase) enzymes have essential roles in the biosynthetic pathways of primary and secondary metabolism in prokaryotes, archaea and eukaryotes (Beld et al, 2014; Lambalot et al, 1996)
Aiming to investigate this further, we discovered that deletion of the gene encoding the PPTase protein PswP was sufficient to negate the antimicrobial activity of Ser. marcescens Db10 against Sta. aureus (Fig. 1a)
In addition to being required for althiomycin biosynthesis, PswP was required for the biosynthesis of one or more fatty acid synthase (FAS), polyketide synthase (PKS) or non-ribosomal peptide synthetase (NRPS) product(s) with antimicrobial activity against Sta. aureus
Summary
Phosphopantetheinyltransferase (PPTase) enzymes have essential roles in the biosynthetic pathways of primary and secondary metabolism in prokaryotes, archaea and eukaryotes (Beld et al, 2014; Lambalot et al, 1996). Fatty acid synthases (FASs), polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are all dependent upon the catalytic action of PPTase enzymes to function (Beld et al, 2014). PPTase enzymes catalyse the transfer of a 49-phosphopantetheine (PPT) prosthetic group from coenzyme A to a conserved serine residue in the carrier protein domain of FASs, PKSs and NRPSs
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