SUMMARY
Trans-acyltransferase polyketide synthases (trans-AT PKSs) are an important group of bacterial enzymes producing bioactive polyketides. One difference from textbook PKSs is the presence of one or more free-standing AT-like enzymes. While one homolog loads the PKS with malonyl units, the function of the second copy (AT2) was unknown. We studied the two ATs PedC and PedD involved in pederin biosynthesis in an uncultivated symbiont. PedD displayed malonyl- but not acetyltransferase activity toward various acyl carrier proteins (ACPs). In contrast, the AT2 PedC efficiently hydrolyzed acyl units bound to N-acetylcysteamine or ACP. It accepted substrates with various chain lengths and functionalizations but did not cleave malonyl-ACP. These data are consistent with the role of PedC in PKS proofreading, suggesting a similar function for other AT2 homologs and providing strategies for polyketide titer improvement and biosynthetic investigations.
Targeted gene inactivation and metabolic profiling revealed that the cryptic PKS-NRPS gene cluster in the genome of the plant commensal Pseudomonas fluorescens Pf-5 codes for the biosynthesis of antiproliferative and antifungal rhizoxin derivatives.
Chain armor against tumor cells: The oxazole side chain in the antimitotic agent rhizoxin S2 (1) was successfully replaced through mutasynthesis by using an engineered mutant impaired in heterocyclization. Incorporation of 12 non-natural surrogates into fully processed rhizoxin analogues revealed a remarkable substrate flexibility of the PKS-NRPS hybrid.
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