Substrate Profile Analysis and ACP‐Mediated Acyl Transfer in Streptomyces coelicolor Type III Polyketide Synthases

Abstract

Polyketides represent a diverse family of natural products synthesized by bacteria, fungi, plants, and animals, and have found extensive use as pharmaceuticals (e.g. , antimicrobials, antivirals, and antineoplastics) and other commercially important products (e.g. , food ingredients, nutraceuticals, and pigments). Although naturally occurring polyketides have diverse structures, the majority are produced by three broad classes of polyketide synthases (PKSs) that share a common mechanism involving sequential decarboxylative condensation reactions to form C C bonds between simple carboxylic acid extender units and the nascent acyl chain. Whereas the vast majority of studies have focused on the modular and iterative type I and iterative type II PKSs, recent work has led to a new appreciation for the homodimeric type III PKSs that give rise to a range of aromatic compounds, including flavonoids and chalcones as well as some a-pyrone acylketides. Here we report the potential for removing type III PKSs from their natural biosynthetic context and adapting them to accept unnatural substrates in order to access a more structurally diverse chemical space. In addition, we show the remarkable ability of one Streptomyces coelicolor type III PKS to accept efficiently an acyl-ACP as its starter unit. Pyrone-containing natural products exhibit a wide range of biological activities; this is a consequence of their structural diversity (Scheme 1). Pyrones are synthesized by PKSs through successive condensations of malonyl-CoA derived C2 units followed by lactonization. The fungal metabolites fusapyrone and D8646-2-6 are most likely derived from iterative type I PKSs, and enterocin is produced by a type II PKS. On the other hand, germicidins A, B, and C, as well as the signaling