Covering: 2003 to July 2015 for polyketide synthase starter units and 2012 to September 2015 for polyketide synthase extender units
This highlight provides an overview of recent advances in understanding the diversity of polyketide synthase (PKS) substrate building blocks. Substrates functioning as starter units and extender units contribute significantly to the chemical complexity and structural diversity exhibited by this class of natural products. This article complements and extends upon the current comprehensive reviews that have been published on these two topics (Moore and Hertweck, Nat. Prod. Rep., 2002, 19, 70; Chan et. al., Nat. Prod. Rep., 2009, 1, 90; Wilson and Moore, Nat. Prod. Rep., 2012, 29, 72).
A chemoenzymatic approach to generate fully functional acyl coenzyme A molecules that are then used as substrates to drive in situ acyl transfer reactions is described. Mass spectrometry-based assays to verify the identity of acyl coenzyme A enzymatic products are also illustrated. The approach is responsive to a diverse array of carboxylic acids that can be elaborated to their corresponding coenzyme A thioesters, with potential applications in wide-ranging chemical biology studies that utilize acyl coenzyme A substrates.
Salinamide A belongs to a rare class of bicyclic depsipeptide antibiotics in which the installation of a (4-methylhexa-2,4-dienoyl)glycine handle across a hexadepsipeptide core contributes to its chemical complexity and biological properties. Here we report the genetic and biochemical basis for salinamide construction in the marine bacterium Streptomyces sp. CNB-091 that involves a novel intermolecular transesterification reaction catalyzed by a type I thioesterase. Heterologous biosynthesis studies revealed the central role of the nonribosomal peptide synthetase Sln9 in constructing and installing salinamides distinctive acylglycine “basket” handle. Biochemical characterization of the Sln9 thioesterase domain established the transesterification of desmethylsalinamide E’s serine residue with acylated glycyl thioesters to yield desmethylsalinamide C.
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