Fatty acid synthases (FASs) and polyketide synthases (PKSs) form carbon-carbon bonds via a decarboxylative Claisen-like condensation reaction, catalyzed by β-ketoacyl-ACP synthases (KSs), to produce a myriad of natural products from fatty acids to complex bioactive metabolites. Substrates are shuttled to KSs by a small 8 kDa acyl carrier protein (ACP) that carries thioester tethered pathway intermediates. KSs utilize a complex two-step ping-pong reaction mechanism and must discriminate between subtly different, yet chemically distinct, ACPs. Therefore, KSs must limit the number of non-productive protein-protein interactions (PPIs) to facilitate pathway flux and maintain product fidelity. In order to determine how KSs control these and other aspects of the condensation process, we elucidated the structures of ACP in complex with the KSs, FabF and FabB, from <i>Escherichia coli </i>fatty acid biosynthesis using site-specific crosslinking probes that mimic key catalytic intermediates. While this interdisciplinary study utilizes chemical biology, structural biology, and molecular dynamics simulations to interrogate these systems, this paper will focus on the structural and biochemical analysis of these complexes.

Gating mechanism of β-ketoacyl-ACP synthases

2019 Fall National Meeting

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