Gating mechanism of elongating β-ketoacyl-ACP synthases

Jeffrey T. Mindrebo, Ashay Patel, Woojoo E. Kim, Tony D. Davis, Aochiu Chen, Thomas G. Bartholow, James J. Clair, J. Andrew McCammon, Joseph P. Noel () and Michael D. Burkart ()
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Jeffrey T. Mindrebo: University of California
Ashay Patel: University of California
Woojoo E. Kim: University of California
Tony D. Davis: University of California
Aochiu Chen: University of California
Thomas G. Bartholow: University of California
James J. Clair: University of California
J. Andrew McCammon: University of California
Joseph P. Noel: University of California
Michael D. Burkart: University of California

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Carbon-carbon bond forming reactions are essential transformations in natural product biosynthesis. During de novo fatty acid and polyketide biosynthesis, β-ketoacyl-acyl carrier protein (ACP) synthases (KS), catalyze this process via a decarboxylative Claisen-like condensation reaction. KSs must recognize multiple chemically distinct ACPs and choreograph a ping-pong mechanism, often in an iterative fashion. Here, we report crystal structures of substrate mimetic bearing ACPs in complex with the elongating KSs from Escherichia coli, FabF and FabB, in order to better understand the stereochemical features governing substrate discrimination by KSs. Complemented by molecular dynamics (MD) simulations and mutagenesis studies, these structures reveal conformational states accessed during KS catalysis. These data taken together support a gating mechanism that regulates acyl-ACP binding and substrate delivery to the KS active site. Two active site loops undergo large conformational excursions during this dynamic gating mechanism and are likely evolutionarily conserved features in elongating KSs.

Date: 2020
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DOI: 10.1038/s41467-020-15455-x

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