Roles of the active site water, histidine-303 and phenylalanine-396 in the catalytic mechanism of the elongation condensing enzyme of streptococcus pneumoniae

doi:10.1074/jbc.M513199200

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Papers In Press, published online ahead of print April 16, 2006
J. Biol. Chem, 10.1074/jbc.M513199200
Submitted on December 12, 2005
Revised on April 13, 2006
Accepted on April 16, 2006

Roles of the active site water, histidine-303 and phenylalanine-396 in the catalytic mechanism of the elongation condensing enzyme of streptococcus pneumoniae

Yong-Mei Zhang, Jason Hurlbert, Stephen W. White, and Charles O. Rock

Infectious Diseases, St. Jude Childrens Research Hospital, Memphis, TN 38105-2794

Corresponding Author: charles.rock{at}stjude.org

$beta$ -Ketoacyl-ACP synthases catalyze the condensation steps in fatty acid and polyketide synthesis and are targets for the development of novel antibiotics, anti-obesity and anticancer agents. The roles of the active site residues in Streptococcus pneumoniae FabF (SpFabF) were investigated to clarify the mechanism for this enzyme superfamily. The nucleophilic cysteine of the active site triad was required for acyl-enzyme formation and the overall condensation activity. The two active site histidines in the elongation condensing enzyme have different electronic states and functions. His337 is essential for condensation activity and its protonated N stabilizes the negative charge developed on the malonyl thioester carbonyl in the transition state. The N of His303 accelerated catalysis by deprotonating a structured active site water for nucleophilic attack on the C3 of malonate releasing bicarbonate. Lys332 controls the electronic state of His303 and also plays a critical role in the positioning of His337. Phe396 functions as a gatekeeper that controls the order of substrate addition. These data assign specific roles for each active site residue and lead to a revised general mechanism for this important class of enzymes.

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