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

The Journal of Biological Chemistry
Yong-Mei ZhangCharles O Rock

Abstract

beta-Ketoacyl-ACP synthases catalyze the condensation steps in fatty acid and polyketide synthesis and are targets for the development of novel antibiotics and anti-obesity and anti-cancer agents. The roles of the active site residues in Streptococcus pneumoniae FabF (beta-ketoacyl-ACP synthase II; 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 Nepsilon stabilizes the negative charge developed on the malonyl thioester carbonyl in the transition state. The Nepsilon 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 mecha...Continue Reading

References

Mar 1, 1991·Acta Crystallographica. Section A, Foundations of Crystallography·T A JonesM Kjeldgaard
May 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·C M AmyS Smith
Jun 13, 1966·Biochemical and Biophysical Research Communications·D J Brock, K Bloch
Apr 1, 1969·European Journal of Biochemistry·M YalpaniF Lynen
Jan 1, 1981·Methods in Enzymology·C O RockJ E Cronan
Jan 26, 1996·The Journal of Biological Chemistry·R J Heath, C O Rock
Jul 12, 1996·Biochimica Et Biophysica Acta·C O Rock, J E Cronan
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Mar 13, 2001·Journal of Molecular Biology·X QiuA K Konstantinidis
Mar 30, 2001·The Journal of Biological Chemistry·J N ScarsdaleH T Wright
Sep 7, 2001·Annual Review of Microbiology·J W Campbell, J E Cronan
Oct 10, 2001·Progress in Lipid Research·R J HeathC O Rock
Apr 24, 2002·Biochemical and Biophysical Research Communications·Charles O Rock, Suzanne Jackowski
Nov 15, 2002·Natural Product Reports·Richard J Heath, Charles O Rock
Apr 12, 2003·Progress in Lipid Research·Stuart SmithAnil K Joshi
May 2, 2003·Proceedings of the National Academy of Sciences of the United States of America·Su Gao, M Daniel Lane
Apr 6, 2004·Biochemical and Biophysical Research Communications·Seung Hun ChaM Daniel Lane
Jul 6, 2004·Proceedings of the National Academy of Sciences of the United States of America·Javier A MenendezRuth Lupu
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Apr 16, 2005·Science·Chaitan Khosla, Yi Tang

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Citations

Sep 28, 2007·Natural Product Reports·Stuart Smith, Shiou-Chuan Tsai
Aug 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Patrik JohanssonMartin Grininger
Dec 19, 2009·The Journal of Biological Chemistry·Carl A MachuttaPeter J Tonge
May 6, 2008·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Bagautdin BagautdinovNaoki Kunishima
Jan 1, 2013·Applied and Environmental Microbiology·Amaro E Trindade-SilvaFabiano L Thompson
Aug 11, 2011·Protein Science : a Publication of the Protein Society·Yingfei ChenPeter J Reilly
Feb 11, 2014·Structure·Darren C GayAdrian T Keatinge-Clay
Jul 6, 2010·Biochimica Et Biophysica Acta·Rachel BenistyNurith Porat
Oct 1, 2008·Molecular Phylogenetics and Evolution·Chenguang JiangDae-Yeon Suh
Jun 14, 2018·Angewandte Chemie·Srividhya SundaramChristian Hertweck
Mar 29, 2014·Chembiochem : a European Journal of Chemical Biology·Sarah M BouhiredGabriele M König
May 27, 2010·Chembiochem : a European Journal of Chemical Biology·Ozlem ErolGabriele M König
Nov 26, 2013·Organic & Biomolecular Chemistry·Shuichi Nakamura
Apr 9, 2020·Nature Communications·Jeffrey T MindreboMichael D Burkart
May 6, 2020·Nature Chemical Biology·Danyao DuYasuo Ohnishi
Aug 4, 2012·Natural Product Reports·Adrian T Keatinge-Clay
Mar 31, 2020·Organic & Biomolecular Chemistry·Kengo Hyodo, Shuichi Nakamura
May 25, 2021·Chemical Society Reviews·Pan XiaoSamuel Couve-Bonnaire
Jun 23, 2021·Chemical Reviews·Pedro PaivaPedro A Fernandes
Feb 22, 2018·The Journal of Physical Chemistry. B·Aaron C RobinsonBertrand García-Moreno E

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