The deacylation mechanism of AmpC beta-lactamase at ultrahigh resolution

Journal of the American Chemical Society
Yu ChenBrian K Shoichet

Abstract

Beta-lactamases confer bacterial resistance to beta-lactam antibiotics, such as penicillins. The characteristic class C beta-lactamase AmpC catalyzes the reaction with several key residues including Ser64, Tyr150, and Lys67. Here, we describe a 1.07 A X-ray crystallographic structure of AmpC beta-lactamase in complex with a boronic acid deacylation transition-state analogue. The high quality of the electron density map allows the determination of many proton positions. The proton on the Tyr150 hydroxyl group is clearly visible and is donated to the boronic oxygen mimicking the deacylation water. Meanwhile, Lys67 hydrogen bonds with Ser64Ogamma, Asn152Odelta1, and the backbone oxygen of Ala220. This suggests that this residue is positively charged and has relinquished the hydrogen bond with Tyr150 observed in acyl-enzyme complex structures. Together with previous biochemical and NMR studies, these observations indicate that Tyr150 is protonated throughout the reaction coordinate, disfavoring mechanisms that involve a stable tyrosinate as the general base for deacylation. Rather, the hydroxyl of Tyr150 appears to be well positioned to electrostatically stabilize the negative charge buildup in the tetrahedral high-energy intermedi...Continue Reading

References

Feb 22, 1990·European Journal of Biochemistry·K TsukamotoT Sawai
Dec 1, 1988·The Biochemical Journal·B P Murphy, R F Pratt
Jun 1, 1995·Antimicrobial Agents and Chemotherapy·K BushA A Medeiros
May 11, 1995·Biochemical Pharmacology·M GalleniJ M Frère
Aug 15, 1994·The Biochemical Journal·D MonnaieJ M Frère
Feb 27, 1999·Antimicrobial Agents and Chemotherapy·S TrépanierA Huletsky
May 18, 1999·Acta Crystallographica. Section D, Biological Crystallography·E A Merritt
May 17, 2000·Proteins·J Lamotte-BrasseurR C Wade
May 17, 2001·Bioorganic & Medicinal Chemistry Letters·Y Kato-Toma, M Ishiguro
May 9, 2002·Journal of the American Chemical Society·George MinasovBrian K Shoichet
May 23, 2002·Antimicrobial Agents and Chemotherapy·Sergei B VakulenkoStephen A Lerner
Jul 12, 2002·Journal of Medicinal Chemistry·Rachel A Powers, Brian K Shoichet
Jul 30, 2002·Journal of Molecular Biology·Beth M Beadle, Brian K Shoichet
Jan 7, 2003·The Biochemical Journal·Yoko Kato-TomaMasaji Ishiguro
Dec 10, 2003·Biochemistry·Tomer A RothBrian K Shoichet
Jan 1, 1997·Methods in Enzymology·Z Dauter

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Citations

Apr 24, 2012·Chemical Reviews·Reem SmoumMorris Srebnik
Mar 13, 2008·Journal of Medicinal Chemistry·Kerim BabaogluBrian K Shoichet
May 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Denise G TeoticoBrian K Shoichet
Oct 9, 2012·Proceedings of the National Academy of Sciences of the United States of America·Oliv EidamFabio Prati
Jul 29, 2011·The Journal of Biological Chemistry·Damien DuboisRichard Bonnet
Feb 15, 2012·Antimicrobial Agents and Chemotherapy·Wei KeFocco van den Akker
Sep 13, 2011·Applied and Environmental Microbiology·Jeong Ho JeonJung-Hyun Lee
Jan 13, 2009·Clinical Microbiology Reviews·George A Jacoby
Jan 13, 2010·Clinical Microbiology Reviews·Sarah M Drawz, Robert A Bonomo
Mar 19, 2014·Future Medicinal Chemistry·Derek A NicholsYu Chen
May 6, 2015·International Journal of Molecular Sciences·Jeong Ho JeonSang Hee Lee
Feb 27, 2016·The Journal of Physical Chemistry. B·Ravi Tripathi, Nisanth N Nair
Feb 14, 2015·Journal of Computer-aided Molecular Design·Jacopo SgrignaniGiovanni Grazioso
Jun 22, 2016·Future Medicinal Chemistry·David Yuxin WangChristopher J Schofield
Jun 30, 2016·Journal of Enzyme Inhibition and Medicinal Chemistry·Fatma Gizem AvciBerna Sariyar Akbulut
Aug 1, 2018·International Journal of Molecular Sciences·Warawan EiamphungpornChanin Nantasenamat
Mar 1, 2019·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Neelja SinghalJugsharan Singh Virdi
Aug 28, 2019·Antimicrobial Agents and Chemotherapy·Da-Woon BaeSun-Shin Cha
Jun 7, 2020·Biomolecules·Antonella R PalaciosAlejandro J Vila
Jun 15, 2007·The Journal of Biological Chemistry·Matthew KalpPaul R Carey
May 1, 2020·Biomolecules·Scott T LefurgyRobert A Bonomo
Sep 16, 2010·Expert Opinion on Therapeutic Patents·Karen Bush, Mark J Macielag
May 18, 2011·Journal of the American Chemical Society·Astrid ZervosenEric Sauvage
Apr 7, 2012·The Journal of Physical Chemistry. B·Ravi Tripathi, Nisanth N Nair
May 31, 2018·Chemical Reviews·David A DikShahriar Mobashery
Sep 10, 2013·Journal of the American Chemical Society·Ravi Tripathi, Nisanth N Nair
Sep 19, 2014·ACS Chemical Biology·Viachaslau BernatNuska Tschammer
Sep 14, 2011·The Journal of Physical Chemistry. B·Liang ChenHualiang Jiang
May 11, 2010·Journal of Molecular Biology·Julien DelmasRichard Bonnet

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