QM/MM simulations identify the determinants of catalytic activity differences between type II dehydroquinase enzymes

Organic & Biomolecular Chemistry
Emilio LenceAdrian J Mulholland

Abstract

Type II dehydroquinase enzymes (DHQ2), recognized targets for antibiotic drug discovery, show significantly different activities dependent on the species: DHQ2 from Mycobacterium tuberculosis (MtDHQ2) and Helicobacter pylori (HpDHQ2) show a 50-fold difference in catalytic efficiency. Revealing the determinants of this activity difference is important for our understanding of biological catalysis and further offers the potential to contribute to tailoring specificity in drug design. Molecular dynamics simulations using a quantum mechanics/molecular mechanics potential, with correlated ab initio single point corrections, identify and quantify the subtle determinants of the experimentally observed difference in efficiency. The rate-determining step involves the formation of an enolate intermediate: more efficient stabilization of the enolate and transition state of the key step in MtDHQ2, mainly by the essential residues Tyr24 and Arg19, makes it more efficient than HpDHQ2. Further, a water molecule, which is absent in MtDHQ2 but involved in generation of the catalytic Tyr22 tyrosinate in HpDHQ2, was found to destabilize both the transition state and the enolate intermediate. The quantification of the contribution of key residues ...Continue Reading

References

Feb 1, 1990·The Biochemical Journal·P J WhiteJ R Coggins
Apr 9, 2002·Structure·Aleksander W RoszakAdrian J Lapthorn
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Mar 24, 2005·Journal of the American Chemical Society·Johannes C HermannHans-Dieter Höltje
Jun 28, 2005·Nucleic Acids Research·John C GordonAlexey Onufriev
Sep 20, 2008·Chemical Communications : Chem Comm·Anna L BowmanAdrian J Mulholland
Aug 29, 2009·Science·Michael A Fischbach, Christopher T Walsh
Oct 27, 2009·ChemMedChem·Verónica F V PrazeresConcepción González-Bello
Mar 24, 2010·Chemical Communications : Chem Comm·Richard LonsdaleAdrian J Mulholland
Feb 3, 2011·MBio·Gyanu LamichhaneWilliam R Bishai
Jul 26, 2011·Journal of Medicinal Chemistry·Lorena TizónConcepción González-Bello
Nov 4, 2011·Nature Reviews. Microbiology·Karen BushHelen I Zgurskaya
Jan 27, 2012·Chemical Society Reviews·Richard LonsdaleAdrian J Mulholland
Mar 27, 2012·Organic & Biomolecular Chemistry·Beatriz BlancoConcepción González-Bello
Oct 4, 2012·Journal of the American Chemical Society·Fátima FonsecaJames Spencer
Dec 4, 2012·ACS Chemical Biology·Emilio LenceConcepción González-Bello
Apr 6, 2013·Biochemistry·Marc W van der Kamp, Adrian J Mulholland
Dec 21, 2013·Scientific Reports·Christopher J WoodsAdrian J Mulholland
Jan 8, 2014·The Biochemical Journal·Claire CoderchConcepción González-Bello
May 9, 2014·Current Topics in Medicinal Chemistry·Richard Lonsdale, Adrian J Mulholland
Oct 17, 2014·Chemical Communications : Chem Comm·Ewa I ChudykAdrian J Mulholland
May 12, 2009·Journal of Chemical Theory and Computation·L Mattias BlombergJochen Blumberger
Jan 23, 2016·Nature·Eric D Brown, Gerard D Wright
May 4, 2016·Journal of the American Chemical Society·Matthew J ByrnePaul R Race

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Citations

Jan 30, 2021·Biotechnology Advances·Joan Planas-IglesiasDavid Bednar
Apr 30, 2021·The Journal of Physical Chemistry. B·Kiyoshi YagiYuji Sugita
Oct 3, 2018·The Journal of Organic Chemistry·Raúl Pérez-RuizM Consuelo Jiménez
Sep 3, 2021·Computational and Structural Biotechnology Journal·Levente M MihalovitsGyörgy M Keserű

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Methods Mentioned

BETA
chemical modification

Software Mentioned

AMBER
DFTB
SCC
GAFF

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