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Article: Mechanism of OMP decarboxylation in orotidine 5′-monophosphate decarboxylase

TitleMechanism of OMP decarboxylation in orotidine 5′-monophosphate decarboxylase
Authors
Issue Date2008
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.html
Citation
Journal Of The American Chemical Society, 2008, v. 130 n. 44, p. 14493-14503 How to Cite?
AbstractDespite extensive experimental and theoretical studies, the detailed catalytic mechanism of orotidine 5′-monophosphate decarboxylase (ODCase) remains controversial. In particular simulation studies using high level quantum mechanics have failed to reproduce experimental activation free energy. One common feature of many previous simulations is that there is a water molecule in the vicinity of the leaving CO2 group whose presence was only observed in the inhibitor bound complex of ODCase/BMP. Various roles have even been proposed for this water molecule from the perspective of stabilizing the transition state and/or intermediate state. We hypothesize that this water molecule is not present in the active ODCase/OMP complex. Based on QM/MM minimum free energy path simulations with accurate density functional methods, we show here that in the absence of this water molecule the enzyme functions through a simple direct decarboxylation mechanism. Analysis of the interactions in the active site indicates multiple factors contributing to the catalysis, including the fine-tuned electrostatic environment of the active site and multiple hydrogen-bonding interactions. To understand better the interactions between the enzyme and the inhibitor BMP molecule, simulations were also carried out to determine the binding free energy of this special water molecule in the ODCase/BMP complex. The results indicate that the water molecule in the active site plays a significant role in the binding of BMP by contributing ∼ -3 kcal/mol to the binding free energy of the complex. Therefore, the complex of BMP plus a water molecule, instead of the BMP molecule alone, better represents the tight binding transition state analogue of ODCase. Our simulation results support the direct decarboxylation mechanism and highlight the importance of proper recognition of protein bound water molecules in the protein - ligand binding and the enzyme catalysis. © 2008 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/168341
ISSN
2015 Impact Factor: 13.038
2015 SCImago Journal Rankings: 7.123
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorHu, Hen_US
dc.contributor.authorBoone, Aen_US
dc.contributor.authorYang, Wen_US
dc.date.accessioned2012-10-08T03:17:48Z-
dc.date.available2012-10-08T03:17:48Z-
dc.date.issued2008en_US
dc.identifier.citationJournal Of The American Chemical Society, 2008, v. 130 n. 44, p. 14493-14503en_US
dc.identifier.issn0002-7863en_US
dc.identifier.urihttp://hdl.handle.net/10722/168341-
dc.description.abstractDespite extensive experimental and theoretical studies, the detailed catalytic mechanism of orotidine 5′-monophosphate decarboxylase (ODCase) remains controversial. In particular simulation studies using high level quantum mechanics have failed to reproduce experimental activation free energy. One common feature of many previous simulations is that there is a water molecule in the vicinity of the leaving CO2 group whose presence was only observed in the inhibitor bound complex of ODCase/BMP. Various roles have even been proposed for this water molecule from the perspective of stabilizing the transition state and/or intermediate state. We hypothesize that this water molecule is not present in the active ODCase/OMP complex. Based on QM/MM minimum free energy path simulations with accurate density functional methods, we show here that in the absence of this water molecule the enzyme functions through a simple direct decarboxylation mechanism. Analysis of the interactions in the active site indicates multiple factors contributing to the catalysis, including the fine-tuned electrostatic environment of the active site and multiple hydrogen-bonding interactions. To understand better the interactions between the enzyme and the inhibitor BMP molecule, simulations were also carried out to determine the binding free energy of this special water molecule in the ODCase/BMP complex. The results indicate that the water molecule in the active site plays a significant role in the binding of BMP by contributing ∼ -3 kcal/mol to the binding free energy of the complex. Therefore, the complex of BMP plus a water molecule, instead of the BMP molecule alone, better represents the tight binding transition state analogue of ODCase. Our simulation results support the direct decarboxylation mechanism and highlight the importance of proper recognition of protein bound water molecules in the protein - ligand binding and the enzyme catalysis. © 2008 American Chemical Society.en_US
dc.languageengen_US
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.htmlen_US
dc.relation.ispartofJournal of the American Chemical Societyen_US
dc.subject.meshAlgorithmsen_US
dc.subject.meshCatalysisen_US
dc.subject.meshCatalytic Domainen_US
dc.subject.meshComputer Simulationen_US
dc.subject.meshCrystallography, X-Rayen_US
dc.subject.meshDecarboxylationen_US
dc.subject.meshKineticsen_US
dc.subject.meshMethanobacterium - Enzymologyen_US
dc.subject.meshModels, Chemicalen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshOrotidine-5'-Phosphate Decarboxylase - Chemistry - Metabolismen_US
dc.subject.meshQuantum Theoryen_US
dc.subject.meshStatic Electricityen_US
dc.subject.meshThermodynamicsen_US
dc.subject.meshUridine Monophosphate - Analogs & Derivatives - Chemistry - Metabolismen_US
dc.titleMechanism of OMP decarboxylation in orotidine 5′-monophosphate decarboxylaseen_US
dc.typeArticleen_US
dc.identifier.emailHu, H:haohu@hku.hken_US
dc.identifier.authorityHu, H=rp00707en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1021/ja801202jen_US
dc.identifier.pmid18839943-
dc.identifier.scopuseid_2-s2.0-55549093783en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-55549093783&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume130en_US
dc.identifier.issue44en_US
dc.identifier.spage14493en_US
dc.identifier.epage14503en_US
dc.identifier.isiWOS:000260533400062-
dc.publisher.placeUnited Statesen_US
dc.identifier.f10001124544-
dc.identifier.scopusauthoridHu, H=7404097564en_US
dc.identifier.scopusauthoridBoone, A=7003715962en_US
dc.identifier.scopusauthoridYang, W=7407757509en_US

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