Document Detail


Hydrolysis of cyclic phosphates by ribonuclease A: a computational study using a simplified ab initio quantum model.
MedLine Citation:
PMID:  12964199     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The second step in the enzyme-catalyzed hydrolysis of phosphate esters by ribonuclease A (RNase A) was studied using an ab initio quantum-based model of the active site including constrained parts of three critical residues, His-12, His-119, and Lys-41, and a small substrate. The competition between release of the cyclic phosphate intermediate and subsequent hydrolysis following transphosphorylation was explored to determine the electronic factors that contribute to preferential intermediate product release observed experimentally. The structural and energetic results obtained at both the RHF and MP2 levels reveal several contributing factors consistent with experimental observation. Although the intrinsic electronic effects tend to favor hydrolysis slightly with an overall activation free energy of approximately 70 kJ mol(-1), entropic and environmental effects favor release of the cyclic phosphate intermediate over hydrolysis. Exploration of the second, hydrolysis step also revealed interesting similarity with the transphosphorylation step, including the observation of autocatalysis by the substrate. Moreover, both steps of the overall RNase A reaction reveal multiple pathways involving proton transfers to sites of similar proton affinities. The anionic phosphate in both steps can act as a stable proton binding site as protons are moved around the active site throughout the progress of the reaction. These results suggest autocatalysis may be representative of more general behavior in enzymes containing highly charged substrates, especially phosphates.
Authors:
Brian D Wladkowski; Paul Ostazeski; Sarah Chenoweth; Steven J Broadwater; Morris Krauss
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of computational chemistry     Volume:  24     ISSN:  0192-8651     ISO Abbreviation:  J Comput Chem     Publication Date:  2003 Nov 
Date Detail:
Created Date:  2003-09-09     Completed Date:  2004-03-16     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9878362     Medline TA:  J Comput Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1803-11     Citation Subset:  IM    
Copyright Information:
Copyright 2003 Wiley Periodicals, Inc.
Affiliation:
Department of Chemistry, McDaniel College, 2 College Hill, Westminster, MD 21157, USA.
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MeSH Terms
Descriptor/Qualifier:
Catalysis
Hydrolysis
Mathematical Computing
Molecular Conformation
Phosphates / chemistry*
Phosphorylation
Quantum Theory
Ribonuclease, Pancreatic / chemistry*
Solvents / chemistry
Chemical
Reg. No./Substance:
0/Phosphates; 0/Solvents; EC 3.1.27.5/Ribonuclease, Pancreatic

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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