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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 23, Number 6
BKCSDE 23(6)
June 20, 2002 

Theoretical Evaluation of the Electrophilic Catalyses in Successive Enolization and Reketonization Reaction by Δ5-3-Ketosteroid Isomerase
Hwangseo Park, Junghun Suh, Sangyoub Lee
Ab initio study of enzyme reactivity, -3-Ketosteroid isomerase.
Based on ab initio calculations at the MP2(FULL)/6-31+G**//RHF/ 6-31G** level, we compare the energeric and mechanistic features of a model reaction for catalytic action of △5-3-ketosteroid isomerase (KSI, E.C. with those of a corresponding nonenzymatic reaction in aqueous solution. The results show that the two catalytic acid residues, Tyrl14 and Asp99,can lower free energy of activation by 8.6 Kcal/mol, which is in good agreement with the experimetally predicted∼9Kcal/mol contribution of electrophilic catalyses to the whole enzymatic rate enhancement. The dienolate intermediate formed by proton transfer from the substrate carbon acid th the catalytic base residue (Asp38) is predicted to be stabilized by 12.0 Kcal/mol in the enzymatic reaction, making its formation thermodynamically favorable. It has been argued that enzymes catalyzing the reaction of carbon acids should resolve the thermodynamic problem of stabilizing the enolate intermediate as well as the kinetic problem of lowering the free energy of activation for proton abstration. We find that KSI can successfully overcome the thermodynamic difficulty inherent in the nonenzymatic reaction through the electrophilic catalyses of the two acid residues. Owing to the stbilization of dienolate intermediate, the reketonization step could influence the overall reaction rate more significantly in the KSI-catalyzed reaction than in the nonenzymatic reaction, further supporting the previous experimental findings. However, the electrophilic catalyses alone cannot account for the whole catalytic (12-13 Kcal/mol), confirming the earlier experimental implications for the involvement of additional catalytic capability(12-13 Kcal/mol), confirming the computational study indicates clearly how catalytic residues of KSI resolve the fundamantal problems associated with the entropic penalty for forming the rate-limiting the rate-limiting transition state and its destabilization in the bulk solvation environment.
837 - 844
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