The Important Role of Active Site Water in the Catalytic Mechanism of Human Carbonic Anhydrase II -A Semiempirical MO Approach to the Hydration of CO 2 -/sup>

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• 作者：Michael Hartmann ; Kenneth M. Merz ; Rudi van Eldik and Timothy Clark
• 关键词：Keywords Human Carbonic Anhydrase II ; Semiempirical MO Theory ; AM1 ; Enzyme Catalysis
• 刊名：Journal of Molecular Modeling
• 出版年：1998
• 出版时间：November 1998
• 年：1998
• 卷：4
• 期：11
• 页码：355-365
• 全文大小：951 KB
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Computer Applications in Chemistry
  Biomedicine
  Molecular Medicine
  Health Informatics and Administration
  Life Sciences
  Computer Application in Life Sciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：0948-5023

文摘

The approach of CO₂ to a series of active site model complexes of human carbonic anhydrase II (HCAII) and its catalytic hydration to bicarbonate anion have been investigated using semiempirical MO theory (AM1). The results show that direct nucleophilic attack of zinc-bound hydroxide to the substrate carbon occurs in each model system. Further rearrangement of the bicarbonate complex thus formed via a rotation-like movement of the bicarbonate ligand can only be found in active site model systems that include at least one additional water molecule. Further refinement of the model complex by adding a methanol molecule to mimic Thr-199 makes this process almost activationless. The formation of the final bicarbonate complex by an internal (intramolecular) proton transfer is only possible in the simplest of all model systems, namely {[Im₃Zn(OH)]+·CO₂}. The energy of activation for this process, however, is 36.8 kcal·mol–1 and thus too high for enzymatic catalysis. Therefore, we conclude that within the limitations of the model systems presented and the level of theory employed, the overall mechanism for the formation of the bicarbonate complex comprises an initial direct nucleophilic attack of zinc-bound hydroxide to carbon dioxide followed by a rotation-like rearrangement of the bicarbonate ligand via a penta-coordinate Zn2+ transition state structure, including the participation of an extra active site water molecule.