MECHANISM OF THE HUMAN CARBONIC ANHYDRASE-II CATALYZED HYDRATION OF CARBON-DIOXIDE

被引:105
作者
ZHENG, YJ [1 ]
MERZ, KM [1 ]
机构
[1] PENN STATE UNIV,DEPT CHEM,152 DAVEY LAB,UNIV PK,PA 16802
关键词
D O I
10.1021/ja00052a054
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The catalytic mechanism of human carbonic anhydrase II (HCAII) has been studied by using a combined high-level ab initio and free energy perturbation approach. We have examined two hydration reaction mechanisms. The first involves hydration of CO2 followed by loss of bicarbonate. The second, originally proposed by Liang and Lipscomb, involves hydration of CO2 followed by an internal proton transfer and then loss of bicarbonate. We find that the former mechanism is more likely than the latter. On the basis of our results we have been able to predict the location of the bicarbonate proton in the recently solved X-ray structure of the HCAII-bicarbonate complex. We find that the proton is hydrogen bound to Thr-199, while one of the bicarbonate oxygens is hydrogen bound to the main-chain NH of Thr-199. This hydrogen-bonding pattern is analogous to that seen for sulfonamides, which suggests that these molecules are substrate (or transition-state) mimics. Our calculated free energy barrier for CO2 hydration is in reasonable accord with experiment, while that for the dehydration of bicarbonate is in poor agreement. The reasons for this disagreement are discussed. The molecular-level details obtained from this study have been used to construct a detailed catalytic mechanism for the mode of action of HCAII.
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收藏
页码:10498 / 10507
页数:10
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