THE BINDING AND REGIOSELECTIVITY OF REACTION OF (R)-NICOTINE AND (S)-NICOTINE WITH CYTOCHROME-P-450CAM - PARALLEL EXPERIMENTAL AND THEORETICAL-STUDIES
THE BINDING AND REGIOSELECTIVITY OF REACTION OF (R)-NICOTINE AND (S)-NICOTINE WITH CYTOCHROME-P-450CAM - PARALLEL EXPERIMENTAL AND THEORETICAL-STUDIES
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DOI：
10.1021/ja00055a002
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发表时间：
1993-01-27
影响因子：
15
通讯作者：
CARLSON, TJ
中科院分区：
文献类型：
--
作者：
JONES, JP;TRAGER, WF;CARLSON, TJ
(S)-和(R)-烟碱用于检验细胞色素P-450结合和区域选择性的理论模型。理论研究预测(R)-尼古丁的结合比(S)-尼古丁的结合更有利0.400 ~ 0.600 kcal，平行实验研究确定了(R)-尼古丁的结合常数相差0.333 kcal, (R)-尼古丁的总代谢速率比(S)-尼古丁快1.4倍，这与预测的结合能差异一致。理论上预测，两种对映体在吡咯烷环的5'亚甲基上的产物生成速度都比在n -甲基上的产物生成速度快。实验结果证实了这一预测。讨论了影响这两种对映体差异结合的重要因素。理论与实验结果的吻合表明，所计算的力场对预测衬底与p -450凸轮的结合具有普遍的适用性。
(S)- and (R)-nicotine were used to test a theoretical model for the binding and regioselectivity of cytochrome P-450. Theoretical studies predict that the binding of (R)-nicotine will be more favorable than the binding of (S)-nicotine by between 0.400 and 0.600 kcal. A parallel experimental study determined that the binding constants differed by 0.333 kcal. The overall metabolic rate of (R)-nicotine is 1.4-fold faster than (S)-nicotine which is consistent with the predicted difference in binding energy. Product formation is theoretically predicted to occur at a faster rate at the 5' methylene group than at the N-methyl group of the pyrrolidine ring for both enantiomers. This prediction was confirmed by the experimental results. The factors that are important in the differential binding of the two enantiomers are discussed. The agreement between theory and experiment indicates that the force field used in these calculations may be of general applicability for the prediction of the binding of substrates to P-450cam.