Proton-Transfer Dynamics in the Activation of Cytochrome P450eryF

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• 作者：Victor Guallar ; Danni L. Harris ; Victor S. Batista ; and William H. Miller
• 刊名：Journal of the American Chemical Society
• 出版年：2002
• 出版时间：February 20, 2002
• 年：2002
• 卷：124
• 期：7
• 页码：1430 - 1437
• 全文大小：182K
• 年卷期：v.124,no.7(February 20, 2002)
• ISSN：1520-5126

文摘

Molecular dynamics simulations are combined with quantum chemistry calculations of instantaneous proton-transfer energy profiles to investigate proton-transfer events in the transient pathway ofcytochrome P450eryF (6-deoxyerythronolide B hydroxylase; CYP107A1), from the oxyferrous species tothe catalytically active ferryl oxygen species (compound I). This reaction is one of the most fundamentalunresolved aspects in the mechanism of oxidation that is common to all cytochrome P450s. We find thatthis process involves an ultrafast proton transfer from the crystallographic water molecule W519 to thedistal oxygen bound to the heme group, and a subsequent proton-transfer event from W564 to W519.Both proton-transfer events are found to be endothermic in the oxyferrous state, suggesting that theoxyferrous reduction is mechanistically linked to the proton-transfer dynamics. These findings indicate thatthe hydrogen bond network, proximate to the O₂-binding cleft, plays a crucial functional role in the enzymaticactivation of P450s. Our results are consistent with the effect of mutations on the enzymatic efficacy.