QM/MM study of the insertion of metal ion into protoporphyrin IX by ferrochelatase.
QM/MM study of the insertion of metal ion into protoporphyrin IX by ferrochelatase.
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DOI：
10.1016/j.jinorgbio.2009.09.013
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发表时间：
2009-12
影响因子：
3.9
通讯作者：
Yaxue Wang;Yong Shen;U. Ryde
中科院分区：
文献类型：
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作者：
Yaxue Wang;Yong Shen;U. Ryde
铁螯合酶在血红素生物合成的最后步骤中催化原卟啉 IX 的金属化。亚铁螯合酶基因突变可导致红细胞生成性卟啉症。亚铁螯合酶的催化机制仍不完全清楚。在本文中，我们利用量子力学和分子力学（QM/MM）相结合的计算方法，研究了枯草芽孢杆菌亚铁螯合酶将 Fe2+ 插入原卟啉 IX 环的过程。几何结构在 BP86/6-31G* 水平上进行优化，能量在 B3LYP/TZVP 水平上进行计算。整个过程包括从 Fe2+ 中逐步置换 Glu-264、His-183 和一个水分子，并从卟啉环上除去两个质子。速率决定步骤是 Glu-264 的氧原子和 Fe2+ 之间的键断裂，同时形成第一个 Fe-N 键。它的能垒为 57kJmol−1。卟啉环在酶活性位点仅轻微变形。残基 Tyr-13 在从原卟啉 IX 中提取两个质子的催化过程中起着关键作用。
Ferrochelatase catalyzes the metallation of protoporphyrin IX in the terminal step of heme biosynthesis. Mutations in the ferrochelatase gene can lead to the disease erythropoietic porphyria. The catalyzing mechanism of ferrochelatase is still not fully understood. In this paper, we have studied the insertion of Fe2+into the protoporphyrin IX ring by Bacillussubtilis ferrochelatase using combined quantum mechanical and molecular mechanics (QM/MM) calculations. Geometries were optimized at the BP86/6-31G∗ level and energies were calculated at the B3LYP/TZVP level. The overall process involves the stepwise displacement of Glu-264, His-183, and a water molecule from Fe2+, and the removal of two protons from the porphyrin ring. The rate-determining step is the cleavage of the bond between the oxygen atom of Glu-264 and Fe2+, concomitant with the formation of the first Fe–N bond. It has an energy barrier of 57kJmol−1. The porphyrin ring is only slightly distorted in the enzyme active site. The residue Tyr-13 plays a key role for the catalytic process extracting two protons from protoporphyrin IX.