Geometric and Electronic Structure Contributions to Function in Non-heme Iron Enzymes
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- 作者：Edward I. Solomon ; Kenneth M. Light ; Lei V. Liu ; Martin Srnec ; Shaun D. Wong
- 刊名：Accounts of Chemical Research
- 出版年：2013
- 出版时间：November 19, 2013
- 年：2013
- 卷：46
- 期：11
- 页码：2725-2739
- 全文大小：1116K
- 年卷期：v.46,no.11(November 19, 2013)
- ISSN：1520-4898
文摘
Mononuclear non-heme Fe (NHFe) enzymes play key roles in DNA repair, the biosynthesis of antibiotics, the response to hypoxia, cancer therapy, and many other biological processes. These enzymes catalyze a diverse range of oxidation reactions, including hydroxylation, halogenation, ring closure, desaturation, and electrophilic aromatic substitution (EAS). Most of these enzymes use an FeII site to activate dioxygen, but traditional spectroscopic methods have not allowed researchers to insightfully probe these ferrous active sites. We have developed a methodology that provides detailed geometric and electronic structure insights into these NHFeII active sites. Using these data, we have defined a general mechanistic strategy that many of these enzymes use: they control O2 activation (and limit autoxidation and self-hydroxylation) by allowing FeII coordination unsaturation only in the presence of cosubstrates. Depending on the type of enzyme, O2 activation either involves a 2e鈥?/sup> reduced FeIII鈥揙OH intermediate or a 4e鈥?/sup> reduced FeIV鈺怬 intermediate. Nuclear resonance vibrational spectroscopy (NRVS) has provided the geometric structure of these intermediates, and magnetic circular dichroism (MCD) has defined the frontier molecular orbitals (FMOs), the electronic structure that controls reactivity. This Account emphasizes that experimental spectroscopy is critical in evaluating the results of electronic structure calculations. Therefore these data are a key mechanistic bridge between structure and reactivity.
For the FeIII鈥揙OH intermediates, the anticancer drug activated bleomycin (BLM) acts as the non-heme Fe analog of compound 0 in heme (e.g., P450) chemistry. However BLM shows different reactivity: the low-spin (LS) FeIII鈥揙OH can directly abstract a H atom from DNA. The LS and high-spin (HS) FeIII鈥揙OHs have fundamentally different transition states. The LS transition state goes through a hydroxyl radical, but the HS transition state is activated for EAS without O鈥揙 cleavage. This activation is important in one class of NHFe enzymes that utilizes a HS FeIII鈥揙OH intermediate in dioxygenation.
For FeIV鈺怬 intermediates, the LS form has a 蟺-type FMO activated for attack perpendicular to the Fe鈥揙 bond. However, the HS form (present in the NHFe enzymes) has a 蟺 FMO activated perpendicular to the Fe鈥揙 bond and a 蟽 FMO positioned along the Fe鈥揙 bond. For the NHFe enzymes, the presence of 蟺 and 蟽 FMOs enables enzymatic control in determining the type of reactivity: EAS or H-atom extraction for one substrate with different enzymes and halogenation or hydroxylation for one enzyme with different substrates.
For the FeIII鈥揙OH intermediates, the anticancer drug activated bleomycin (BLM) acts as the non-heme Fe analog of compound 0 in heme (e.g., P450) chemistry. However BLM shows different reactivity: the low-spin (LS) FeIII鈥揙OH can directly abstract a H atom from DNA. The LS and high-spin (HS) FeIII鈥揙OHs have fundamentally different transition states. The LS transition state goes through a hydroxyl radical, but the HS transition state is activated for EAS without O鈥揙 cleavage. This activation is important in one class of NHFe enzymes that utilizes a HS FeIII鈥揙OH intermediate in dioxygenation.
For FeIV鈺怬 intermediates, the LS form has a 蟺-type FMO activated for attack perpendicular to the Fe鈥揙 bond. However, the HS form (present in the NHFe enzymes) has a 蟺 FMO activated perpendicular to the Fe鈥揙 bond and a 蟽 FMO positioned along the Fe鈥揙 bond. For the NHFe enzymes, the presence of 蟺 and 蟽 FMOs enables enzymatic control in determining the type of reactivity: EAS or H-atom extraction for one substrate with different enzymes and halogenation or hydroxylation for one enzyme with different substrates.