Nature of the Fe−O<sub>2</sub> Bonding in Oxy-Myoglobin: Effect of the Protein

Chen, Hui; Ikeda‐Saito, Masao; Shaik, Sason

doi:10.1021/ja805434m

Cited by 241 publications

(328 citation statements)

References 124 publications

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“…Note that the 1.29-Å O-O distance obtained by QM/MM is still larger than the 1.23-Å X-ray diffraction distance. This points to electronic structure differences in the crystal compared with those obtained from theory (11). However, it is also possible that differences between oxy-Mb and oxy-Hb result in the differences observed in this study between crystalline oxy-Hb and the QM/MM study on oxy-Mb.…”

mentioning

confidence: 46%

X-ray absorption spectroscopic investigation of the electronic structure differences in solution and crystalline oxyhemoglobin

Wilson

Green

Mathews

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Hemoglobin (Hb) is the heme-containing O 2 transport protein essential for life in all vertebrates. The resting high-spin (S = 2) ferrous form, deoxy-Hb, combines with triplet O 2 , forming diamagnetic (S = 0) oxy-Hb. Understanding this electronic structure is the key first step in understanding transition metal-O 2 interaction. However, despite intense spectroscopic and theoretical studies, the electronic structure description of oxy-Hb remains elusive, with at least three different descriptions proposed by Pauling, Weiss, and McClureGoddard, based on theory, spectroscopy, and crystallography. Here, a combination of X-ray absorption spectroscopy and extended X-ray absorption fine structure, supported by density functional theory calculations, help resolve this debate. X-ray absorption spectroscopy data on solution and crystalline oxy-Hb indicate both geometric and electronic structure differences suggesting that two of the previous descriptions are correct for the Fe-O 2 center in oxy-Hb. These results support the multiconfigurational nature of the ground state developed by theoretical results. Additionally, it is shown here that small differences in hydrogen bonding and solvation effects can tune the ground state, tipping it into one of the two probable configurations. These data underscore the importance of solution spectroscopy and show that the electronic structure in the crystalline form may not always reflect the true ground-state description in solution.H emoglobin (Hb) is the iron-containing heme protein essential for oxygen transport in all vertebrates. The protein is an assembly of four globular subunits, each containing a heme B (protoporphyrin IX group) (1). The first characterization of Hb was done in the mid-1800s (2, 3), with the magnetic properties first elucidated in early 1900s. Later, Pauling and Coryell (4) showed that whereas resting venous Hb is paramagnetic, the oxygenated arterial form (oxy-Hb) is diamagnetic in nature. The first structure determination (X-ray diffraction) was done by Perutz et al. (5) in 1960, who was awarded the Nobel prize for this work. In 1974, the geometry of O 2 binding was shown to be end-on η 1 -Fe-O 2 , based on X-ray diffraction data on a biomimetic model complex (6), which was later confirmed by diffraction data on oxyHb. However, the debate over the electronic structure of O 2 binding in Hb and the nature of the Fe-O 2 bond continues today.Although the diamagnetic nature of oxy-Hb has been described by several different models, three have persisted. Starting from deoxy-Hb (Fe 2+ , S = 5/2) and O 2 (neutral, S = 1) and using a valence bond theory, Pauling proposed that the oxy-Hb is a Fe 2+ , S = 0 system that accepts one lone pair from the sp 2 hybridized O 2 , forming a dative bond (Scheme 1) (7). The Weiss model involves one-electron reduction of O 2 by the ferrous heme in deoxy-Hb (8), which leads to antiferromagnetic coupling between the Fe 3+ (S = 1/2) and O In this study, quantitative Fe K-edge XAS and density functional theory (DFT) calculations have ...

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confidence: 46%

X-ray absorption spectroscopic investigation of the electronic structure differences in solution and crystalline oxyhemoglobin

Wilson

Green

Mathews

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…35,39,[113][114][115][116] Fig. 5b shows the experimental and calculated pre-edge spectrum for MbO 2 , which exhibits a clear pre-edge feature at À13 eV.…”

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confidence: 99%

Probing the electronic and geometric structure of ferric and ferrous myoglobins in physiological solutions by Fe K-edge absorption spectroscopy

Lima

Penfold

Veen

et al. 2014

Phys. Chem. Chem. Phys.

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We present an iron K-edge X-ray absorption study of carboxymyoglobin (MbCO), nitrosylmyoglobin (MbNO), oxymyoglobin (MbO 2 ), cyanomyoglobin (MbCN), aquomet myoglobin (metMb) and unligated myoglobin (deoxyMb) in physiological media. The analysis of the XANES region is performed using the full-multiple scattering formalism, implemented within the MXAN package. This reveals trends within the heme structure, absent from previous crystallographic and X-ray absorption analysis. In particular, the iron-nitrogen bond lengths in the porphyrin ring converge to a common value of about 2 Å, except for deoxyMb whose bigger value is due to the doming of the heme. The trends of the Fe-N e (His93) bond length is found to be consistent with the effect of ligand binding to the iron, with the exception of MbNO, which is explained in terms of the repulsive trans effect. We derive a high resolution description of the relative geometry of the ligands with respect to the heme and quantify the magnitude of the heme doming in the deoxyMb form. Finally, time-dependent density functional theory is used to simulate the pre-edge spectra and is found to be in good agreement with the experiment. The XAS spectra typically exhibit one pre-edge feature which arises from transitions into the unoccupied d s and d p À p ligand * orbitals. 1s -d p transitions contribute weakly for MbO 2 , metMb and deoxyMb.However, despite this strong Fe d contribution these transitions are found to be dominated by the dipole (1s -4p) moment due to the low symmetry of the heme environment.

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“…2, C and D) due to formation of the oxy-form of NGB*. The loss of the redox activity is related to the formation of the charge-transfer state involving orbitals of Fe 2ϩ and O 2 (55), which precludes the transition from Fe 2ϩ to Fe 3ϩ in the presence of O 2 .…”

Section: Resultsmentioning

confidence: 99%

Electrochemical Evidence for Neuroglobin Activity on NO at Physiological Concentrations

Trashin¹,

Jong²,

Luyckx

et al. 2016

Journal of Biological Chemistry

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The true function of neuroglobin (Ngb) and, particularly, human Ngb (NGB) has been under debate since its discovery 15 years ago. It has been expected to play a role in oxygen binding/ supply, but a variety of other functions have been put forward, including NO dioxygenase activity. However, in vitro studies that could unravel these potential roles have been hampered by the lack of an Ngb-specific reductase. In this work, we used electrochemical measurements to investigate the role of an intermittent internal disulfide bridge in determining NO oxidation kinetics at physiological NO concentrations. The use of a polarized electrode to efficiently interconvert the ferric (Fe 3؉ ) and ferrous (Fe 2؉ ) forms of an immobilized NGB showed that the disulfide bridge both defines the kinetics of NO dioxygenase activity and regulates appearance of the free ferrous deoxy-NGB, which is the redox active form of the protein in contrast to oxy-NGB. Our studies further identified a role for the distal histidine, interacting with the hexacoordinated iron atom of the heme, in oxidation kinetics. These findings may be relevant in vivo, for example, in blocking apoptosis by reduction of ferric cytochrome c, and gentle tuning of NO concentration in the tissues. Neuroglobin (Ngb)2 is the vertebrate globin that has been hypothesized to be involved in, e.g. O 2 binding/supply, the metabolism of reactive nitrogen and oxygen species, apoptosis through different pathways, intracellular signaling, and cell protection during hypoxia and ischemia (1-6). Besides the central and peripheral nervous system and retina, Ngb is also expressed in endocrine tissues, hematopoietic stem cells, the gastrointestinal tract, and cancer cells (7,8). Although the first publication on the subject was in 2000, the in vivo role of Ngb is still uncertain. Studies on Ngb knock-out mice and regional gene expression did not clarify it further (3, 9 -13), but most of the reports in the topic supported its neuroprotective function at least under conditions of neuroglobin overexpression (11,14,15). Some histological data additionally indicated that Ngb can be involved in regulation of the circadian rhythm (sleep-wake cycle) (12, 16) and protection of neurons from neurodegenerative disorders, such as Alzheimers disease (17)(18)(19). Obviously, further in vivo and in vitro studies of Ngb are necessary to clarify its molecular mechanisms of action.As other globins, e.g. myoglobin and hemoglobin, Ngb displays the three-over-three ␣-helical sandwich structure. However, Ngb structurally differs somewhat from myoglobin and hemoglobin, suggesting a different functional destination for Ngb compared with the classic globins (20). Both its weak O 2 binding affinity under physiological conditions (21) and its hexacoordinated structure of the iron atom of the heme leading to a possible intrinsic binding competition with external gaseous ligands such as O 2 , CO, and NO, support the hypothesis that Ngb is not constructed to transport or store O 2 (22). The unclear mechanism of actio...

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Nature of the Fe−O₂ Bonding in Oxy-Myoglobin: Effect of the Protein

Cited by 241 publications

References 124 publications

X-ray absorption spectroscopic investigation of the electronic structure differences in solution and crystalline oxyhemoglobin

X-ray absorption spectroscopic investigation of the electronic structure differences in solution and crystalline oxyhemoglobin

Probing the electronic and geometric structure of ferric and ferrous myoglobins in physiological solutions by Fe K-edge absorption spectroscopy

Electrochemical Evidence for Neuroglobin Activity on NO at Physiological Concentrations

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Nature of the Fe−O2 Bonding in Oxy-Myoglobin: Effect of the Protein

Cited by 241 publications

References 124 publications

X-ray absorption spectroscopic investigation of the electronic structure differences in solution and crystalline oxyhemoglobin

X-ray absorption spectroscopic investigation of the electronic structure differences in solution and crystalline oxyhemoglobin

Probing the electronic and geometric structure of ferric and ferrous myoglobins in physiological solutions by Fe K-edge absorption spectroscopy

Electrochemical Evidence for Neuroglobin Activity on NO at Physiological Concentrations

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Nature of the Fe−O₂ Bonding in Oxy-Myoglobin: Effect of the Protein