Crystal Structure Analysis of a Synthetic Non‐Heme DiironO<sub>2</sub> Adduct: Insight into the Mechanism of Oxygen Activation

Dong, Yanhong; Yan, Shi‐Ping; Young, Victor G.; Que, Lawrence

doi:10.1002/anie.199606181

Cited by 196 publications

(224 citation statements)

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“…Indeed a number of metastable synthetic complexes are characterized to have core structures like that shown in Fig. 6; some in fact are stable enough to have been crystallized (31)(32)(33)(34). As the target hydroxylation site of hDOHH resides on a protein substrate, it seems plausible that substrate binding triggers a conformation change that activates the ( -1,2-peroxo)diiron(III) intermediate to carry out eIF5A(Dhp) hydroxylation (Scheme 1).…”

Section: Discussionmentioning

confidence: 99%

Human deoxyhypusine hydroxylase, an enzyme involved in regulating cell growth, activates O ₂ with a nonheme diiron center

Emerson

Martinho

et al. 2009

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

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107

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Deoxyhypusine hydroxylase is the key enzyme in the biosynthesis of hypusine containing eukaryotic translation initiation factor 5A (eIF5A), which plays an essential role in the regulation of cell proliferation. Recombinant human deoxyhypusine hydroxylase (hDOHH) has been reported to have oxygen-and iron-dependent activity, an estimated iron/holoprotein stoichiometry of 2, and a visible band at 630 nm responsible for the blue color of the as-isolated protein. EPR, Mö ssbauer, and XAS spectroscopic results presented herein provide direct spectroscopic evidence that hDOHH has an antiferromagnetically coupled diiron center with histidines and carboxylates as likely ligands, as suggested by mutagenesis experiments. Resonance Raman experiments show that its blue chromophore arises from a ( -1,2-peroxo)diiron(III) center that forms in the reaction of the reduced enzyme with O 2, so the peroxo form of hDOHH is unusually stable. Nevertheless we demonstrate that it can carry out the hydroxylation of the deoxyhypusine residue present in the elF5A substrate. Despite a lack of sequence similarity, hDOHH has a nonheme diiron active site that resembles both in structure and function those found in methane and toluene monooxygenases, bacterial and mammalian ribonucleotide reductases, and stearoyl acyl carrier protein ⌬ 9 -desaturase from plants, suggesting that the oxygen-activating diiron motif is a solution arrived at by convergent evolution. Notably, hDOHH is the only example thus far of a human hydroxylase with such a diiron active site.H ypusine is an unusual, but highly conserved, amino acid that is found only in the eukaryotic translational initiation factor 5A (eIF5A), a protein that regulates cell proliferation (1, 2). The biosynthesis of eIF5A involves a posttranslational modification of the eIF5A precursor, where a lysine residue is first modified to deoxyhypusine (Dhp) by deoxyhypusine synthase (DHS) and then the nascent Dhp is hydroxylated by deoxyhypusine hydroxylase (DOHH) to form hypusine (Hpu) (Scheme 1) (1, 2). The importance of hypusine and these 2 enzymes has been shown by several studies where depletion of spermidine (3) or inhibition of either DHS or DOHH (4, 5) leads to a decrease of hypusinecontaining eIF5A [eIF5A(Hpu)] and inhibition of eukaryotic cell growth. Consequently, these results suggest that eIF5A and DOHH could be promising targets for antitumor (6) and anti-HIV-1 therapies (7).The hydroxylase activity of recombinant human DOHH (hDOHH) has been shown to depend on Fe(II) and not on any other physiologically relevant divalent metal ion. An estimated iron-to-holoprotein stoichiometry of 2 is observed (8). Sequence examination, homology modeling, and mutagenesis experiments suggest 2 possible iron binding sites consisting of histidine and carboxylate ligands (8,9). Thus at first glance, hDOHH appears to resemble members of the superfamily of bacterial diiron multicomponent monooxygenases, like methane or toluene monooxygenase, that use nonheme diiron centers to activate dioxygen for the hydroxylat...

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Section: Discussionmentioning

confidence: 99%

Human deoxyhypusine hydroxylase, an enzyme involved in regulating cell growth, activates O ₂ with a nonheme diiron center

Emerson

Martinho

et al. 2009

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

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107

141

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“…The importance of homolytic cleavage of bound dioxygen for activating an oxidative reaction in a dinuclear model complex has been emphasized, as indicated in Figure 4. 17 The¯-η 1 :η 1 -O 2 binding mode mentioned above is one possibility for the peroxo-bound forms of sMMO. However, there is a potential alternative: the¯-η 2 :η 2 -O 2 mode indicated in Figure 4.…”

Section: Introductionmentioning

confidence: 94%

“…This type of peroxo-bridged diiron(III) model complex, which can be classified as a cis-¯-1,2-O 2 mode, has been crystallographically established in the research groups of Suzuki 16 and Que. 17 The¯-η 1 :η 1 -O 2 (cis-¯-1,2-) binding mode was proposed 19 to be energetically preferred to¯-η 2 :η 2 -O 2 and¯-1,1-O 2 modes for a hypothetical sMMO active site in which one of the monodentate bridging ligands (water or hydroxo) is removed from the molecular structure of sMMO. 15 We used extended Hückel calculations using YAeHMOP 3336 with the standard parameters collected by Alvarez.…”

Section: Diiron End-on Peroxo Speciesmentioning

confidence: 99%

Quantum Chemical Studies on Dioxygen Activation and Methane Hydroxylation by Diiron and Dicopper Species as well as Related Metal–Oxo Species

Yoshizawa

2013

Bulletin of the Chemical Society of Japan

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Quantum chemical studies by the author and co-workers on dioxygen activation and methane hydroxylation by diiron and dicopper enzyme species as well as related metaloxo species are reviewed. The activation of the OO bond of dioxygen at the mono-and dimetal sites of metalloenzymes is an essential process in the initial catalytic stages of naturally occurring oxygenation reactions. A way of orbital thinking about dioxygen activation at diiron and dicopper enzymes is developed at the extended Hückel level of theory. Two different reaction pathways that lead from dimetal peroxo complexes with¯-η , and CuO + are systematically analyzed on the basis of density functional theory (DFT) calculations. An important feature in the reaction is the spin crossover between the highspin and low-spin potential energy surfaces in particular in the CH activation process. The spin inversion from the highspin state to the low-spin state effectively decreases the barrier height of CH activation. Another feature in the reaction is that no radical species is involved in the course of the hydroxylation because the methyl species formed as a result of the CH bond cleavage can directly coordinate to the metal active site. The coupling of the OH and CH 3 ligands occurs to produce methanol at the metal active center. The reaction profiles obtained from DFT calculations are similar to those of the Gif chemistry proposed by D. H. R. Barton, in particular the involvement of the HOMCH 3 species as an intermediate in the hydroxylation of methane. The nonradical mechanism is extended to methane hydroxylation by the diiron and dicopper species of methane monooxygenase (MMO). This mechanism is possible when the metal active center is coordinatively unsaturated to have a space for the coordination of the OH and CH 3 groups as ligands. Although compelling discussion to support the involvement of oxygen-and carbon-centered radicals is provided, the nonradical mechanism still seems to be applicable for methane hydroxylation from the viewpoint of reaction selectivity. Kinetic isotope effects (KIEs) in the CH activation process by the bare FeO + complex and diiron and dicopper enzyme models are compared with respect to the radical and nonradical mechanisms by using transition state theory.

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“…Not surprisingly, this bond distance is somewhat longer than the Fe-O peroxo bond lengths associated with those (average 1.89 Å) of high-spin iron complexes with end-on peroxo ligands. 61,62,66,67 The Fe-O bond length of 1b also compares well with the 1.89 and 1.90 Å distances observed for the Mn-O bonds in [Mn(TPP)(η 2 -O 2 )] -68 but is longer than the average 1.86 Å Mn-O distance associated with [Mn III -(Tp 3,5-iPr2 )(3,5-iPr 2 pzH)(η 2 -O 2 )]. 69 Features in the outer sphere can be fit with carbon scatterers at 3, 4.1, and 4.6 Å.…”

Section: Peroxo Deriwatiwes Of Non-heme Iron Complexesmentioning

confidence: 99%

End-On and Side-On Peroxo Derivatives of Non-Heme Iron Complexes with Pentadentate Ligands: Models for Putative Intermediates in Biological Iron/Dioxygen Chemistry

et al. 2003

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Mononuclear iron(III) species with end-on and side-on peroxide have been proposed or identified in the catalytic cycles of the antitumor drug bleomycin and a variety of enzymes, such as cytochrome P450 and Rieske dioxygenases. Only recently have biomimetic analogues of such reactive species been generated and characterized at low temperatures. We report the synthesis and characterization of a series of iron(II) complexes with pentadentate N5 ligands that react with H 2 O 2 to generate transient low-spin Fe III −OOH intermediates. These intermediates have low-spin iron(III) centers exhibiting hydroperoxo-to-iron(III) charge-transfer bands in the 500−600-nm region. Their resonance Raman frequencies, ν O-O , near 800 cm -1 are significantly lower than those observed for high-spin counterparts. The hydroperoxo-to-iron(III) charge-transfer transition blue-shifts and the ν O-O of the Fe−OOH unit decreases as the N5 ligand becomes more electron donating. Thus, increasing electron density at the low-spin Mononuclear iron(III) peroxide species are implicated as intermediates in the mechanisms of oxygen activating biomolecules such as cytochrome P450, 1 heme oxygenase, 2 the antitumor drug bleomycin, 3 and Rieske dioxygenases, 4,5 as well as superoxide reductases from anaerobic bacteria. [6][7][8][9] Experimental evidence for some of these intermediates has

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Crystal Structure Analysis of a Synthetic Non‐Heme DiironO₂ Adduct: Insight into the Mechanism of Oxygen Activation

Cited by 196 publications

References 41 publications

Human deoxyhypusine hydroxylase, an enzyme involved in regulating cell growth, activates O ₂ with a nonheme diiron center

Human deoxyhypusine hydroxylase, an enzyme involved in regulating cell growth, activates O ₂ with a nonheme diiron center

Quantum Chemical Studies on Dioxygen Activation and Methane Hydroxylation by Diiron and Dicopper Species as well as Related Metal–Oxo Species

End-On and Side-On Peroxo Derivatives of Non-Heme Iron Complexes with Pentadentate Ligands: Models for Putative Intermediates in Biological Iron/Dioxygen Chemistry

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Crystal Structure Analysis of a Synthetic Non‐Heme DiironO2 Adduct: Insight into the Mechanism of Oxygen Activation

Cited by 196 publications

References 41 publications

Human deoxyhypusine hydroxylase, an enzyme involved in regulating cell growth, activates O 2 with a nonheme diiron center

Human deoxyhypusine hydroxylase, an enzyme involved in regulating cell growth, activates O 2 with a nonheme diiron center

Quantum Chemical Studies on Dioxygen Activation and Methane Hydroxylation by Diiron and Dicopper Species as well as Related Metal–Oxo Species

End-On and Side-On Peroxo Derivatives of Non-Heme Iron Complexes with Pentadentate Ligands: Models for Putative Intermediates in Biological Iron/Dioxygen Chemistry

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Crystal Structure Analysis of a Synthetic Non‐Heme DiironO₂ Adduct: Insight into the Mechanism of Oxygen Activation

Human deoxyhypusine hydroxylase, an enzyme involved in regulating cell growth, activates O ₂ with a nonheme diiron center

Human deoxyhypusine hydroxylase, an enzyme involved in regulating cell growth, activates O ₂ with a nonheme diiron center