<i>cis</i>-μ-1,2-Peroxo Diiron Complex:  Structure and Reversible Oxygenation

Ookubo, Akira; Sugimoto, Ayumi; Nagayama, Ariaki; Masuda, b Hideki; Sato, Chizuko; Tanaka, Daichi; Maeda, E.; Ōkawa, e Hisashi; Hayashi, Yoshihito; Uehara, Akira; Suzuki, Akihito

doi:10.1021/ja953705n

Cited by 221 publications

(227 citation statements)

References 22 publications

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“…The two Fe(III) ions are bridged by two carboxylates and one peroxo dianion. Figure 10 reproduces the structure of [Fe 2 (O 2 )(Ph-bimp)(OBz)] 2+ found by Ookubo et al [44]. This complex uses the assembling heptadentate, monoanionic, ligand Ph-bimp ) .…”

Section: Peroxo Bridged Diiron Units Fe(iii)oofe(iii)supporting

confidence: 74%

Characterization and Properties of Non-Heme Iron Peroxo Complexes

Girerd

Banse

Simaan

2000

Structure and Bonding

154

168

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Section: Peroxo Bridged Diiron Units Fe(iii)oofe(iii)supporting

confidence: 74%

Characterization and Properties of Non-Heme Iron Peroxo Complexes

Girerd

Banse

Simaan

2000

Structure and Bonding

154

168

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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.

107

141

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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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“…[23] Between the end of the 1980s and the beginning of the 1990s a large number of diiron(II) compounds resembling the active centre of the MMOH red were synthesised and investigated with respect to their reactivity towards dioxygen, [24,25] but it took several more years until the successful crystallisation of the primary product of such a reaction: In 1996 Suzuki et al reported the first molecular structure of a complex exhibiting a m-peroxido-mcarboxylatodiironA C H T U N G T R E N N U N G (III) unit. [26] While various different complexes with this structural motif had been characterised previously in solution, [25] the isolation of such a compound and its structural authentication represented a major breakthrough: The exposure of a solution of [(Ph-BIMP)Fe 2 - …”

Section: Structural Models Containing Bioinspired Highvalent Oxidodiimentioning

confidence: 99%

“…[13,30] The UV/Vis spectrum of 2 in acetonitrile shows a broad absorption band between 800 and 500 nm, [26] while…”

Section: Structural Models Containing Bioinspired Highvalent Oxidodiimentioning

confidence: 99%

Low‐Molecular‐Weight Analogues of the Soluble Methane Monooxygenase (sMMO): From the Structural Mimicking of Resting States and Intermediates to Functional Models

Siewert

Limberg

2009

Chemistry A European J

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The active centre of sMMO contains a diiron core ligated by histidine and glutamate residues, which is capable of catalysing a remarkable reaction: the oxidation of methane with O(2) yielding methanol. This review describes the results of efforts to prepare low-molecular-weight analogues of this active site directing towards 1) the assignment of the spectroscopic signatures identified for certain intermediates of the sMMO catalytic cycle to structural features and 2) the synthesis of molecular compounds that can mimic the reactivity. The historical development of the model chemistry, which is subdivided into structural and functional mimicking, is illustrated and achievements reached so far are highlighted.

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cis-μ-1,2-Peroxo Diiron Complex: Structure and Reversible Oxygenation

Cited by 221 publications

References 22 publications

Characterization and Properties of Non-Heme Iron Peroxo Complexes

Characterization and Properties of Non-Heme Iron Peroxo Complexes

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

Low‐Molecular‐Weight Analogues of the Soluble Methane Monooxygenase (sMMO): From the Structural Mimicking of Resting States and Intermediates to Functional Models

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cis-μ-1,2-Peroxo Diiron Complex: Structure and Reversible Oxygenation

Cited by 221 publications

References 22 publications

Characterization and Properties of Non-Heme Iron Peroxo Complexes

Characterization and Properties of Non-Heme Iron Peroxo Complexes

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

Low‐Molecular‐Weight Analogues of the Soluble Methane Monooxygenase (sMMO): From the Structural Mimicking of Resting States and Intermediates to Functional Models

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