Structural and Spectroscopic Characterization of (μ-Hydroxo or μ-Oxo)(μ-peroxo)diiron(III) Complexes:  Models for Peroxo Intermediates of Non-Heme Diiron Proteins

Zhang, Xi; Furutachi, Hideki; Fujinami, Shuhei; Nagatomo, Shigenori; Maeda, Yonezo; Watanabe, Yoshihito; Kitagawa, Teizo; Suzuki, Masatatsu

doi:10.1021/ja045594a

Cited by 89 publications

(129 citation statements)

References 13 publications

(33 reference 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.

107

140

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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.

107

140

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“…In 2005 systematic investigations by Suzuki et al provided deeper insights into the spectroscopic behaviour of peroxidodiironA C H T U N G T R E N N U N G (III) compounds. [32] They found that the IR spectroscopic properties can sensitively depend on subtle changes in the coordination spheres of the iron centres. So, for instance the data recorded for the two similar complexes 5 and 6 (Scheme 4), which only differ from each other in one bridging ligand (oxido vs. hydroxido) vary significantly.…”

mentioning

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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“…n [197], pz' ¼ 3,5-bis(isopropyl)-pyrazolyl. o [198], BPP ¼ N,N-bis(2-pyridylmethyl)-3-aminopropionate.…”

Section: Dimetallic Activation Of O 2 and Methanementioning

confidence: 99%

Methane Monooxygenase: Functionalizing Methane at Iron and Copper

Sazinsky

Lippard

2014

Sustaining Life on Planet Earth: Metalloenzymes Mastering Dioxygen and Other Chewy Gases

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Methane monooxygenases (MMOs) catalyze the conversion of methane to methanol as the first committed step in the assimilation of this hydrocarbon into biomass and energy by methanotrophs, thus playing a significant role in the biogeochemistry of this potent greenhouse gas. Two distinct enzymes, a copper-dependent membrane protein, particulate methane monooxygenase (pMMO), and an iron-dependent cytosolic protein, soluble methane monooxygenase (sMMO), carry out this transformation using large protein scaffolds that help to facilitate the timely transport of hydrocarbon, O₂, proton, and electron substrates to buried dimetallic active sites. For both enzymes, reaction of the reduced metal centers with O₂leads to intermediates that activate the relatively inert C-H bonds of hydrocarbons to yield oxidized products. Among synthetic and biological catalysts, MMOs are unique because they are the only ones known to hydroxylate methane at ambient temperatures. As a need for new industrial catalysts and green chemical transformations increases, understanding how the different MMO metal centers efficiently accomplish this challenging chemistry has become the focus of intense study. This chapter examines current understanding of the sMMO and pMMO protein structures, their methods for substrate channeling, and mechanisms for the dimetallic activation of O₂and C-H bonds.

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Structural and Spectroscopic Characterization of (μ-Hydroxo or μ-Oxo)(μ-peroxo)diiron(III) Complexes: Models for Peroxo Intermediates of Non-Heme Diiron Proteins

Cited by 89 publications

References 13 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

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

Methane Monooxygenase: Functionalizing Methane at Iron and Copper

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Structural and Spectroscopic Characterization of (μ-Hydroxo or μ-Oxo)(μ-peroxo)diiron(III) Complexes: Models for Peroxo Intermediates of Non-Heme Diiron Proteins

Cited by 89 publications

References 13 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

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

Methane Monooxygenase: Functionalizing Methane at Iron and Copper

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Product

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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