Structure/function correlations over binuclear non-heme iron active sites

Solomon, Edward I.; Park, Kiyoung

doi:10.1007/s00775-016-1372-9

Cited by 29 publications

(36 citation statements)

References 127 publications

(122 reference statements)

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“…11 Our finding is not in agreement with this report. The Mössbauer spectra of Figure 7 clearly indicate a large value of J for FDP red and deflavo-FDP red .…”

Section: Discussioncontrasting

confidence: 99%

“…11,12 Prototypical examples are ribonucleotide reductase (RNR), methane monooxygenase (MMO), and hemerythrin (Hr). These active sites contain a diiron center, bridged by either one or two carboxylates, and a solvent-derived ligand (oxo, hydroxo, or aqua).…”

Section: Introductionmentioning

confidence: 99%

“…13 More recent examples of 3- and 4His-ligated, carboxylate-bridged diiron sites in O 2 -activating enzymes have been reported. 11,14 The diferrous sites in RNR, MMO, Hr, and FDP all bind NO; 15–17 however, only FDPs have been shown to be competent NORs. Detailed kinetic and spectroscopic investigations of Tm FDP have identified key active site oxidation states and intermediates in the NOR pathway.…”

Section: Introductionmentioning

confidence: 99%

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Spectroscopy and DFT Calculations of a Flavo-diiron Enzyme Implicate New Diiron Site Structures

et al. 2017

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Flavo-diiron proteins (FDPs) are non-heme iron containing enzymes that are widespread in anaerobic bacteria, archaea, and protozoa, serving as the terminal components to dioxygen and nitric oxide reductive scavenging pathways in these organisms. FDPs contain a dinuclear iron active site similar to that in hemerythrin, ribonucleotide reductase, and methane monooxygenase, all of which can bind NO and O2. However, only FDP competently turns over NO to N2O. Here, EPR and Mössbauer spectroscopies allow electronic characterization of the diferric and diferrous species of FDP. The exchange-coupling constant J (Hex = JS1·S2) was found to increase from +20 cm−1 to +32 cm−1 upon reduction of the diferric to the diferrous species, indicative of (1) at least one hydroxo bridge between the iron ions for both states and (2) a change to the diiron core structure upon reduction. In comparison to characterized diiron proteins and synthetic complexes, the experimental values were consistent with a dihydroxo bridged diferric core, which loses one hydroxo bridge upon reduction. DFT calculations of these structures gave values of J and Mössbauer parameters in agreement with experiment. Although the crystal structure shows a hydrogen bond between the iron bound aspartate and the bridging solvent molecule, the DFT calculations of structures consistent with the crystal structure gave calculated values of J incompatible with the spectroscopic results. We conclude that the crystal structure of the diferric state does not represent the frozen solution structure and that a mono-μ-hydroxo diferrous species is the catalytically functional state that reacts with NO and O2. The new EPR spectroscopic probe of the diferric state indicated that the diferric structure of FDP prior to and immediately after turnover with NO are flavin mononucleotide (FMN) dependent, implicating an additional proton transfer role for FMN in turnover of NO.

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“…11 Our finding is not in agreement with this report. The Mössbauer spectra of Figure 7 clearly indicate a large value of J for FDP red and deflavo-FDP red .…”

Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Spectroscopy and DFT Calculations of a Flavo-diiron Enzyme Implicate New Diiron Site Structures

et al. 2017

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“…The reaction coordinate involving the μ -1,1-hydroperoxide has been suggested for the electrophilic aromatic substitution reaction. 3 …”

Section: Results and Analysismentioning

confidence: 99%

Peroxide Activation for Electrophilic Reactivity by the Binuclear Non-heme Iron Enzyme AurF

Park

Kwak

et al. 2017

J. Am. Chem. Soc.

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Binuclear non-heme iron enzymes activate O2 for diverse chemistries that include oxygenation of organic substrates and hydrogen atom abstraction. This process often involves the formation of peroxo-bridged biferric intermediates, only some of which can perform electrophilic reactions. To elucidate the geometric and electronic structural requirements to activate peroxo reactivity, the active peroxo intermediate in 4-aminobenzoate N-oxygenase (AurF) has been characterized spectroscopically and computationally. A magnetic circular dichroism study of reduced AurF shows that its electronic and geometric structures are poised to react rapidly with O2. Nuclear resonance vibrational spectroscopic definition of the peroxo intermediate formed in this reaction shows that the active intermediate has a protonated peroxo bridge. Density functional theory computations on the structure established here show that the protonation activates peroxide for electrophilic/single-electron-transfer reactivity. This activation of peroxide by protonation is likely also relevant to the reactive peroxo intermediates in other binuclear non-heme iron enzymes.

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“…O 2 activation by the majority of diiron enzymes is initiated by dioxygen binding to a diferrous center, generating a diferric peroxo species [31]. Subsequent O–O bond cleavage generates a high-valent diiron-oxo center (Fe(III)Fe(IV) or Fe(IV) 2 ) that effects substrate oxidation [5, 32], but the detailed steps in the mechanisms by which the O–O unit is converted to the active oxidizing species remains unclear.…”

Section: Introductionmentioning

confidence: 99%

X-ray absorption spectroscopic characterization of the diferric-peroxo intermediate of human deoxyhypusine hydroxylase in the presence of its substrate eIF5a

Jasniewski

Engstrom

et al. 2016

J Biol Inorg Chem

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Human deoxyhypusine hydroxylase (hDOHH) is an enzyme that is involved in the critical post-translational modification of the eukaryotic translation initiation factor 5A (eIF5A). Following the conversion of a lysine residue on eIF5A to deoxyhypusine (Dhp) by deoxyhypusine synthase, hDOHH hydroxylates Dhp to yield the unusual amino acid residue hypusine (Hpu), a modification that is essential for eIF5A to promote peptide synthesis at the ribosome, among other functions. Purification of hDOHH overexpressed in E. coli affords enzyme that is blue in color, a feature that has been associated with the presence of a peroxo-bridged diiron(III) active site. To gain further insight into the nature of the diiron site and how it may change as hDOHH goes through the catalytic cycle, we have conducted X-ray absorption spectroscopic studies of hDOHH on five samples that represent different species along its reaction pathway. Structural analysis of each species has been carried out, starting with the reduced diferrous state, proceeding through its O2 adduct, and ending with a diferric decay product. Our results show that the Fe•••Fe distances found for the five samples fall within a narrow range of 3.4–3.5 Å, suggesting that hDOHH has a fairly constrained active site. This pattern differs significantly from what has been associated with canonical dioxygen activating nonheme diiron enzymes such as soluble methane monooxygenase and Class 1A ribonucleotide reductases, for which the Fe•••Fe distance can change by as much as 1 Å during the redox cycle. These results suggest that the O2 activation mechanism for hDOHH deviates somewhat from that associated with the canonical nonheme diiron enzymes, opening the door to new mechanistic possibilities for this intriguing family of enzymes.

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Structure/function correlations over binuclear non-heme iron active sites

Cited by 29 publications

References 127 publications

Spectroscopy and DFT Calculations of a Flavo-diiron Enzyme Implicate New Diiron Site Structures

Spectroscopy and DFT Calculations of a Flavo-diiron Enzyme Implicate New Diiron Site Structures

Peroxide Activation for Electrophilic Reactivity by the Binuclear Non-heme Iron Enzyme AurF

X-ray absorption spectroscopic characterization of the diferric-peroxo intermediate of human deoxyhypusine hydroxylase in the presence of its substrate eIF5a

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