Spectroscopic and Computational Characterization of the NO Adduct of Substrate-Bound Fe(II) Cysteine Dioxygenase: Insights into the Mechanism of O<sub>2</sub> Activation

Blaesi, Elizabeth J.; Gardner, Jessica D.; Fox, Brian G.; Brunold, Thomas C.

doi:10.1021/bi400825c

Cited by 34 publications

(87 citation statements)

References 63 publications

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“…[114,115] O2 activation [116,117] and the preceding required water dissociation [118] was also investigated in the tetrahydrobiopterin-iron amino acid hydroxylases.…”

Section: Miscellaneous Monoiron Systemsmentioning

confidence: 99%

“…Figure 10: Proposed mechanism of CDO. [114] It was earlier predicted by the theoretical calculations [142,201] that S = 2 Fe IV =O species are more reactive in the oxidative reactions than their S = 1 analogues. It should be, however, noted that the direct experimental evidence is still lacking.…”

Section: Mononuclear Ferryl Active Sitementioning

confidence: 99%

“…[168] The inability to bind O2 was found to be the reason why CDO does not convert selenocysteine into the corresponding seleninic acid. [114] In dimanganese class Ib ribonucleotide reductase, the rate by which the H2O2 oxidant is supplied seems to be of key importance in the selectivity toward the native tyrosyl radical generation instead of the possible catalase activity. [239] …”

Section: Chemoselectivitymentioning

confidence: 99%

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Mono- and binuclear non-heme iron chemistry from a theoretical perspective

et al. 2016

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In this minireview, we provide an account of the current state-of-the-art developments in the area of mono-and binuclear non-heme enzymes (NHFe and NHFe2) and the smaller NHFe(2) synthetic models, mostly from a theoretical and computational perspective. The sheer complexity, and at the same time the beauty, of the NHFe(2) world represent a challenge for both experimental as well as theoretical methods. We emphasize that the concerted progress on both theoretical and experimental side is a conditio sine qua non for future understanding, exploration and utilization of the NHFe(2) systems.After briefly discussing the current challenges and advances in the computational methodology, we review the recent spectroscopic and computational studies of NHFe(2) enzymatic and inorganic systems and highlight the correlations between various experimental data (spectroscopic, kinetic, thermodynamic, electrochemical) and computations. Throughout, we attempt to keep in mind the most fascinating and attractive phenomenon in the NHFe(2) chemistry which is the fact that despite the strong oxidative power of many reactive intermediates, the NHFe(2) enzymes perform catalysis with high selectivity. We conclude with our personal viewpoint and hope that further developments in quantum chemistry and especially in the field of multireference wave function methods are needed to have a solid theoretical basis for the NHFe(2) studies, mostly by providing benchmarking and calibration of the computationally efficient and easy-to-use DFT methods.

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“…[114,115] O2 activation [116,117] and the preceding required water dissociation [118] was also investigated in the tetrahydrobiopterin-iron amino acid hydroxylases.…”

Section: Miscellaneous Monoiron Systemsmentioning

confidence: 99%

Section: Mononuclear Ferryl Active Sitementioning

confidence: 99%

Section: Chemoselectivitymentioning

confidence: 99%

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Mono- and binuclear non-heme iron chemistry from a theoretical perspective

et al. 2016

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“…Like PDO, the reaction mechanism of isopencillin N-synthase involves Fe-S-peptide interactions as the linear cysteinyl-tripeptide substrate is transformed into isopenicillin N via desaturative ring closure and concomitant reduction of O 2 to water (22). Fe-SCys interactions are also important in the cysteine dioxygenase-catalyzed dioxygenation of cysteine to cysteinesulfinic acid (23). Both isopencillin Nsynthase and cysteine dioxygenase involve Fe-SCH 2 R complexes versus an Fe-S-SCH 2 R complex in PDO.…”

Section: Discussionmentioning

confidence: 99%

Mechanism-based inhibition of human persulfide dioxygenase by γ-glutamyl-homocysteinyl-glycine

Kabil

Motl

Strack

et al. 2018

Journal of Biological Chemistry

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Hydrogen sulfide (H 2 S) is a signaling molecule with many beneficial effects. However, its cellular concentration is strictly regulated to avoid toxicity. Persulfide dioxygenase (PDO or ETHE1) is a mononuclear non-heme ironcontaining protein in the sulfide oxidation pathway catalyzing the conversion of glutathione persulfide (GSSH) to sulfite and glutathione. PDO mutations result in the autosomal recessive disorder, ethylmalonic encephalopathy (EE). Here, we developed γ-glutamyl-homocysteinyl-glycine (GHcySH) in which the cysteinyl moiety in glutathione is substituted with homocysteine, as a mechanismbased PDO inhibitor. Human PDO used GHcySH as an alternate substrate and converted it to GHcy-SO 2 H, mimicking GS-SO 2 H, the putative oxygenated intermediate formed with the natural substrate. Since GHcy-SO 2 H contains a C-S bond rather than an S-S bond in GS-SO 2 H, it failed to undergo the final hydrolysis step in the catalytic cycle, leading to PDO inhibition. We also characterized the biochemical penalties incurred by the L55P, T136A, C161Y and R163W mutations reported in EE patients. The variants displayed lower iron content (1.4-to 11-fold) and lower thermal stability (1.2-to 1.7-fold) than wild-type PDO. They also exhibited varying degrees of catalytic impairment; the k cat /K m values for R163W, L55P and C161Y PDOs were 18-, 42-and 65-fold lower, respectively and the T136A variant was most affected with a 200-fold lower k cat /K m . Like wild-type enzyme, these variants were inhibited by GHcySH. This study provides the first characterization of an intermediate in the PDO-catalyzed reaction and reports on deficits associated with EE-linked mutations that are distal from the active site.Ethylmalonic encephalopathy (EE) 1 is an autosomal recessive disorder that is associated with pathological effects in the brain, gastrointestinal tract and peripheral vessels (1-3). It results in acrocyanosis, petechiae, hemorrhagic diarrhea, developmental delay and progressive neurological failure leading to necrotic lesions in the deep gray matter of the brain. Patients with EE usually succumb to the disease within the first decade of life (4). The clinical profile of EE includes elevated ethylmalonic acid in urine, C4 and C5 acrylcarnitines in blood and a deficiency of cytochrome c oxidase in brain and muscle (5). EE is caused by mutations in the ethe1 gene that encodes persulfide dioxygenase (PDO or ETHE1). Over 20 mutations have been described in the ethe1 gene, of which a subset represents missense mutations (3,4,6).PDO is a mitochondrial matrix protein that participates in the mitochondrial sulfide oxidation pathway, which converts H 2 S to the end products, thiosulfate and sulfate (7,8). In addition to PDO, the other enzymes involved in the mitochondrial sulfur oxidation pathway are sulfide quinone oxidoreductase (9), rhodanese (10), and sulfite oxidase (11). PDO catalyzes the second step in the pathway, i.e. the oxidation of glutathione persulfide (GSSH) to sulfite (Eq. 1) (12). Sulfite is either oxidized b...

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“…NO can be regarded as an important cellular signaling molecule involved in many physiological and pathological processes. The interaction of NO with iron centers of hemoproteins [24] and nonheme enzymes with cysteine environment [25] plays an important role in its biological activity. To put it simply, the formation of a Fe(L)-NO bond (L means ligand) triggers the opening of a blood vessel.…”

Section: Reactive System Fe II (No)mentioning

confidence: 99%

Reactive Mass Transfer of Single NO Bubbles and Bubble Bouncing in Aqueous Ferric Solutions – A Feasibility Study

Hlawitschka

Oßberger

Backes

et al. 2017

Oil Gas Sci. Technol. – Rev. IFP Energies nouvelles

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-Reactive bubble columns are widely used in the chemical, petrochemical, biochemical and metal industries. While the reactive mass transfer around a single spherical shaped bubble is quite well described in literature, the influence of hydrodynamic interactions, such as bubble bouncing or coalescence on mass transfer -with and without chemical reaction -is not well understood. As to this, high resolution simulations and sophisticated experimental analysis based on high-speed camera images and local color changes gives a new firm basis. In this work, a new system is presented, based on Nitric Oxide (NO) gas absorbed in a Fe II -solution. The reaction rate can be adjusted by the addition of ligands and the resulting local color change is detected. The impact of the colliding bubbles leads to a deformation of the bubble shapes and creates a fast movement of the bubble interfaces, which, finally, leads to an increased mass transfer. The results of five tested ligands reveal the high potential of the reactive Fe II (NO) system to investigate basic phenomena affecting yield and selectivity of mixing-sensitive chemical reactions.Résumé -Transfert de masse réactive de bulles simples et de bulles rebondissantes dans les solutions ferriques aqueuses -Une étude de faisabilité -Les colonnes à bulles réactives sont largement utilisées dans les industries chimiques, pétrochimiques, biochimiques et métalliques. Bien que le transfert de masse réactif autour d'une seule bulle de forme sphérique soit assez bien décrit dans la littérature, l'influence des interactions hydrodynamiques, comme le rebond des bulles ou la coalescence sur le transfert de masse -avec ou sans réaction chimique -n'est pas bien comprise. Pour ce faire, des simulations de haute résolution et des analyses expérimentales sophistiquées basées sur des images de caméras à haute vitesse et des changements de couleur locaux donnent une nouvelle base solide. Dans ce travail, un nouveau système est présenté, basé sur l'oxyde nitrique (NO) gazeux absorbé dans une solution de Fe II . La vitesse de réaction peut être ajustée par addition de ligands et le changement de couleur local résultant est détecté. L'impact des bulles de collision entraîne une déformation des formes de bulles et crée un mouvement rapide des interfaces de bulles, ce qui conduit finalement à un transfert de masse accru. Les résultats de cinq ligands testés révèlent le haut potentiel du système réactif Fe II (NO) pour étudier les phénomènes fondamentaux affectant le rendement et la sélectivité des réactions chimiques sensibles au mélange.

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Spectroscopic and Computational Characterization of the NO Adduct of Substrate-Bound Fe(II) Cysteine Dioxygenase: Insights into the Mechanism of O₂ Activation

Cited by 34 publications

References 63 publications

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

Mechanism-based inhibition of human persulfide dioxygenase by γ-glutamyl-homocysteinyl-glycine

Reactive Mass Transfer of Single NO Bubbles and Bubble Bouncing in Aqueous Ferric Solutions – A Feasibility Study

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Spectroscopic and Computational Characterization of the NO Adduct of Substrate-Bound Fe(II) Cysteine Dioxygenase: Insights into the Mechanism of O2 Activation

Cited by 34 publications

References 63 publications

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

Mechanism-based inhibition of human persulfide dioxygenase by γ-glutamyl-homocysteinyl-glycine

Reactive Mass Transfer of Single NO Bubbles and Bubble Bouncing in Aqueous Ferric Solutions – A Feasibility Study

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Spectroscopic and Computational Characterization of the NO Adduct of Substrate-Bound Fe(II) Cysteine Dioxygenase: Insights into the Mechanism of O₂ Activation