An iron–oxygen intermediate formed during the catalytic cycle of cysteine dioxygenase

Tchesnokov, Egor P.; Faponle, Abayomi S.; Davies, Casey G.; Quesne, Matthew G.; Turner, Rufus; Fellner, M.; Souness, R.J.; Wilbanks, Sigurd M.; Visser, Sam P. de; Jameson, Guy N. L.

doi:10.1039/c6cc03904a

Cited by 67 publications

(106 citation statements)

References 27 publications

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“…Supporting computational modeling of the transient UV-visible spectra suggest that this transient species is consistent with a cyclic [Fe-O-O-S Cys ]-structure with a quintet ( S = 2) spin state. However, rapid freeze-quench Mössbauer experiments were unable to corroborate this assignment [22]. Therefore, direct spectroscopic validation of the transient intermediate produced during native catalysis is absent.…”

Section: Introductionmentioning

confidence: 99%

Thiol dioxygenase turnover yields benzothiazole products from 2-mercaptoaniline and O2-dependent oxidation of primary alcohols

Morrow

Sardar

Thapa

et al. 2017

Archives of Biochemistry and Biophysics

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Thiol dioxygenases are non-heme mononuclear iron enzymes that catalyze the O2-dependent oxidation of free thiols (-SH) to produce the corresponding sulfinic acid (-SO2−). Previous chemical rescue studies identified a putative FeIII-O2•− intermediate that precedes substrate oxidation in Mus musculus cysteine dioxygenase (Mm CDO). Given that a similar reactive intermediate has been identified in the extradiol dioxygenase 2, 3-HCPD, it is conceivable that these enzymes share other mechanistic features with regard to substrate oxidation. To explore this possibility, enzymatic reactions with Mm CDO (as well as the bacterial 3-mercaptopropionic acid dioxygenase, Av MDO) were performed using a substrate analogue (2-mercaptoaniline, 2ma). This aromatic thiol closely approximates the catecholic substrate of homoprotocatechuate of 2, 3-HPCD while maintaining the 2-carbon thiol-amine separation preferred by Mm CDO. Remarkably, both enzymes exhibit 2ma-gated O2-consumption; however, none of the expected products for thiol dioxygenase or intra/extradiol dioxygenase reactions were observed. Instead, benzothiazoles are produced by the condensation of 2ma with aldehydes formed by an off-pathway oxidation of primary alcohols added to aqueous reactions to solubilize the substrate. The observed oxidation of 1°-alcohols in 2ma-reactions is consistent with the formation of a high-valent intermediate similar to what has been reported for cytochrome P450 and mononuclear iron model complexes.

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Section: Introductionmentioning

confidence: 99%

Thiol dioxygenase turnover yields benzothiazole products from 2-mercaptoaniline and O2-dependent oxidation of primary alcohols

Morrow

Sardar

Thapa

et al. 2017

Archives of Biochemistry and Biophysics

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“…The intermediate could not be further characterized, but time-dependent density functional theory (TD-DFT) calculations predict it to be the peroxo-bridged intermediate that precedes the ferryl oxo/sulfoxide. 29 …”

Section: Introductionmentioning

confidence: 99%

Spectroscopic and Electronic Structure Study of ETHE1: Elucidating the Factors Influencing Sulfur Oxidation and Oxygenation in Mononuclear Nonheme Iron Enzymes

et al. 2018

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ETHE1 is a member of a growing subclass of nonheme Fe enzymes that catalyzes transformations of sulfur containing substrates without a cofactor. ETHE1 dioxygenates glutathione persulfide (GSSH) to glutathione (GSH) and sulfite in a reaction that is similar to that of cysteine dioxygenase (CDO), but with monodentate (vs. biden-tate) substrate coordination and a 2-His/1-Asp (vs. 3-His) ligand set. In this study, we demonstrate that GSS− binds directly to the iron active site causing coordination unsaturation to prime the site for O2 activation. Nitrosyl complexes without and with GSSH were generated and spectroscopically characterized as unreactive analogs for the invoked ferric superoxide intermediate. New spectral features from persulfide binding to the FeIII include the appearance of a low energy FeIII ligand field transition, an energy shift of a NO− to FeIII CT transition, and two new GSS− to FeIII CT transitions. Time-dependent density functional theory calculations were used to simulate the experimental spectra to determine the persulfide orientation. Correlation of these spectral features with those of monodentate cysteine binding in isopenicillin N synthase (IPNS) shows that the persulfide is a poorer donor, but still results in an equivalent frontier molecular orbital for reactivity. The ETHE1 persulfide dioxygenation reaction coordinate was calculated, and while the initial steps are similar to the reaction coordinate of CDO, an additional hydrolysis step is required in ETHE1 to break the S-S bond. Unlike ETHE1 and CDO, which both oxygenate sulfur, IPNS oxidizes sulfur through an initial H-atom abstraction. Thus, factors that determine oxygenase vs. oxidase reactivity were evaluated. In general, sulfur oxygenation is thermodynamically favored and has a lower barrier for reactivity. However, in IPNS, second sphere residues in the active site pocket constrain the substrate raising the barrier for sulfur oxygenation relative to oxidation via H-atom abstraction.

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“…structure A in Figure 3) of cysteine-bound CDO but only the cysteine-CDO would go through the dioxygenation reaction under the appropriate conditions. 82 It was observed that when an anaerobic cysteinebound CDO was titrated with oxygenated buffer at 4°C in a glove-box, this led to the appearance of two absorption peaks at 500 and 640 nm. These peaks were found to scale linearly with concentration of CDO as well as the amount of dioxygen supplied.…”

Section: Short-lived Iron-dioxygen Complex In Cdo Enzymesmentioning

confidence: 99%

“…82 Unfortunately, the intermediate decays in 20 ms and attempts to characterize a short-lived species further, failed, and no indistinguishable EPR and Mössbauer spectra were obtained. Therefore, we resorted to a computational study at the time dependent-density functional theory (TD-DFT) and complete active space -self consistent field (CASSCF) level of theory to establish the nature of the intermediate.…”

Section: Short-lived Iron-dioxygen Complex In Cdo Enzymesmentioning

confidence: 99%

“…The results were further validated with various experimental methods such as chemical quenching and freeze-quench, and thus giving the same outcomes of dioxygenation reactions for anaerobic cysteine-bound CDO. 82 In addition, computational modeling using density functional theory on model complexes as well as quantum mechanics/molecular mechanics studies on the full enzyme, calculated high reaction barriers for formation of the iron(III)-superoxo and the iron(III)-bicyclic ring species, and, therefore, these calculations predicted a finite lifetime of the two complexes B and C. 35,37 On the other hand, formation of the iron-cysteine sulfoxide and iron-cysteine sulfinic acid products is calculated to be strongly exothermic with small barriers of formation and decay. Consequently, the lifetime of these intermediates is expected to be rather short.…”

Section: Short-lived Iron-dioxygen Complex In Cdo Enzymesmentioning

confidence: 99%

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The Role of Nonheme Transition Metal-Oxo, -Peroxo, and -Superoxo Intermediates in Enzyme Catalysis and Reactions of Bioinspired Complexes

Faponle

Visser

2017

Inorganic Reaction Mechanisms

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Transition metals are common co-factors in enzymes and enable catalysis to take place via reaction barriers that are accessible at room temperature. Oxygen activating metalloenzymes are versatile species in Nature involved in vital processes ranging from biodegradation to biosynthesis. Since oxygen activating intermediates are not readily amenable to experimental study, research has started to focus on biomimetic model systems that have the active site coordination sphere and structural features, but react in solution. In our research group, we have been involved in computational modeling of heme and nonheme iron dioxygenases as well as biomimetic models of these complexes. In this contribution an overview is given on recent results of the characterization and reactivity patterns of metaloxo, metal-peroxo and metal-superoxo complexes. In particular, in recent studies attempts were made to trap and characterize the short-lived oxygen bound intermediate in the catalytic cycle of cysteine dioxygenase. Many suggested structures could be ruled out by theoretical considerations, yet these also provided suggestions of possible candidates for the experimentally observed spectra. In addition, we review recent studies on the nonheme iron(III)-hydroperoxo species and how its reactivity patterns with arenes are dramatically different from those found for heme iron(III)-hydroperoxo species. The final two projects show a series of computational studies on manganese(V)-oxo and side-on manganese(III)-peroxo moieties that identify a unique spin state reactivity pattern with a surprising product distribution.3

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An iron–oxygen intermediate formed during the catalytic cycle of cysteine dioxygenase

Abstract: Combined spectroscopic, kinetic and computational studies provide first evidence of a short-lived intermediate in the catalytic cycle of cysteine dioxygenase.

Cited by 67 publications

References 27 publications

Thiol dioxygenase turnover yields benzothiazole products from 2-mercaptoaniline and O2-dependent oxidation of primary alcohols

Thiol dioxygenase turnover yields benzothiazole products from 2-mercaptoaniline and O2-dependent oxidation of primary alcohols

Spectroscopic and Electronic Structure Study of ETHE1: Elucidating the Factors Influencing Sulfur Oxidation and Oxygenation in Mononuclear Nonheme Iron Enzymes

The Role of Nonheme Transition Metal-Oxo, -Peroxo, and -Superoxo Intermediates in Enzyme Catalysis and Reactions of Bioinspired Complexes

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