DFT Study on the Catalytic Reactivity of a Functional Model Complex for Intradiol-Cleaving Dioxygenases

Georgiev, Valentin; Noack, Holger; Borowski, Tomasz; Blomberg, Margareta R. A.; Siegbahn, Per E. M.

doi:10.1021/jp911217j

Cited by 25 publications

(30 citation statements)

References 33 publications

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“…In our in crystallo studies of 2,3-HPCD, a substrate radical-Fe 2+ -superoxo intermediate precedes the alkylperoxo species (29). Similar discrete precursor complexes, such as a substrate radical-Fe 2+ or substrate radicalFe 3+ -superoxo species, have been proposed in previous studies of the IDOs and models (22,36,37). Although not definitive, we find no evidence for these species in the IDO crystal.…”

Section: Relationship To Spectroscopic and Computational Studies Of Tsupporting

confidence: 69%

“…One possibility supported by computational studies is that the alignment of the O-O bond relative to the scissile bonds of the substrate determines whether acyl (intradiol) or alkenyl (extradiol) migration occurs during the rearrangement. Migration proceeds preferentially into the coplanar bond (22,37). Comparison of the geometries of the EDO and IDO alkylperoxo intermediates shows that they differ substantially in the O-O and C-C bond alignments primarily because the substrate bonding to the iron is not the same.…”

Section: Relationship To Spectroscopic and Computational Studies Of Tmentioning

confidence: 99%

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Crystal structures of alkylperoxo and anhydride intermediates in an intradiol ring-cleaving dioxygenase

Knoot

Purpero

Lipscomb

2014

Proc. Natl. Acad. Sci. U.S.A.

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Intradiol aromatic ring-cleaving dioxygenases use an active site, nonheme Fe 3+ to activate O 2 and catecholic substrates for reaction. The inability of Fe 3+ to directly bind O 2 presents a mechanistic conundrum. The reaction mechanism of protocatechuate 3,4-dioxygenase is investigated here using the alternative substrate 4-fluorocatechol. This substrate is found to slow the reaction at several steps throughout the mechanistic cycle, allowing the intermediates to be detected in solution studies. When the reaction was initiated in an enzyme crystal, it was found to halt at one of two intermediates depending on the pH of the surrounding solution. The X-ray crystal structure of the intermediate at pH 6.5 revealed the key alkylperoxo-Fe 3+ species, and the anhydride-Fe 3+ intermediate was found for a crystal reacted at pH 8.5. Intermediates of these types have not been structurally characterized for intradiol dioxygenases, and they validate four decades of spectroscopic, kinetic, and computational studies. In contrast to our similar in crystallo crystallographic studies of an Fe 2+ -containing extradiol dioxygenase, no evidence for a superoxo or peroxo intermediate preceding the alkylperoxo was found. This observation and the lack of spectroscopic evidence for an Fe 2+ intermediate that could bind O 2 are consistent with concerted formation of the alkylperoxo followed by Criegee rearrangement to yield the anhydride and ultimately ringopened product. Structural comparison of the alkylperoxo intermediates from the intra-and extradiol dioxygenases provides a rationale for site specificity of ring cleavage.dioxygenase | oxygen activation | X-ray crystallography | reaction intermediate | Fe (III)

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Section: Relationship To Spectroscopic and Computational Studies Of Tsupporting

confidence: 69%

Section: Relationship To Spectroscopic and Computational Studies Of Tmentioning

confidence: 99%

Crystal structures of alkylperoxo and anhydride intermediates in an intradiol ring-cleaving dioxygenase

Knoot

Purpero

Lipscomb

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Using models of intradiol dioxygenase enzymes, several aspects of intradiol cleavage were addressed, including partial dissociation of the substrate to allow O2 activation on the metal, [103] stereoelectronic reasons for intradiol selectivity, [ 104 ] and the possible non-innocence of the coordinating tyrosine ligand.…”

Section: Ring-cleaving Dioxygenasesmentioning

confidence: 99%

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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“…[15] Now the crucial question is what determines the positiono ft he oxygen insertion when ostensibly the same alkylperoxo intermediate is generated from each class? [17] The geometries of the extradiol and intra-diol alkylperoxoi ntermediates show that the alignment of the OÀOa nd CÀCb onds differs significantly due to the variance in bindingb etween the Fe andt he substrate. It is suggested, based on computational studies, that the alignment of the OÀOb ond relative to the scissile CÀCb ond controls whether the alkenyl (extradiol) or acyl (intradiol)m igration occurs duringt he rearrangement.…”

Section: Introductionmentioning

confidence: 99%

Catalytic Mechanism of Salicylate Dioxygenase: QM/MM Simulations Reveal the Origin of Unexpected Regioselectivity of the Ring Cleavage

Roy

Kästner

2017

Chemistry A European J

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Salicylate 1,2-dioxygenase (SDO) was the first enzyme discovered, in the family of iron dioxygenases, to catalyze the ring cleavage of a monohydroxylated aromatic compound, salicylate, without a proton donor. Salicylate is not electron-rich like the familiar dihydroxy or aromatic substrates with an electron-donating group that are utilized in the well-known dioxygenases. SDO carries out the intramolecular C-C bond cleavage in salicylate bearing the OH and COOH groups with high regioselectivity in comparison with the extradiol and intradiol dioxygenases. The catalytic cleavage of a nonactivated substrate like salicylate that lacks an electron-donating group, also in the absence of a proton source, raises many puzzling questions about the oxy intermediates in the reaction pathway of dioxygenase enzymes in general. To answer these fundamental queries, we have investigated the full catalytic mechanism of SDO by a combination of quantum mechanics and molecular mechanics (QM/MM) calculations. Herein, our QM/MM study has several unexpected and interesting implications for the mechanistic pathway of SDO in comparison to the experimental observations. Importantly, it unravels the basis for the unexpected "intra"-cleavage regioselectivity in SDO. Ostensibly a similar alkylperoxo intermediate is formed in SDO much like in the extradiol and intradiol dioxygenases. In stark contrast to the two diol enzymes, the O-O bond breaking leads to an unprotonated gem-hydroxy carboxylate intermediate, a paradigm analogue of the elusive gem diol intermediate. This unprotonated gem-hydroxy carboxylate intermediate exclusively dictates the C-C cleavage regiospecificity in SDO, which is unprecedented in the family of dioxygenases. It forms a seven-membered lactone species, which eventually forms the ring-cleavage final product by incorporation of two oxygen atoms in the salicylate. Thus, our computational study unravels a detailed reaction pathway of the oxidative cleavage of salicylate without a proton source by identifying the hitherto elusive intermediates in the catalytic cycle of SDO with testable predictions. Moreover, we describe the atomistic origin of the new catalytic role of Arg127 in the catalysis and regioselectivity of SDO. It also rationalizes the formation of a side product without invoking a dioxetane intermediate. This study is important from a fundamental perspective and opens up a new window in the mechanism of the family of dioxygenase enzymes.

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DFT Study on the Catalytic Reactivity of a Functional Model Complex for Intradiol-Cleaving Dioxygenases

Cited by 25 publications

References 33 publications

Crystal structures of alkylperoxo and anhydride intermediates in an intradiol ring-cleaving dioxygenase

Crystal structures of alkylperoxo and anhydride intermediates in an intradiol ring-cleaving dioxygenase

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

Catalytic Mechanism of Salicylate Dioxygenase: QM/MM Simulations Reveal the Origin of Unexpected Regioselectivity of the Ring Cleavage

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