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Theoretical studies of mononuclear non-heme iron active sites
Stockholm University, Faculty of Science, Department of Physics.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The quantum chemical investigations presented in this thesis use hybrid density functional theory to shed light on the catalytic mechanisms of mononuclear non-heme iron oxygenases, accommodating a ferrous ion in their active sites. More specifically, the dioxygen activation process and the subsequent oxidative reactions in the following enzymes were studied: tetrahydrobiopterin-dependent hydroxylases, naphthalene 1,2-dioxygenase and α-ketoglutarate-dependent enzymes. In light of many experimental efforts devoted to the functional mimics of non-heme iron oxygenases, the reactivity of functional analogues was also examined.

The computed energetics and the available experimental data served to assess the feasibility of the reaction mechanisms investigated. Dioxygen activation in tetrahydrobiopterin- and α-ketoglutarate-dependent enzymes were found to involve a high-valent iron-oxo species, which was then capable of substrate hydroxylation. In the case of naphthalene 1,2-dioxygenase, the reactivity of an iron(III)-hydroxperoxo species toward the substrate was investigated and compared to the biomimetic counterpart.

Place, publisher, year, edition, pages
Stockholm: Fysikum , 2004. , 86 p.
Keyword [en]
quantum chemistry, enzyme catalysis, iron enzymes
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-103ISBN: 91-7265-857-6 (print)OAI: oai:DiVA.org:su-103DiVA: diva2:189257
Public defence
2004-05-07, sal FA32, AlbaNova universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:00
Opponent
Supervisors
Available from: 2004-04-15 Created: 2004-04-15Bibliographically approved
List of papers
1. Mechanism of Dioxygen Cleavage in Tetrahydrobiopterin-Dependent Amino Acid Hydroxylases
Open this publication in new window or tab >>Mechanism of Dioxygen Cleavage in Tetrahydrobiopterin-Dependent Amino Acid Hydroxylases
2003 (English)In: Chemistry: a European Journal, ISSN 0947-6539, Vol. 9, no 1, 106-115 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-22672 (URN)10.1002/chem.200390006 (DOI)
Note
Part of urn:nbn:se:su:diva-103Available from: 2004-04-15 Created: 2004-04-15 Last updated: 2010-07-27Bibliographically approved
2. Mechanism of Aromatic Hydroxylation by an Activated Fe(IV)=O Core in Tetrahydrobiopterin-Dependent Hydroxylases
Open this publication in new window or tab >>Mechanism of Aromatic Hydroxylation by an Activated Fe(IV)=O Core in Tetrahydrobiopterin-Dependent Hydroxylases
2003 (English)In: Chemistry: a European Journal, ISSN 0947-6539, Vol. 9, no 17, 4055-4067 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-22673 (URN)10.1002/chem.200304768 (DOI)
Note
Part of urn:nbn:se:su:diva-103Available from: 2004-04-15 Created: 2004-04-15 Last updated: 2010-01-18Bibliographically approved
3. A Theoretical Study of the Cis-Dihydroxylation Mechanism in Naphthalene 1,2-dioxygenase
Open this publication in new window or tab >>A Theoretical Study of the Cis-Dihydroxylation Mechanism in Naphthalene 1,2-dioxygenase
2004 (English)In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 9, no 4, 439-452 p.Article in journal (Refereed) Published
Abstract [en]

The catalytic mechanism of naphthalene 1,2-dioxygenase has been investigated by means of hybrid density functional theory. This Rieske-type enzyme, which contains an active site hosting a mononuclear non-heme iron(II) complex, uses dioxygen and two electrons provided by NADH to carry out the cis-dihydroxylation of naphthalene. Since a (hydro)peroxo-iron(III) moiety has been proposed to be involved in the catalytic cycle, it was probed whether and how this species is capable of cis-dihydroxylation of the aromatic substrate. Different oxidation and protonation states of the Fe–O2 complex were studied on the basis of the crystal structure of the enzyme with oxygen bound side-on to iron. It was found that feasible reaction pathways require a protonated peroxo ligand, FeIII–OOH; the deprotonated species, the peroxo-iron(III) complex, was found to be inert toward naphthalene. Among the different chemical patterns which have been explored, the most accessible one involves an epoxide intermediate, which may subsequently evolve toward an arene cation, and finally to the cis-diol. The possibility that an iron(V)-oxo species is formed prior to substrate hydroxylation was also examined, but found to implicate a rather high energy barrier. In contrast, a reasonably low barrier might lead to a high-valent iron-oxo species [i.e. iron(IV)-oxo] if a second external electron is supplied to the mononuclear iron center before dioxygenation.

Keyword
Density functional calculations, Enzyme catalysis, Non-heme iron enzymes, O–O bond activation
Identifiers
urn:nbn:se:su:diva-22674 (URN)10.1007/s00775-004-0537-0 (DOI)
Note
Part of urn:nbn:se:su:diva-103Available from: 2004-04-15 Created: 2004-04-15 Last updated: 2017-12-13Bibliographically approved
4. Oxygen Activation by Rieske Non-Heme Iron Oxygenases, a Theoretical Insight
Open this publication in new window or tab >>Oxygen Activation by Rieske Non-Heme Iron Oxygenases, a Theoretical Insight
2004 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 108, no 34, 13031-13041 p.Article in journal (Refereed) Published
Abstract [en]

The first steps of dioxygen activation in naphthalene 1,2-dioxygenase have been investigated by means of hybrid density functional theory. Reduction of molecular oxygen by this Rieske dioxygenase occurs in the catalytic domain accommodating a mononuclear non-heme iron(II) complex, and it requires two external electrons ultimately delivered by a Rieske [2Fe−2S] cluster hosted in the neighboring domain. Theoretical tools have been applied to gain insight into the O2-binding step and into the first one-electron-transfer process involving the mononuclear and the Rieske centers, and yielding an iron(II)−superoxo intermediate. The reaction, which is mimicked with a model including both metal sites, is found to be a reversible equilibrium. Although the entropic loss associated with the binding of O2 to iron(II) is not canceled by the corresponding enthalpic binding energy, it is, however, balanced by the exothermicity of the electron transfer process from the Rieske cluster to the dioxygen-bound iron(II) complex. The rationalization for the calculated energetics is related to the values of the ionization potential (IP) of the Rieske cluster and the electron affinity (EA) of the mononuclear iron complex: the latter is computed to be higher than the former, when dioxygen is bound to the metal. The possibility that a second external electron is delivered to the mononuclear site before dioxygenation of the substrate has also been examined. It is shown that, if the second electron is available in the Rieske domain, the electron transfer process is energetically favored. The results acquired with the large model comprising the two metal centers are compared to the corresponding information collected from the study of smaller models, where either the mononuclear iron complex or the Rieske cluster is included.

Identifiers
urn:nbn:se:su:diva-22675 (URN)10.1021/jp048515q (DOI)
Note
Part of urn:nbn:se:su:diva-103Available from: 2004-04-15 Created: 2004-04-15 Last updated: 2017-12-13Bibliographically approved
5. Mechanism of Dioxygen Activation in 2-Oxoglutarate Dependent Enzymes: A Hybrid DFT Study
Open this publication in new window or tab >>Mechanism of Dioxygen Activation in 2-Oxoglutarate Dependent Enzymes: A Hybrid DFT Study
2004 (English)In: Chemistry: a European Journal, ISSN 0947-6539, Vol. 10, 1031-1041 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-22676 (URN)10.1002/chem.200305306 (DOI)
Note
Part of urn:nbn:se:su:diva-103Available from: 2004-04-15 Created: 2004-04-15 Last updated: 2010-01-18Bibliographically approved
6. A Hybrid Density Functional Study of O-O Bond Cleavage and Phenyl Ring Hydroxylation for a Biomimetic Non-Heme Iron Complex
Open this publication in new window or tab >>A Hybrid Density Functional Study of O-O Bond Cleavage and Phenyl Ring Hydroxylation for a Biomimetic Non-Heme Iron Complex
2004 (English)In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 43, no 10, 3277-3291 p.Article in journal (Refereed) Published
Abstract [en]

Density functional calculations using the B3LYP functional have been used to study the reaction mechanism of [Fe(TpPh2)BF] (TpPh2 = hydrotris(3,5-diphenylpyrazol-1-yl)borate; BF = benzoylformate) with dioxygen. This mononuclear non-heme iron(II) complex was recently synthesized, and it proved to be the first biomimetic complex reproducing the dioxygenase activity of α-ketoglutarate-dependent enzymes. Moreover, the enthalpy and entropy of activation for this biologically interesting process were derived from kinetic experiments offering a unique possibility for direct comparison of theoretical and experimental data. The results reported here support a mechanism in which oxidative decarboxylation of the keto acid is the rate-limiting step. This oxygen activation process proceeds on the septet potential energy surface through a transition state for a concerted O−O and C−C bond cleavage. In the next step, a high-valent iron−oxo species performs electrophilic attack on the phenyl ring of the TpPh2 ligand leading to an iron(III)−radical σ-complex. Subsequent proton-coupled electron-transfer yields an iron(II)−phenol intermediate, which can bind dioxygen and reduce it to a superoxide radical. Finally, the protonated superoxide radical leaves the first coordination sphere of the iron(III)−phenolate complex and dismutates to dioxygen and hydrogen peroxide. The calculated activation barrier (enthalpy and entropy) and the overall reaction energy profile agree well with experimental data. A comparison to the enzymatic process, which is suggested to occur on the quintet surface, has been made.

Identifiers
urn:nbn:se:su:diva-22677 (URN)10.1021/ic035395c (DOI)
Note
Part of urn:nbn:se:su:diva-103Available from: 2004-04-15 Created: 2004-04-15 Last updated: 2017-12-13Bibliographically approved
7. A Density Functional Study of O-O Bond Cleavage for a Biomimetic Non-Heme Iron Complex Demonstrating an Fe(V)-Intermediate
Open this publication in new window or tab >>A Density Functional Study of O-O Bond Cleavage for a Biomimetic Non-Heme Iron Complex Demonstrating an Fe(V)-Intermediate
2002 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 124, no 37, 11056-11063 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-22678 (URN)10.1021/ja026488g (DOI)
Note
Part of urn:nbn:se:su:diva-103Available from: 2004-04-15 Created: 2004-04-15 Last updated: 2017-12-13Bibliographically approved
8. A Density Functional Study of a Biomimetic Non-Heme Iron Catalyst: Insights into Alkane Hydroxylation and Olefin Oxidation by a Formally HO-Fe(V)=O Oxidant
Open this publication in new window or tab >>A Density Functional Study of a Biomimetic Non-Heme Iron Catalyst: Insights into Alkane Hydroxylation and Olefin Oxidation by a Formally HO-Fe(V)=O Oxidant
2004 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 11, no 2, 692-705 p.Article in journal (Refereed) Published
Abstract [en]

The reactivity of [HO(tpa)FeVO] (TPA=tris(2-pyridylmethyl)amine), derived from OO bond heterolysis of its [H2O(tpa)FeIIIOOH] precursor, was explored by means of hybrid density functional theory. The mechanism for alkane hydroxylation by the high-valent iron–oxo species invoked as an intermediate in Fe(tpa)/H2O2 catalysis was investigated. Hydroxylation of methane and propane by HOFeVO was studied by following the rebound mechanism associated with the heme center of cytochrome P450, and it is demonstrated that this species is capable of stereospecific alkane hydroxylation. The mechanism proposed for alkane hydroxylation by HOFeVO accounts for the experimentally observed incorporation of solvent water into the products. An investigation of the possible hydroxylation of acetonitrile (i.e., the solvent used in the experiments) shows that the activation energy for hydrogen-atom abstraction by HOFeVO is rather high and, in fact, rather similar to that of methane, despite the similarity of the HCH2CN bond strength to that of the secondary CH bond in propane. This result indicates that the kinetics of hydrogen-atom abstraction are strongly affected by the cyano group and rationalizes the lack of experimental evidence for solvent hydroxylation in competition with that of substrates such as cyclohexane.

Keyword
density functional calculations, homogeneous catalysis, hydroxylation, iron
National Category
Physical Sciences
Identifiers
urn:nbn:se:su:diva-22679 (URN)10.1002/chem.200400383 (DOI)
Available from: 2004-04-15 Created: 2004-04-15 Last updated: 2017-12-13Bibliographically approved
9. Theoretical Studies on Olefin Oxidation by Biomimetic Non-Heme Iron(III)-Hydroperoxo Complexes
Open this publication in new window or tab >>Theoretical Studies on Olefin Oxidation by Biomimetic Non-Heme Iron(III)-Hydroperoxo Complexes
(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-22680 (URN)
Note
Part of urn:nbn:se:su:diva-103Available from: 2004-04-15 Created: 2004-04-15 Last updated: 2010-01-18Bibliographically approved

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