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Reaction Mechanisms of Metalloenzymes and Synthetic Model Complexes Activating Dioxygen: A Computational study
Stockholm University, Faculty of Science, Department of Physics. (Theoretical Biochemistry)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Quantum chemistry has nowadays become a powerful and efficient tool that can be successfully used for studies of biosystems. It is therefore possibleto model the enzyme active-site and the reactions undergoing into it, as well as obtaining quite accurate energetic profiles. Important conclusions can be drawn from such profiles about the  plausibility of different putative mechanisms.

Density Functional Theory is used in the present thesis for investigation of the catalytic mechanism of dioxygenase metallo-enzymes and synthetic model complexes. Three enzymes were studied – Homoprotocatechuate 2,3-dioxygenase isolated from Brevibacterium fuscum (Bf 2,3-HPCD), Manganese-Dependent Homoprotocatechuate 2,3-Dioxygenase (MndD) and Homogentisate Dioxygenase (HGD). Models consisting of 55 to 208 atoms have been built from X-ray crystal structures and used in the calculations. The computed energies were put in energy curves and were used for estimation of the feasibility of the suggested reaction mechanisms. A non-heme [(L4Me4)Fe(III)]+3 complex that mimics the reactivity of intradiol dioxygenases, and a heme [T(o-Cl)PPFe] complex catalyzing the stepwise oxidation of cyclohexane to adipic acid, were also studied.

For the enzymes and the non-heme biomimetic complex the reaction was found to follow a mechanism that was previously suggested for extradiol and intradiol dioxygenases – ordered substrates binding and formation of peroxo species, which further undergoes homolytic O-O bond cleavage. Different reaction steps appear to be rate limiting in the particular cases: proton transfer from the substrate to the peroxide in Bf 2,3-HPCD, the formation of the peroxo bridge in HGD and the biomimetic complex, and notably, spin transition in MndD.

The catalytic oxidation of cyclohexane to adipic acid in the presence of molecular oxygen as oxidant was studied, a reaction of great importance for the chemical industry. Reaction mechanism is suggested, involving several consecutive oxidative steps. The highest calculated enthalpy of activation is 17.8 kcal/mol for the second oxidative step.

Place, publisher, year, edition, pages
Stockholm: Department of Physics, Stockholm University , 2009. , 104 p.
Keyword [en]
catalysis, density functional theory, extradiol, intradiol, dioxygenases, oxygen, biomimetic complexes, heme, spin transition, adipic acid
National Category
Atom and Molecular Physics and Optics
Research subject
Quantum Chemistry
Identifiers
URN: urn:nbn:se:su:diva-30706ISBN: 978-91-7155-965-4 (print)OAI: oai:DiVA.org:su-30706DiVA: diva2:273747
Public defence
2009-11-20, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, Sweden, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: In progress, Paper 5: In progressAvailable from: 2009-10-28 Created: 2009-10-23 Last updated: 2010-04-09Bibliographically approved
List of papers
1. Catalytic Reaction Mechanism of Homogentisate Dioxygenase: A Hybrid DFT Study
Open this publication in new window or tab >>Catalytic Reaction Mechanism of Homogentisate Dioxygenase: A Hybrid DFT Study
2005 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 127, no 49, 17303-17314 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
American Chemical Society, 2005
National Category
Natural Sciences
Research subject
Chemical Physics
Identifiers
urn:nbn:se:su:diva-30788 (URN)10.1021/ja054433j (DOI)
Available from: 2009-10-26 Created: 2009-10-26 Last updated: 2017-12-12Bibliographically approved
2. A comparison of the reaction mechanisms of iron- and manganese-containing 2,3-HPCD: an important spin transition for manganese
Open this publication in new window or tab >>A comparison of the reaction mechanisms of iron- and manganese-containing 2,3-HPCD: an important spin transition for manganese
2008 (English)In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 13, no 6, 929-40 p.Article in journal (Refereed) Published
Abstract [en]

Homoprotocatechuate (HPCA) dioxygenases are enzymes that take part in the catabolism of aromatic compounds in the environment. They use molecular oxygen to perform the ring cleavage of ortho-dihydroxylated aromatic compounds. A theoretical investigation of the catalytic cycle for HPCA 2,3-dioxygenase isolated from Brevibacterium fuscum (Bf 2,3-HPCD) was performed using hybrid DFT with the B3LYP functional, and a reaction mechanism is suggested. Models of different sizes were built from the crystal structure of the enzyme and were used in the search for intermediates and transition states. It was found that the enzyme follows a reaction pathway similar to that for other non-heme iron dioxygenases, and for the manganese-dependent analog MndD, although with different energetics. The computational results suggest that the rate-limiting step for the whole reaction of Bf 2,3-HPCD is the protonation of the activated oxygen, with an energy barrier of 17.4 kcal/mol, in good agreement with the experimental value of 16 kcal/mol obtained from the overall rate of the reaction. Surprisingly, a very low barrier was found for the O-O bond cleavage step, 11.3 kcal/mol, as compared to 21.8 kcal/mol for MndD (sextet spin state). This result motivated additional studies of the manganese-dependent enzyme. Different spin coupling between the unpaired electrons on the metal and on the evolving substrate radical was observed for the two enzymes, and therefore the quartet spin state potential energy surface of the MndD reaction was studied. The calculations show a crossing between the sextet and the quartet surfaces, and it was concluded that a spin transition occurs and determines a barrier of 14.4 kcal/mol for the O-O bond cleavage, which is found to be the rate-limiting step in MndD. Thus the two 83% identical enzymes, using different metal ions as co-factors, were found to have similar activation energies (in agreement with experiment), but different rate-limiting steps.

Place, publisher, year, edition, pages
Berlin: Springer, 2008
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:su:diva-30694 (URN)10.1007/s00775-008-0380-9 (DOI)000257934500009 ()18458966 (PubMedID)
Available from: 2009-10-26 Created: 2009-10-22 Last updated: 2017-12-12Bibliographically approved
3. Theoretical study of the catalytic reaction mechanism of MndD
Open this publication in new window or tab >>Theoretical study of the catalytic reaction mechanism of MndD
2006 (English)In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 11, no 5, 571-85 p.Article in journal (Refereed) Published
Abstract [en]

Manganese-dependent homoprotocatechuate 2,3-dioxygenase (MndD) is an enzyme taking part in the catabolism of aromatic compounds in the environment. It uses molecular oxygen to perform an extradiol cleavage of the ring of the ortho-dihydroxylated aromatic compound homoprotocatechuate. A theoretical investigation of the reaction path for MndD was performed using hybrid density functional theory with the B3LYP functional, and a catalytic mechanism has been suggested. Models of different size were built from the crystal structure of the enzyme and were used in the search for intermediates and transition states. It was found that the substrate first binds at the active site as a monoanion. Next the dioxygen is bound, forming a hydroperoxo intermediate. The O-O bond, activated in this way undergoes homolytic cleavage leading to an oxyl and then to an extra epoxide radical with subsequent opening of the aromatic ring. The lactone ring is then hydrolyzed by the Mn-bound OH group, and the final product is obtained in the last reaction steps. Alternative reaction paths were considered, and their calculated barriers were found to be higher than for the suggested mechanism. The selectivity between the extra- and intra-cleavage pathways was found to be determined by the barriers for the decay of the radical state.

Place, publisher, year, edition, pages
Berlin: Springer, 2006
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:su:diva-30693 (URN)10.1007/s00775-006-0106-9 (DOI)16791641 (PubMedID)
Available from: 2009-10-26 Created: 2009-10-22 Last updated: 2017-12-12Bibliographically approved
4. A DFT Study on the Catalytic Reactivity of a Functional Model Complex for  Intradiol-Cleaving Dioxygenases
Open this publication in new window or tab >>A DFT Study on the Catalytic Reactivity of a Functional Model Complex for  Intradiol-Cleaving Dioxygenases
2010 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 114, no 17, 5878-5885 p.Article in journal (Refereed) Published
Abstract [en]

The enzymatic ring cleavage of catechol derivatives is catalyzed by two groups of dioxygenases: extradiol- and intradiol-cleaving dioxygenases. Although having different oxidation state of their nonheme iron sites and different ligand coordinations, both groups of enzymes involve a common peroxy intermediate in their catalytic cycles. The factors that lead to either extradiol cleavage resulting in 2-hydroxymuconaldehyde or intradiol cleavage resulting in muconic acid are not fully understood. Well-characterized model compounds that mimic the functionality of these enzymes offer a basis for direct comparison to theoretical results. In this study the mechanism of a biomimetic iron complex is investigated with density functional theory (DFT). This complex catalyzes the ring opening of catecholate with exclusive formation of the intradiol cleaved product. Several spin states are possible for the transition metal system, with the quartet state found to be of main importance during the reaction course. The mechanism investigated provides an explanation for the observed selectivity of the complex. First, a bridging peroxide is formed, which decomposes to an alkoxy radical by O−O homolysis. In contrast to the subsequent barrier-free intradiol C−C bond cleavage, the extradiol pathway proceeds via the formation of an epoxide, which requires an additional activation barrier.

Keyword
homogeneous catalysis, density functional theory, intradiol, extradiol, dioxy- genase, non-heme iron, biomimetic, oxo-radical
National Category
Natural Sciences
Research subject
Chemical Physics
Identifiers
urn:nbn:se:su:diva-30776 (URN)10.1021/jp911217j (DOI)000277053900033 ()
Available from: 2009-10-26 Created: 2009-10-26 Last updated: 2017-12-12Bibliographically approved
5. The Conversion of Cyclohexane to Adipic Acid catalyzed by an Iron-Porphirin Complex. A theoretical study
Open this publication in new window or tab >>The Conversion of Cyclohexane to Adipic Acid catalyzed by an Iron-Porphirin Complex. A theoretical study
Show others...
(English)Manuscript (preprint) (Other academic)
Keyword
biomimetic complexes, adipic acid, heme, density functional calculations, spin transition, catalysis
National Category
Natural Sciences
Research subject
Biophysics
Identifiers
urn:nbn:se:su:diva-30782 (URN)
Available from: 2009-10-26 Created: 2009-10-26 Last updated: 2010-04-01Bibliographically approved

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