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Theoretical study of the catalytic reaction mechanism of MndD
Stockholm University, Faculty of Science, Department of Physics. (Theoretical Biochemistry)
Stockholm University, Faculty of Science, Department of Physics. (Theoretical Biochemistry)
Stockholm University, Faculty of Science, Department of Physics. (Theoretical Biochemistry)
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. Vol. 11, no 5, 571-85 p.
National Category
Inorganic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-30693DOI: 10.1007/s00775-006-0106-9PubMedID: 16791641OAI: oai:DiVA.org:su-30693DiVA: diva2:273630
Available from: 2009-10-26 Created: 2009-10-22 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Reaction Mechanisms of Metalloenzymes and Synthetic Model Complexes Activating Dioxygen: A Computational study
Open this publication in new window or tab >>Reaction Mechanisms of Metalloenzymes and Synthetic Model Complexes Activating Dioxygen: A Computational study
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
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:nbn:se:su:diva-30706 (URN)978-91-7155-965-4 (ISBN)
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

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