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Oxygen cleavage with manganese and iron in ribonucleotide reductase from Chlamydia trachomatis
Stockholm University, Faculty of Science, Department of Physics.
Stockholm University, Faculty of Science, Department of Physics.
2011 (English)In: Journal of Biological Inorganic Chemistry, ISSN 0949-8257, E-ISSN 1432-1327, Vol. 16, no 4, 553-565 p.Article in journal (Refereed) Published
Abstract [en]

The oxygen cleavage in Chlamydia trachomatis ribonucleotide reductase (RNR) has been studied using B3LYP* hybrid density functional theory. Class Ic C. trachomatis RNR lacks the radical-bearing tyrosine, crucial for activity in conventional class I (subclass a and b) RNR. Instead of the Fe(III)Fe(III)-Tyr(rad) active state, C. trachomatis RNR has a mixed Mn(IV)Fe(III) metal center in subunit II (R2). A mixed MnFe metal center has never been observed as a radical cofactor before. The active state is generated by reductive oxygen cleavage at the metal site. On the basis of calculated barriers for oxygen cleavage in C. trachomatis R2 and R2 from Escherichia coli with a diiron, a mixed manganese iron, and a dimanganese center, conclusions can be drawn about the effect of changing metals in R2. The oxygen cleavage is found to be governed by two factors: the redox potentials of the metals and the relative stability of the different peroxides. Mn(IV) has higher stability than Fe(IV), and the barrier is therefore lower with a mixed metal center than with a diiron center. With a dimanganese center, an asymmetric peroxide is more stable than the symmetric peroxide, and the barrier therefore becomes too high. Calculated proton-coupled redox potentials are compared to identify three possible R2 active states, the Fe(III)-Fe(III)-Tyr(rad) state, the Mn(IV)Fe(III) state, and. the Mn(IV)Mn(IV) state. A tentative energy profile of the thermodynamics of the radical transfer from R2 to subunit I is constructed to illustrate how the stability of the active states can be understood from a thermodynamical point of view.

Place, publisher, year, edition, pages
2011. Vol. 16, no 4, 553-565 p.
Keyword [en]
Ribonucleotide reductase, Oxygen cleavage, Manganese, Iron, Density functional theory
National Category
Physical Sciences
Research subject
Chemical Physics
Identifiers
URN: urn:nbn:se:su:diva-68806DOI: 10.1007/s00775-011-0755-1ISI: 000290284600003OAI: oai:DiVA.org:su-68806DiVA: diva2:474586
Note
authorCount :2Available from: 2012-01-09 Created: 2012-01-07 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Manganese and Iron Heterodimers and Homodimers in Enzymes: Insights from Density Functional Theory
Open this publication in new window or tab >>Manganese and Iron Heterodimers and Homodimers in Enzymes: Insights from Density Functional Theory
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The enzyme ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides, the building blocks of DNA, and is essential for all organisms. Canonical class I RNR R2 proteins use a diiron cofactor to generate a tyrosyl radical, which is required for catalysis. Recent discoveries have established that the different subgroups of class I RNR employ different metal cofactors. Class Ib R2 (R2F) utilizes a dimanganese cofactor and a flavoprotein to generate the tyrosyl radical. Class Ic R2 (R2c) lacks the radical-bearing tyrosine, and instead has an oxidized heterodinuclear manganese-iron center, the first known redox active MnFe cofactor. A second group of MnFe proteins with different functions, denoted R2-like ligand binding oxidases (R2lox), was later identified. R2lox proteins are capable of performing two-electron oxidations and are believed to be hydrocarbon oxidases. In the present thesis density functional theory, a quantum mechanical method, is employed to study the manganese and iron heterodimers and homodimers in the R2 and R2lox proteins, with the aim to shed light on the mechanistic details and stress the main features of the alternative metal centers. Some of the questions addressed are the radical generation with the homodimers and heterodimer in R2, the radical transfer between R2 and the RNR catalytic subunit, and the function of R2lox. A Mn(IV)Fe(III) state is shown to be an equally strong oxidant as a tyrosyl radical, giving a rationalization for the presence of the heterodimer in R2c. A reaction mechanism for the formation of an unprecedented tyrosine-valine crosslink catalyzed by the heterodimer in R2lox is modeled, and the potential of the protein to perform hydroxylations of hydrocarbons based on calculated barriers for methane hydroxylation is discussed. An energetically possible reaction mechanism is suggested for activation of dimanganese R2F by hydrogen peroxide, and a hypothetical role of the flavoprotein in radical generation is proposed.

Place, publisher, year, edition, pages
Stockholm: Department of Physics, Stockholm University, 2012. 86 p.
Keyword
Ribonucleotide reductase, manganese, iron, density functional theory
National Category
Theoretical Chemistry Biochemistry and Molecular Biology Inorganic Chemistry
Research subject
Chemical Physics
Identifiers
urn:nbn:se:su:diva-78814 (URN)978-91-7447-543-2 (ISBN)
Public defence
2012-09-14, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 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: Submitted. Paper 5: Manuscript.

Available from: 2012-08-23 Created: 2012-08-13 Last updated: 2015-10-27Bibliographically approved

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