Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Theoretical Modeling of Enzyme Catalysis with Focus on Radical Chemistry
Stockholm University, Faculty of Science, Department of Physics.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hybrid density functional theory (DFT) B3LYP method is applied to study the four diverse enzyme systems: zinc-containing peptidases (thermolysin and stromelysin), methyl-coenzyme M reductase, ribonucleotide reductases (classes I and III), and superoxide dismutases (Cu,Zn- and Ni-dependent enzymes). Powerfull tools of modern quantum chemistry are used to address the questions of biological pathways at their molecular level, proposing a novel mechanism for methane production by methyl-coenzyme M reductase and providing additional insights into hydrolysis by zinc peptidases, substrate conversion by ribonucleotide reductases, and biological superoxide dismutation. Catalysis by these enzymes, with the exception of zinc peptidases, involves radical chemistry.

Place, publisher, year, edition, pages
Stockholm: Fysikum , 2005. , 104 p.
Keyword [en]
density functional theory, enzyme catalysis, radical chemistry, zinc-containing peptidase, methyl-coenzyme M reductase, ribonucleotide reductase, superoxide dismutase
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:su:diva-513ISBN: 91-7155-018-6 (print)OAI: oai:DiVA.org:su-513DiVA: diva2:194874
Public defence
2005-05-26, sal FA32, AlbaNova universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:00
Opponent
Supervisors
Available from: 2005-05-05 Created: 2005-05-05Bibliographically approved
List of papers
1. A theoretical study of the mechanism for peptide hydrolysis by thermolysin
Open this publication in new window or tab >>A theoretical study of the mechanism for peptide hydrolysis by thermolysin
2002 In: Journal of biological inorganic chemistry, ISSN 0949-8257, Vol. 7, no 3, 284-298 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-23840 (URN)
Note
Part of urn:nbn:se:su:diva-513Available from: 2005-05-05 Created: 2005-05-05Bibliographically approved
2. Catalytic Mechanism of Matrix Metalloproteinases: Two-Layered ONIOM Study
Open this publication in new window or tab >>Catalytic Mechanism of Matrix Metalloproteinases: Two-Layered ONIOM Study
2002 In: Inorganic Chemistry, ISSN 0020-1669, Vol. 41, no 22, 5659 -5666 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-23841 (URN)
Note
Part of urn:nbn:se:su:diva-513Available from: 2005-05-05 Created: 2005-05-05Bibliographically approved
3. A Mechanism from Quantum Chemical Studies for Methane Formation in Methanogenesis
Open this publication in new window or tab >>A Mechanism from Quantum Chemical Studies for Methane Formation in Methanogenesis
2002 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 124, no 15, 4039-4049 p.Article in journal (Refereed) Published
Abstract [en]

The mechanism for methane formation in methyl-coenzyme M reductase (MCR) has been investigated using the B3LYP hybrid density functional method and chemical models consisting of 107 atoms. The experimental X-ray crystal structure of the enzyme in the inactive MCRox1-silent state was used to set up the initial model structure. The calculations suggest a mechanism not previously proposed, in which the most remarkable feature is the formation of an essentially free methyl radical at the transition state. The reaction cycle suggested starts from a Michaelis complex with CoB and methyl-CoM coenzymes bound and with a squareplanar coordination of the Ni(I) center in the tetrapyrrole F430 prosthetic group. In the rate-limiting step the methyl radical is released from methyl-CoM, induced by the attack of Ni(I) on the methyl-CoM thioether sulfur. In this step, the metal center is oxidized from Ni(I) to Ni(II). The resulting methyl radical is rapidly quenched by hydrogen-atom transfer from the CoB thiol group, yielding the methane molecule and the CoB radical. The estimated activation energy is around 20 kcal/mol, which includes a significant contribution from entropy due to the formation of the free methyl. The mechanism implies an inversion of configuration at the reactive carbon. The size of the inversion barrier is used to explain the fact that CF3−S−CoM is an inactive substrate. Heterodisulfide CoB−S−S−CoM formation is proposed in the final step in which nickel is reduced back to Ni(I). The suggested mechanism agrees well with experimental observations.

Place, publisher, year, edition, pages
American Chemical Society, 2002
National Category
Physical Sciences
Identifiers
urn:nbn:se:su:diva-23842 (URN)10.1021/ja011664r (DOI)
Note
Part of urn:nbn:se:su:diva-513Available from: 2005-05-05 Created: 2005-05-05 Last updated: 2010-07-07Bibliographically approved
4. Catalysis by methyl-coenzyme M reductase: a theoretical study for heterodisulfide product formation
Open this publication in new window or tab >>Catalysis by methyl-coenzyme M reductase: a theoretical study for heterodisulfide product formation
2003 In: Journal of biological inorganic chemistry, ISSN 0949-8257, Vol. 8, no 6, 653-662 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-23843 (URN)
Note
Part of urn:nbn:se:su:diva-513Available from: 2005-05-05 Created: 2005-05-05Bibliographically approved
5. Class I ribonucleotide reductase revisited: The effect of removing a proton on Glu441
Open this publication in new window or tab >>Class I ribonucleotide reductase revisited: The effect of removing a proton on Glu441
2004 In: Journal of computational chemistry, ISSN 0192-8651, Vol. 25, no 3, 311-321 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-23844 (URN)
Note
Part of urn:nbn:se:su:diva-513Available from: 2005-05-05 Created: 2005-05-05Bibliographically approved
6. Density Functional Calculations on Class III Ribonucleotide Reductase: Substrate Reaction Mechanism with Two Formates
Open this publication in new window or tab >>Density Functional Calculations on Class III Ribonucleotide Reductase: Substrate Reaction Mechanism with Two Formates
2004 In: The Journal Of Physical Chemistry B, ISSN 1089-5647, Vol. 108, no 6, 2056-2065 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-23845 (URN)
Note
Part of urn:nbn:se:su:diva-513Available from: 2005-05-05 Created: 2005-05-05Bibliographically approved
7. Copper-Zinc Superoxide Dismutase: Theoretical Insights into the Catalytic Mechanism
Open this publication in new window or tab >>Copper-Zinc Superoxide Dismutase: Theoretical Insights into the Catalytic Mechanism
2005 In: Inorganic Chemistry, ISSN 0020-1669, Vol. 44, no 9, 3311 -3320 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-23846 (URN)
Note
Part of urn:nbn:se:su:diva-513Available from: 2005-05-05 Created: 2005-05-05Bibliographically approved
8. Nickel superoxide dismutase reaction mechanism studied by hybrid density functional methods
Open this publication in new window or tab >>Nickel superoxide dismutase reaction mechanism studied by hybrid density functional methods
2006 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 128, no 23, 7466-7475 p.Article in journal (Refereed) Published
Abstract [en]

The reaction mechanism for the disproportionation of the toxic superoxide radical to molecular oxygen and hydrogen peroxide by the nickel-dependent superoxide dismutase (NiSOD) has been studied using the B3LYP hybrid DFT method. Based on the recent X-ray structures of the enzyme in the resting oxidized Ni(III) and X-ray-reduced Ni(II) states, the model investigated includes the backbone spacer of six residues (sequence numbers 1−6) as a structural framework. The side chains of residues His1, Cys2, and Cys6, which are essential for nickel binding and catalysis, were modeled explicitly. The catalytic cycle consists of two half-reactions, each initiated by the successive substrate approach to the metal center. The two protons necessary for the dismutation are postulated to be delivered concertedly with the superoxide radical anions. The first (reductive) phase involves Ni(III) reduction to Ni(II), and the second (oxidative) phase involves the metal reoxidation back to its resting state. The Cys2 thiolate sulfur serves as a transient protonation site in the interim between the two half-reactions, allowing for the dioxygen and hydrogen peroxide molecules to be released in the reductive and oxidative phases, respectively. The His1 side chain nitrogen and backbone amides of the active site channel are shown to be less favorable transient proton locations, as compared to the Cys2 sulfur. Comparisons are made to the Cu- and Zn-dependent SOD, studied previously using similar models.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-23847 (URN)10.1021/ja053665f (DOI)
Note
Part of urn:nbn:se:su:diva-513Available from: 2005-05-05 Created: 2005-05-05 Last updated: 2010-08-09Bibliographically approved

Open Access in DiVA

fulltext(13729 kB)482 downloads
File information
File name FULLTEXT01.pdfFile size 13729 kBChecksum SHA-1
22d8ba0712b3a4d9823a0adaf64afe6a7eae6ebe6add60169e8a2a243e388089fc5372c3
Type fulltextMimetype application/pdf

By organisation
Department of Physics
Theoretical Chemistry

Search outside of DiVA

GoogleGoogle Scholar
Total: 482 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 833 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf