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Catalytic Mechanism of Porphobilinogen Synthase: The Chemical Step Revisited by QM/MM Calculations
University of Borås, School of Engineering.
2012 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, no 40, p. 12105-12112Article in journal (Refereed) Published
Abstract [en]

Porphobilinogen synthase (PBGS) catalyzes the asymmetric condensation and cyclization of two 5-aminolevulinic acid (5-ALA) substrate molecules to give porphobilinogen (PBG). The chemical step of PBGS is herein revisited using QM/MM (ONIOM) calculations. Two different protonation states and several different mechanisms are considered. Previous mechanisms based on DFT-only calculations are shown unlikely to occur. According to these new calculations, the deprotonation step rather than ring closure is rate-limiting. Both the C–C bond formation first mechanism and the C–N bond formation first mechanism are possible, depending on how the A-site ALA binds to the enzyme. We furthermore propose that future work should focus on the substrate binding step rather than the enzymatic mechanism.

Place, publisher, year, edition, pages
American Chemical Society , 2012. Vol. 116, no 40, p. 12105-12112
Keywords [en]
Enzymes, QM/MM, Simulation, Reaction mechanism, Porphobilinogen synthase, Resursåtervinning
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:hb:diva-1418DOI: 10.1021/jp304743cISI: 000309648900005PubMedID: 22974111Local ID: 2320/11733OAI: oai:DiVA.org:hb-1418DiVA, id: diva2:869473
Available from: 2015-11-13 Created: 2015-11-13 Last updated: 2017-10-17Bibliographically approved

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Erdtman, Edvin

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