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Computational insights into the mechanism of porphobilinogen synthase
Örebro University, School of Science and Technology. (Biofysikalisk kemi)
Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4 ,Canada.
Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada.
School of Chemistry, NUI Galway, Galway, Ireland.
2010 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 114, no 50, p. 16860-16870Article in journal (Refereed) Published
Abstract [en]

Porphobilinogen synthase (PBGS) is a key enzyme in heme biosynthesis that catalyzes the formation of porphobilinogen (PBG) from two 5-aminolevulinic acid (5-ALA) molecules via formation of intersubstrateC-N and C-C bonds. The active site consists of several invariant residues, including two lysyl residues (Lys210 and Lys263; yeast numbering) that bind the two substrate moieties as Schiff bases. Based on experimental studies, various reaction mechanisms have been proposed for this enzyme that generally can be classified according to whether the intersubstrate C-C or C-N bond is formed first. However, the detailed catalytic mechanism of PBGS remains unclear. In the present study, we have employed density functional theory methods in combination with chemical models of the two key lysyl residues and two substrate moieties in order to investigate various proposed reaction steps and gain insight into the mechanism of PBGS. Importantly, it is found that mechanisms in which the intersubstrate C-N bond is formed first have a ratelimiting barrier (17.5 kcal/mol) that is lower than those in which the intersubstrate C-C bond is formed first (22.8 kcal/mol).

Place, publisher, year, edition, pages
Washington: American Chemical Society (ACS), 2010. Vol. 114, no 50, p. 16860-16870
National Category
Natural Sciences Physical Chemistry Physical Chemistry
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:oru:diva-13960DOI: 10.1021/jp103590dISI: 000285236700023PubMedID: 21090799Scopus ID: 2-s2.0-78650384685OAI: oai:DiVA.org:oru-13960DiVA: diva2:387645
Available from: 2011-01-14 Created: 2011-01-14 Last updated: 2017-12-11Bibliographically approved

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Erdtman, Edvin

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