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Computational studies on Schiff-base formation: Implications for the catalytic mechanism of porphobilinogen synthase
Örebro universitet, Akademin för naturvetenskap och teknik.ORCID iD: 0000-0001-9455-9558
Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
School of Chemistry, National University of Ireland (NUI Galway), Galway, Ireland.
2011 (English)In: Computational and Theoretical Chemistry, ISSN 2210-271X, E-ISSN 2210-2728, Vol. 963, no 2-3, p. 479-489Article in journal (Refereed) Published
Abstract [en]

Schiff bases are common and important intermediates in many bioenzymatic systems. The mechanism by which they are formed, however,is dependent on the solvent, pH and other factors. In the present study we have used density functional theory methods in combination with appropriate chemical models to get a better understanding of the inherent chemistry of the formation of two Schiff bases that have been proposed to be involved in the catalytic mechanism of porphobilinogensynthase (PBGS), a key enzyme in the biosynthesis of porphyrins. More specifically, we have investigated the uncatalysed reaction of its substrate 5-aminolevulinic acid (5-ALA) with a lysine residue for theformation of the P-site Schiff base, and as possibly catalysed by the second active site lysine, water or the 5-ALA itself. It is found that cooperatively both the second lysine and the amino group of the initial 5-ALA itself are capable of reducing the rate-limiting energy barrier to14.0 kcal mol-1. We therefore propose these to be likely routes involved in the P-site Schiff-base formation in PBGS.

Place, publisher, year, edition, pages
Amsterdam: Elsevier , 2011. Vol. 963, no 2-3, p. 479-489
Keywords [en]
Schiff base, 5-Aminolevulinic acid, Porphobilinogen synthase, Density functional theory, Catalysis
National Category
Natural Sciences Physical Chemistry Physical Chemistry Theoretical Chemistry
Identifiers
URN: urn:nbn:se:liu:diva-150070DOI: 10.1016/j.comptc.2010.11.015ISI: 000288834500036Scopus ID: 2-s2.0-80054879916OAI: oai:DiVA.org:liu-150070DiVA, id: diva2:1237566
Available from: 2011-01-14 Created: 2018-08-09 Last updated: 2018-08-09
In thesis
1. 5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions
Open this publication in new window or tab >>5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

5-aminolevulinic acid (5-ALA) and derivatives thereof are widely usedprodrugs in treatment of pre-malignant skin diseases of the cancer treatmentmethod photodynamic therapy (PDT). The target molecule in 5-ALAPDTis protoporphyrin IX (PpIX), which is synthesized endogenously from5-ALA via the heme pathway in the cell. This thesis is focused on 5-ALA,which is studied in different perspectives and with a variety of computationalmethods. The structural and energetic properties of 5-ALA, itsmethyl-, ethyl- and hexyl esters, four different 5-ALA enols, and hydrated5-ALA have been investigated using Quantum Mechanical (QM) first principlesdensity functional theory (DFT) calculations. 5-ALA is found to bemore stable than its isomers and the hydrolysations of the esters are morespontaneous for longer 5-ALA ester chains than shorter. The keto-enoltautomerization mechanism of 5-ALA has been studied, and a self-catalysismechanism has been proposed to be the most probable. Molecular Dynamics(MD) simulations of a lipid bilayer have been performed to study themembrane permeability of 5-ALA and its esters. The methyl ester of 5-ALAwas found to have the highest permeability constant (PMe-5-ALA = 52.8 cm/s).The mechanism of the two heme pathway enzymes; Porphobilinogen synthase(PBGS) and Uroporphyrinogen III decarboxylase (UROD), have beenstudied by DFT calculations and QM/MM methodology. The rate-limitingstep is found to have a barrier of 19.4 kcal/mol for PBGS and 13.7kcal/mol for the first decarboxylation step in UROD. Generally, the resultsare in good agreement with experimental results available to date.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2010. p. 76
Series
Örebro Studies in Life Science, ISSN 1653-3100 ; 6
Keywords
5-Aminolevulinic acid, tautomerization, PDT, DFT, MM, QM/MM, Porphobilinogen synthase, Uroporphyrinogen III decarboxylase, membrane penetration, enzyme mechanism
National Category
Physical Chemistry Theoretical Chemistry Theoretical Chemistry
Identifiers
urn:nbn:se:liu:diva-150067 (URN)9789176687185 (ISBN)
Public defence
2010-04-28, Hörsal M, Musikhögskolan, Örebro Universitet, 10:15 (English)
Opponent
Supervisors
Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-09Bibliographically approved

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