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The first branching point in porphyrin biosynthesis: a systematic docking, molecular dynamics and quantum mechanical/molecular mechanical study of substrate binding and mechanism of uroporphyrinogen-III decarboxylase
Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, Canada.
Örebro universitet, Akademin för naturvetenskap och teknik, Örebro Universitet, Örebro, Sweden.ORCID iD: 0000-0001-9455-9558
Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, Canada.
Örebro universitet, Akademin för naturvetenskap och teknik; School of Chemistry, National University of Ireland, Galway, Ireland.
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2011 (English)In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 32, no 5, p. 822-834Article in journal (Refereed) Published
Abstract [en]

In humans, uroporphyrinogen decarboxylase is intimately involved in the synthesis of heme, where the decarboxylation of the uroporphyrinogen-III occurs in a single catalytic site. Several variants of the mechanistic proposal exist; however, the exact mechanism is still debated. Thus, using an ONIOM quantum mechanical/molecular mechanical approach, the mechanism by which uroporphyrinogen decarboxylase decarboxylates ring D of uroporphyrinogen-III has been investigated. From the study performed, it was found that both Arg37 and Arg50 are essential in the decarboxylation of ring D, where experimentally both have been shown to be critical to the catalytic behavior of the enzyme. Overall, the reaction was found to have a barrier of 10.3 kcal mol−1 at 298.15 K. The rate-limiting step was found to be the initial protontransfer from Arg37 to the substrate before the decarboxylation. In addition, it has been found that several key interactions exist between the substrate carboxylate groups and backbone amides of various activesite residues as well as several other functional groups.

Place, publisher, year, edition, pages
New York: John Wiley & Sons , 2011. Vol. 32, no 5, p. 822-834
Keywords [en]
uroporphyrinogen decarboxylase III, uroporphyrinogen III, porphyrin biosynthesis, quantum mechanics/molecular mechanics and density functional theory
National Category
Natural Sciences Physical Chemistry Physical Chemistry Theoretical Chemistry Theoretical Chemistry
Identifiers
URN: urn:nbn:se:liu:diva-150066DOI: 10.1002/jcc.21661ISI: 000288400600007PubMedID: 20941734Scopus ID: 2-s2.0-79951968121OAI: oai:DiVA.org:liu-150066DiVA, id: diva2:1237567
Available from: 2011-01-14 Created: 2018-08-09 Last updated: 2018-10-29
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)
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Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-09Bibliographically approved

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Erdtman, EdvinEriksson, Leif A.

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