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Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism
Örebro University, Department of Natural Sciences.
Örebro University, Department of Natural Sciences.
2008 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, no 18, p. 4367-4374Article in journal (Refereed) Published
Abstract [en]

5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. In this study density functional theory calculations were performed on the tautomers of 5ALA and the tautomerization reaction mechanism from its enolic forms (5-amino-4-hydroxypent-3-enoic acid and 5-amino-4-hydroxypent-4-enoic acid) to the more stable 5ALA. The hydrated form 5-amino-4,4-dihydroxypentanoic acid was also studied. The lowest energy pathway of 5ALA tautomerization is by means of autocatalysis, in that an oxygen of the carboxylic group transfers the hydrogen atom as a "crane", with an activation energy of similar to 15 kcal/mol. This should be compared to the barriers of about 35 kcal/mol for water assisted tautomerization, and 60 kcal/mol for direct hydrogen transfer. For hydration of 5ALA, the water catalyzed activation barrier is found to be similar to 35 kcal/mol, approximately 5 kcal/mol lower than direct hydration.

Place, publisher, year, edition, pages
Washington DC: American Chemical Society , 2008. Vol. 112, no 18, p. 4367-4374
Keyword [en]
Aminolevulinic Acid/*chemistry, Carboxylic Acids/chemistry, Catalysis, Isomerism, Protons, Quantum Theory, Thermodynamics, Water/chemistry
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Physical Chemistry Theoretical Chemistry
Research subject
Biochemistry; Physical Chemistry
Identifiers
URN: urn:nbn:se:oru:diva-4625DOI: 10.1021/jp7118197ISI: 000255486400026PubMedID: 18416542Scopus ID: 2-s2.0-43949116597OAI: oai:DiVA.org:oru-4625DiVA, id: diva2:138924
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2017-10-17Bibliographically approved
In thesis
1. A theoretical study of 5-Aminolevulinic acid and its esters: properties and lipid permeability
Open this publication in new window or tab >>A theoretical study of 5-Aminolevulinic acid and its esters: properties and lipid permeability
2008 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

5-aminolevulinic acid (5ALA) is a widely used prodrug in Photodynamic therapy (PDT). The target molecule in 5ALA-PDT is Protoporphyrin IX (PpIX), which is synthesized endogenously via the heme pathway in the cell. In this thesis; the structural and energetic properties of 5ALA, its methyl-, ethyl- and hexyl esters, four different 5ALA enols, and hydrated 5ALA have been investigated using Quantum Mechanical (QM) first principles calculations. The vacuum proton affinity (PA) of 5ALA is found to be in good agreement with other similar compounds. The keto-enol tautomerization mechanism of 5ALA has been studied, and a self-catalysis mechanism has been proposed to be the most probable. Molecular Dynamics (MD) simulations of a lipid bilayer have been performed to study the membrane permeability of 5ALA and its esters. In the simulations the molecules were inserted in the middle of the membrane, equilibrated, and then simulated in 20 ns. It has been found that there are some differences in penetration between the molecules studied. The methyl ester of 5ALA is diverging from the others by having its barrier not in the middle of the membrane, as the others have.

Publisher
p. 37
Series
Licentiate Thesises in Life Science, ISSN 1653-9516 ; 5
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:oru:diva-4627 (URN)
Presentation
2008-03-06, 00:00 (English)
Opponent
Supervisors
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2017-10-18
2. 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 ; 6
Keyword
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
Research subject
Physical Chemistry; Biochemistry
Identifiers
urn:nbn:se:oru:diva-9951 (URN)978-91-7668-718-5 (ISBN)
Public defence
2010-04-28, Hörsal M, Musikhögskolan, Örebro Universitet, Örebro, 10:15 (English)
Opponent
Supervisors
Available from: 2010-03-17 Created: 2010-03-10 Last updated: 2017-10-17Bibliographically approved

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Erdtman, EdvinEriksson, Leif A.

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