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5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions
Örebro University, School of Science and Technology. (Biofysikalisk kemi)
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. , 76 p.
Series
Örebro Studies in Life Science, 6
Keyword [en]
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: urn:nbn:se:oru:diva-9951ISBN: 978-91-7668-718-5 (print)OAI: oai:DiVA.org:oru-9951DiVA: diva2:303427
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: 2011-04-27Bibliographically approved
List of papers
1. Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives
Open this publication in new window or tab >>Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives
2007 (English)In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 434, no 1-3, 101-106 p.Article 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. The addition of extracorporeal 5ALA and its alkyl ester derivatives are in current clinical use in photodynamical diagnostics and photodynamic therapy of tumors and skin disorders. In the current study density functional theory calculations are performed on 5ALA and its methyl, ethyl, and hexyl esters, in order to explore the basic chemical properties of these species. It is concluded that even in aqueous media the zwitterionic form of 5ALA is less stable than the non-zwitterionic one, that the local environment (lipid vs water) affects the energetics of reaction considerably, and that the hexyl species is most prone to hydrolysis of the three alkyl ester derivatives.

Place, publisher, year, edition, pages
Amsterdam: North-Holland Publishing Co, 2007
Keyword
5-aminolevulinic acid, 5ALA, B3LYP, DFT, Protonation states, Alkyl esters
National Category
Theoretical Chemistry Physical Chemistry
Research subject
Biochemistry; Physical Chemistry
Identifiers
urn:nbn:se:oru:diva-4092 (URN)10.1016/j.cplett.2006.11.084 (DOI)
Available from: 2007-06-25 Created: 2007-06-25 Last updated: 2010-07-02Bibliographically approved
2. Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism
Open this publication in new window or tab >>Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism
2008 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, no 18, 4367-4374 p.Article 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
Keyword
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:nbn:se:oru:diva-4625 (URN)10.1021/jp7118197 (DOI)18416542 (PubMedID)
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2010-07-02Bibliographically approved
3. Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
Open this publication in new window or tab >>Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
2008 (English)In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, no 1-3, 178-182 p.Article in journal (Refereed) Published
Abstract [en]

5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic therapy (PDT). The behavior of 5ALA and three esters of 5ALA in a DPPC lipid bilayer is investigated. In particular, the methyl ester displays a very different free energy profile, where the highest barrier is located in the region with highest lipid density, while the others have their peak in the middle of the membrane, and also displays a considerably lower permeability coefficient than neutral 5ALA and the ethyl ester. The zwitterion of 5ALA has the highest permeability constant, but a significant free energy minimum in the polar head-group region renders an accumulation in this region.

Place, publisher, year, edition, pages
Amsterdam: North-Holland Publishing Co, 2008
Keyword
Molecular-dynamics simulations, photodynamic therapy, adenocarcinoma cells, beta transporters, hydrated DPPC, derivates, permeation, protoporphyrin, transition, membranes
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medicinal Chemistry Physical Chemistry Theoretical Chemistry
Research subject
Biochemistry; Physical Chemistry
Identifiers
urn:nbn:se:oru:diva-4624 (URN)10.1016/j.cplett.2008.08.021 (DOI)
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2011-05-11Bibliographically approved
4. Computational Insights into the Mechanism of Substrate Binding in Potphobilinogen Synthase
Open this publication in new window or tab >>Computational Insights into the Mechanism of Substrate Binding in Potphobilinogen Synthase
(English)Manuscript (preprint) (Other academic)
National Category
Theoretical Chemistry Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:oru:diva-9948 (URN)
Available from: 2010-03-12 Created: 2010-03-10 Last updated: 2011-04-27Bibliographically approved
5. Modelling the mechanism of porphobilinogen synthase
Open this publication in new window or tab >>Modelling the mechanism of porphobilinogen synthase
(English)Manuscript (preprint) (Other academic)
National Category
Physical Chemistry Theoretical Chemistry
Research subject
Physical Chemistry; Biochemistry
Identifiers
urn:nbn:se:oru:diva-9949 (URN)
Available from: 2010-03-12 Created: 2010-03-10 Last updated: 2011-04-28Bibliographically approved
6. Computational insights into the first branching point in porphyrin biosynthesis: decarboxylation of ring D in URO–III by Uroporphyrinogen–III Decarboxylase
Open this publication in new window or tab >>Computational insights into the first branching point in porphyrin biosynthesis: decarboxylation of ring D in URO–III by Uroporphyrinogen–III Decarboxylase
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Physical Chemistry Theoretical Chemistry
Research subject
Physical Chemistry; Biochemistry
Identifiers
urn:nbn:se:oru:diva-9950 (URN)
Available from: 2010-03-12 Created: 2010-03-10 Last updated: 2011-04-28Bibliographically approved

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