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5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions
Örebro universitet, Akademin för naturvetenskap och teknik.ORCID iD: 0000-0001-9455-9558
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 [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
Identifiers
URN: urn:nbn:se:liu:diva-150067ISBN: 9789176687185 (print)OAI: oai:DiVA.org:liu-150067DiVA, id: diva2:1237572
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
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, p. 101-106Article 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
Keywords
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:liu:diva-150073 (URN)10.1016/j.cplett.2006.11.084 (DOI)000243820100020 ()2-s2.0-33846018089 (Scopus ID)
Available from: 2007-06-25 Created: 2018-08-09 Last updated: 2018-08-09
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, 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
Keywords
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
Identifiers
urn:nbn:se:liu:diva-150074 (URN)10.1021/jp7118197 (DOI)000255486400026 ()18416542 (PubMedID)2-s2.0-43949116597 (Scopus ID)
Available from: 2008-10-13 Created: 2018-08-09 Last updated: 2018-08-09
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, p. 178-182Article 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
Keywords
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
Identifiers
urn:nbn:se:liu:diva-150071 (URN)10.1016/j.cplett.2008.08.021 (DOI)000259150400035 ()2-s2.0-51349091343 (Scopus ID)
Available from: 2008-10-13 Created: 2018-08-09 Last updated: 2018-08-09
4. Computational studies on Schiff-base formation: Implications for the catalytic mechanism of porphobilinogen synthase
Open this publication in new window or tab >>Computational studies on Schiff-base formation: Implications for the catalytic mechanism of porphobilinogen synthase
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
Keywords
Schiff base, 5-Aminolevulinic acid, Porphobilinogen synthase, Density functional theory, Catalysis
National Category
Natural Sciences Physical Chemistry Physical Chemistry Theoretical Chemistry
Identifiers
urn:nbn:se:liu:diva-150070 (URN)10.1016/j.comptc.2010.11.015 (DOI)000288834500036 ()2-s2.0-80054879916 (Scopus ID)
Available from: 2011-01-14 Created: 2018-08-09 Last updated: 2018-08-09
5. Computational insights into the mechanism of porphobilinogen synthase
Open this publication in new window or tab >>Computational insights into the mechanism of porphobilinogen synthase
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
National Category
Natural Sciences Physical Chemistry Physical Chemistry
Identifiers
urn:nbn:se:liu:diva-150069 (URN)10.1021/jp103590d (DOI)000285236700023 ()21090799 (PubMedID)2-s2.0-78650384685 (Scopus ID)
Available from: 2011-01-14 Created: 2018-08-09 Last updated: 2018-08-09
6. 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
Open this publication in new window or tab >>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
Show others...
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
Keywords
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:nbn:se:liu:diva-150066 (URN)10.1002/jcc.21661 (DOI)000288400600007 ()20941734 (PubMedID)2-s2.0-79951968121 (Scopus ID)
Available from: 2011-01-14 Created: 2018-08-09 Last updated: 2018-08-09

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