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  • 1.
    Bushnell, Eric A C
    et al.
    University of Windsor, Windsor, ON, N9B 3P4, Canada.
    Erdtman, Edvin
    Örebro University, School of Science and Technology.
    Llano, Jorge
    University of Windsor, Windsor, ON, N9B 3P4, Canada.
    Eriksson, Leif A.
    National University of Ireland, Galway, University Road, Galway, Ireland.
    Gauld, James W.
    University of Windsor, Windsor, ON, N9B 3P4, Canada.
    Computational insights into the first branching point in porphyrin biosynthesis: decarboxylation of ring D in URO–III by Uroporphyrinogen–III DecarboxylaseManuscript (preprint) (Other academic)
  • 2.
    Bushnell, Eric A. C.
    et al.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Erdtman, Edvin
    Örebro University, School of Science and Technology.
    Llano, Jorge
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Gauld, James W.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    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 decarboxylase2011In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 32, no 5, p. 822-834Article in journal (Refereed)
    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.

  • 3.
    Erdtman, Edvin
    Örebro University, School of Science and Technology.
    5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions2010Doctoral 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.

    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:oru:diva-4092 (URN)10.1016/j.cplett.2006.11.084 (DOI)000243820100020 ()2-s2.0-33846018089 (Scopus ID)
    Available from: 2007-06-25 Created: 2007-06-25 Last updated: 2019-12-13Bibliographically 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, 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
    Research subject
    Biochemistry; Physical Chemistry
    Identifiers
    urn:nbn:se:oru:diva-4625 (URN)10.1021/jp7118197 (DOI)000255486400026 ()18416542 (PubMedID)2-s2.0-43949116597 (Scopus ID)
    Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2019-12-13Bibliographically 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, 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
    Research subject
    Biochemistry; Physical Chemistry
    Identifiers
    urn:nbn:se:oru:diva-4624 (URN)10.1016/j.cplett.2008.08.021 (DOI)000259150400035 ()2-s2.0-51349091343 (Scopus ID)
    Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2019-12-13Bibliographically 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: 2019-12-13Bibliographically 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: 2019-12-13Bibliographically 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: 2019-12-13Bibliographically approved
  • 4.
    Erdtman, Edvin
    Örebro University, Department of Natural Sciences.
    A theoretical study of 5-Aminolevulinic acid and its esters: properties and lipid permeability2008Licentiate 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.

    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:oru:diva-4092 (URN)10.1016/j.cplett.2006.11.084 (DOI)000243820100020 ()2-s2.0-33846018089 (Scopus ID)
    Available from: 2007-06-25 Created: 2007-06-25 Last updated: 2019-12-13Bibliographically 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, 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
    Research subject
    Biochemistry; Physical Chemistry
    Identifiers
    urn:nbn:se:oru:diva-4625 (URN)10.1021/jp7118197 (DOI)000255486400026 ()18416542 (PubMedID)2-s2.0-43949116597 (Scopus ID)
    Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2019-12-13Bibliographically 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, 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
    Research subject
    Biochemistry; Physical Chemistry
    Identifiers
    urn:nbn:se:oru:diva-4624 (URN)10.1016/j.cplett.2008.08.021 (DOI)000259150400035 ()2-s2.0-51349091343 (Scopus ID)
    Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2019-12-13Bibliographically approved
  • 5.
    Erdtman, Edvin
    et al.
    Örebro University, School of Science and Technology.
    Bushnell, Eric A. C.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Gauld, James W.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Eriksson, Leif A.
    School of Chemistry, National University Ireland (NUI) Galway, Galway, Ireland.
    Computational insights into the mechanism of porphobilinogen synthase2010In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 114, no 50, p. 16860-16870Article in journal (Refereed)
    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).

  • 6.
    Erdtman, Edvin
    et al.
    Örebro University, School of Science and Technology.
    Bushnell, Eric A. C.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Gauld, James W.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada.
    Eriksson, Leif A.
    School of Chemistry, National University of Ireland (NUI Galway), Galway, Ireland.
    Computational studies on Schiff-base formation: Implications for the catalytic mechanism of porphobilinogen synthase2011In: Computational and Theoretical Chemistry, ISSN 2210-271X, E-ISSN 2210-2728, Vol. 963, no 2-3, p. 479-489Article in journal (Refereed)
    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.

  • 7.
    Erdtman, Edvin
    et al.
    Örebro University, Department of Natural Sciences.
    dos Santos, Daniel J. V. A.
    Löfgren, Lennart
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer2008In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, no 1-3, p. 178-182Article in journal (Refereed)
    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.

  • 8.
    Erdtman, Edvin
    et al.
    Örebro University, School of Science and Technology.
    dos Santos, Daniel J. V. A.
    Örebro University, School of Science and Technology.
    Löfgren, Lennart
    Orebro Univ Hosp, Head & Neck Oncol Ctr, S-70185 Orebro, Sweden.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer (vol 463, pg 178, 2008)2009In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 470, no 4-6, p. 369-369Article in journal (Refereed)
  • 9.
    Erdtman, Edvin
    et al.
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives2007In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 434, no 1-3, p. 101-106Article in journal (Refereed)
    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.

  • 10.
    Erdtman, Edvin
    et al.
    Örebro University, Department of Natural Sciences.
    Eriksson, Leif A.
    Örebro University, Department of Natural Sciences.
    Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism2008In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, no 18, p. 4367-4374Article in journal (Refereed)
    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.

  • 11.
    Erdtman, Edvin
    et al.
    Örebro University, School of Science and Technology.
    Gauld, James W
    Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B.
    Eriksson, Leif A.
    School of Chemistry, NUI Galway, Galway, Ireland.
    Computational Insights into the Mechanism of Substrate Binding in Potphobilinogen SynthaseManuscript (preprint) (Other academic)
  • 12.
    Erdtman, Edvin
    et al.
    Örebro University, School of Science and Technology.
    Gauld, James W.
    Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B.
    Eriksson, Leif A.
    School of Chemistry, NUI Galway, Galway, Ireland.
    Modelling the mechanism of porphobilinogen synthaseManuscript (preprint) (Other academic)
1 - 12 of 12
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  • ieee
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