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5-Aminolevulinic acid and derivatives thereof : properties, lipid permeability and enzymatic reactions

Erdtman, Edvin, 1981- (author)
Örebro universitet,Akademin för naturvetenskap och teknik,Biofysikalisk kemi,Örebro universitet, Akademin för naturvetenskap och teknik
Eriksson, Leif, Professor (thesis advisor)
Örebro universitet,Akademin för naturvetenskap och teknik,Örebro universitet, Akademin för naturvetenskap och teknik
Brinck, Tore, Professor (opponent)
Fysikalisk kemi, Skolan för kemivetenskap, Kungliga Tekniska Högskolan, Stockholm
 (creator_code:org_t)
ISBN 9789176687185
Örebro : Örebro universitet, 2010
English 76 s.
Series: Örebro Studies in Life Science, 1653-3100 ; 6
  • Doctoral thesis (other academic/artistic)
Abstract Subject headings
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  • 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.

Subject headings

NATURVETENSKAP  -- Kemi -- Fysikalisk kemi (hsv//swe)
NATURAL SCIENCES  -- Chemical Sciences -- Physical Chemistry (hsv//eng)
NATURVETENSKAP  -- Kemi -- Teoretisk kemi (hsv//swe)
NATURAL SCIENCES  -- Chemical Sciences -- Theoretical Chemistry (hsv//eng)

Keyword

5-Aminolevulinic acid
tautomerization
PDT
DFT
MM
QM/MM
Porphobilinogen synthase
Uroporphyrinogen III decarboxylase
membrane penetration
enzyme mechanism
Biophysical chemistry
Biofysikalisk kemi
Quantum chemistry
Kvantkemi
Theoretical chemistry
Teoretisk kemi
Fysikalisk kemi
Physical Chemistry
Biochemistry
Biokemi

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vet (subject category)
dok (subject category)

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