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5-Aminolevulinic ac...
5-Aminolevulinic acid and derivatives thereof : properties, lipid permeability and enzymatic reactions
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- Erdtman, Edvin, 1981- (författare)
- Örebro universitet,Akademin för naturvetenskap och teknik,Biofysikalisk kemi,Örebro universitet, Akademin för naturvetenskap och teknik
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- Eriksson, Leif, Professor (preses)
- Örebro universitet,Akademin för naturvetenskap och teknik,Örebro universitet, Akademin för naturvetenskap och teknik
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- Brinck, Tore, Professor (opponent)
- Fysikalisk kemi, Skolan för kemivetenskap, Kungliga Tekniska Högskolan, Stockholm
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(creator_code:org_t)
- ISBN 9789176687185
- Örebro : Örebro universitet, 2010
- Engelska 76 s.
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Serie: Örebro Studies in Life Science, 1653-3100 ; 6
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- 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)
Nyckelord
- 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 (ämneskategori)
- dok (ämneskategori)
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