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Kvantno-kemijska študija  izvora oksidativnega stresa v dopaminergičnih nevronih
ID Pograjc, Vid (Author), ID Mavri, Janez (Mentor) More about this mentor... This link opens in a new window

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Abstract
L-DOPA je trenutno zlati standard farmakoloških intervencij pri obvladovanju Parkinsonove bolezni. Zdravilo je prekurzor dopamina. Njegova uporaba je povezana z oksidativnim stresom, saj ob povišanih pH vrednostih dopamin avtooksidira, pri čemer nastanejo reaktivne kisikove zvrsti. L-DOPA je tudi sposobna avtooksidacije kjer nastajajo reaktivne kisikove zvrsti. Zdravilo se lahko vgradi v proteine zaradi svoje strukturne podobnosti z aromatskimi aminokislinami. Do sedaj še ni bilo znano, ali avtooksidacija L-DOPA lahko poteče v proteinskem okolju. Magistrska naloga je bila zasnovana z namenom razumevanja avtooksidacije L-DOPA na molekularnem nivoju. Stopnja, ki omejuje hitrost avtooksidacije L-DOPA, je ciklizacija dopakinona, ki poteče po mehanizmu Michaelove adicije s prenosom protona. Zanimalo nas je, ali reakcija lahko poteka v proteinskem okolju. Raziskavo smo izvedli na kvantno-kemijskem nivoju teorije z metodo molekulskih gruč (angl. cluster model). Za reakcijo smo si izbrali dopakinon, ki je vgrajen v aktivno mesto monoaminske oksidaze B, ki reagira z OH- . Pridobili smo aktivacijsko energijo in prosto energijo reakcije, ki pri pH 7,4 in 37oC znašata 19,35 kcal/mol in -13,65 kcal/mol. Iz aktivacijske energije reakcije smo izračunali tudi konstanto hitrosti reakcije in razpolovno dobo reakcije, ki znašata 0,16 s-1 in 4,33 s. Hitrost reakcije je pogojena s pH. Ugotovili smo, da L-DOPA, ki je vgrajena v proteine vstopa v intermolekularno Michaelovo adicijo s prenosom protona, ki je mehanistično enaka ustrezni reakciji v vodni raztopini.

Language:Slovenian
Keywords:L-DOPA, dopakinon, avtooksidacija, oksidativni stres, model gruč, Parkinsonova bolezen, kvantna kemija, dopamin, mehanizem reakcije, reaktivne kisikove zvrsti
Work type:Master's thesis/paper
Typology:2.09 - Master's Thesis
Organization:BF - Biotechnical Faculty
Publisher:[V. Pograjc]
Year:2024
PID:20.500.12556/RUL-163159 This link opens in a new window
UDC:544.18:616.858(043.2)
COBISS.SI-ID:211944451 This link opens in a new window
Publication date in RUL:03.10.2024
Views:148
Downloads:419
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Secondary language

Language:English
Title:Quantum chemical study of oxidative stress in dopaminergic neurons
Abstract:
L-DOPA is currently the gold standard of pharmacological interventions in the treatment of Parkinson's disease. The drug is a precursor of dopamine. Its use is associated with oxidative stress because at elevated pH levels, dopamine autoxidizes to form reactive oxygen species. L-DOPA is also capable of autoxidation where reactive oxygen species are formed. The drug can be incorporated into proteins due to its structural similarity to aromatic amino acids. It has not yet been known whether the autoxidation of L-DOPA can take place within a protein environment. This MSc thesis was designed to understand the autoxidation of L-DOPA at the molecular level. The rate-limiting step in the autoxidation of L-DOPA is the cyclisation of the dopaquinone, which proceeds by a Michael addition mechanism with proton transfer. We were interested in whether the reaction can take place within a protein environment. We have carried out the investigation at the quantum chemical level of theory using the cluster model method. We have chosen dopaquinone for the reaction which is incorporated into the active site of monoamine oxidase B reacting with OH-. We have obtained the activation free energy and the reaction free energy, which are 19,35 kcal/mol and -13,65 kcal/mol respectively, at a pH of 7,4 and 37°C. From the activation free energy of the reaction, we also calculated the rate constant and the half-life of the reaction, which are 0,16 s-1 and 4,33 s respectively. The reaction rate is pH dependent. We found that L-DOPA incorporated in proteins enters intermolecular Michael addition with proton transfer, which is mechanistically equivalent to the corresponding reaction in aqueous solution.

Keywords:L-DOPA, doquinone, autoxidation, oxidative stress, cluster model, Parkinson's disease, quantum chemistry, dopamine, reaction mechanism, reactive oxigen species

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