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Ομεηδναλαγωγηθά Έλδπκα Ωο Πξόηππα Εθαξκνγήο Ηεο Κεζόδνπ QSAR (Quantitative Structure-Activity Relations)

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Ομεηδναλαγωγηθά Έλδπκα Ωο Πξόηππα Εθαξκνγήο Ηεο Κεζόδνπ QSAR (Quantitative Structure-Activity Relations) ΔΘΝΗΚΟ ΚΑΗ ΚΑΠΟΓΗ΢ΣΡΗΑΚΟ ΠΑΝΔΠΗ΢ΣΖΜΗΟ ΑΘΖΝΩΝ ΢ΥΟΛΖ ΘΔΣΗΚΩΝ ΔΠΗ΢ΣΖΜΩΝ ΣΜΖΜΑ ΥΖΜΔΗΑ΢ ΜΔΣΑΠΣΤΥΗΑΚΟ ΠΡΟΓΡΑΜΜΑ ΢ΠΟΤΓΧΝ «ΚΑΣΑΛΤ΢Ζ ΚΑΗ ΔΦΑΡΜΟΓΔ΢ ΣΖ΢» ΔΡΔΤΝΖΣΗΚΖ ΔΡΓΑ΢ΗΑ ΓΗΠΛΧΜΑΣΟ΢ ΔΗΓΗΚΔΤ΢Ζ΢ Ομεηδναλαγωγηθά έλδπκα ωο πξόηππα εθαξκνγήο ηεο κεζόδνπ QSAR (Quantitative Structure-Activity relations) ΠΑΝΑΓΗΧΣΑ ΢. ΣΕΑΝΖ ΜΖΥΑΝΗΚΟ΢ ΣΔΥΝΟΛΟΓΗΑ΢ ΠΔΣΡΔΛΑΗΟΤ ΚΑΗ ΦΤ΢ΗΚΟΤ ΑΔΡΗΟΤ ΑΘΖΝΑ ΝΟΔΜΒΡΗΟ΢ 2011 ΔΡΔΤΝΖΣΗΚΖ ΔΡΓΑ΢ΗΑ ΓΗΠΛΧΜΑΣΟ΢ ΔΗΓΗΚΔΤ΢Ζ΢ Ομεηδναλαγσγηθά έλδπκα σο πξφηππα ηεο εθαξκνγήο ηεο κεζφδνπ QSAR (Quantitative Structrure-Activity relations) ΠΑΝΑΓΗΧΣΑ ΢. ΣΕΑΝΖ Α.Μ.: 281604 ΔΠΗΒΛΔΠΧΝ ΚΑΘΖΓΖΣΖ΢: Ι. ΜΑΡΚΟΠΟΤΛΟ΢ , Αλαπιεξσηήο Καζεγεηήο ΔΚΠΑ ΣΡΗΜΔΛΖ΢ ΔΞΔΣΑ΢ΣΗΚΖ ΔΠΗΣΡΟΠΖ Η. ΜΑΡΚΟΠΟΤΛΟ΢ Αλαπιεξωηεο θαζεγεηήο, Σκήκα Υεκείαο, ΔΚΠΑ Γ. ΥΑΣΕΖΝΗΚΟΛΑΟΤ Δπίθνπξνο Καζεγεηήο, Σκήκα Βηνινγίαο, ΔΚΠΑ Π. ΠΑΡΑ΢ΚΔΤΟΠΟΤΛΟΤ Λέθηνξαο, Σκήκα Υεκείαο, ΔΚΠΑ ΗΜΔΡΟΜΗΝΙΑ ΔΞΔΣΑ΢Η΢ 25/11/2011 2 ΠΔΡΗΛΖΦΖ ΢ε απηή ηε δηαηξηβή αξρηθά παξνπζηάδνληαη νη γεληθνί κεραληζκνί ελδπκηθήο θαηάιπζεο νη νπνίνη ζηε ζπλέρεηα εμεηδηθεχνληαη ζηνπο αληίζηνηρνπο κεραληζκνχο ησλ νμεηδνλαγσγηθψλ ζπζηεκάησλ ησλ θαηαιαζψλ θαη ππεξνμεηδαζψλ. Σν έλδπκν ππεξνμεηδάζε ηνπ αγξηνξάπαλνπ (horseradish peroxidase–HRP) απνηειεί ην θεληξηθφ έλδπκν αλαθνξάο ησλ αλσηέξσ κεραληζκψλ θαηάιπζεο ζηνπο νπνίνπο βαζίδεηαη θαη ε κειέηε ησλ ζρέζεσλ δνκήο-δξαζηηθφηεηαο ησλ ζπζηεκάησλ απησλ κέζσ ηεο κεζνδνινγίαο QSAR. Η εξγαζία νινθιεξψλεηαη κε ηελ αλάιπζε ησλ πεηξακαηηθψλ δεδνκέλσλ ηεο βηβιηνγξαθίαο πνπ αθνξνχλ ζηελ πξφβιεςε ησλ ηηκψλ θαη ησλ θηλεηηθψλ παξακέηξσλ δξάζεο ηεο HRP κέζσ QSAR ελψ εμάγνληαη ζπκπεξάζκαηα ηα νπνία απνδεηθλχνπλ ηφζν ηελ εθαξκνζηκφηεηα φζν θαη ηε ρξεζηκφηεηα ηεο πξνηεηλφκελεο κεζνδνινγίαο ζηα ζπζηήκαηα καο. ΘΔΜΑΣΗΚΖ ΠΔΡΗΟΥΖ: Δλδπκηθή θαηάιπζε ΛΔΞΔΗ΢ ΚΛΔΗΓΗΑ: βηνθαηάιπζε, έλδπκα, θαηαιάζεο, ππεξνμεηδάζε ηνπ αγξηνξάπαλνπ (HRP), ζρέζεηο δνκήο-δξαζηηθφηεηαο (QSAR) 3 ABSTRACT In this essay we present the concept of enzymatic catalysis and the general methods for the investigation of this phenomenon. We concentrated on the studies of oxidoreductases and especially in catalases and peroxidases. The application of the Quantitative Structure Activity Relationships (QSAR) methodology in enzymatic catalysis is also studied. The target enzyme is the horseradish peroxidase (HRP) and as substrates fifteen phenolic derivatives are used. The methodology presented correlates the enzymatic parameters km and kcat with molecular descriptors that give us a possible explanation of the enzymatic action. SUBJECT AREA: enzymatic catalysis KEYWORDS: biocatalysis, enzymes, catalases, horseradish peroxidase, QSAR 4 Αθιεπώνεηαι ζηην οικογένεια μος. 5 ΠΔΡΗΔΥΟΜΔΝΑ ΘΔΧΡΖΣΗΚΟ ΜΔΡΟ΢ ................................................................................................... 13 1. ΚΔΦΑΛΑΗΟ 1 ......................................................................................................... 14 1.1 Γεληθά ............................................................................................................... 14 1.2 Βηνθαηάιπζε ..................................................................................................... 15 2. ΚΔΦΑΛΑΗΟ 2 ΈΝΕΤΜΑ ........................................................................................ 16 2.1 Γεληθά ............................................................................................................... 16 2.2 Μεραληζκφο ηεο ελδπκαηηθήο θαηάιπζεο .......................................................... 17 2.3 Κηλεηηθή ελδπκηθψλ αληηδξάζεσλ ...................................................................... 18 2.3.1 Τπφζεζε Michaelis–Menten ..................................................................... 21 2.3.2 Τπφζεζε Briggs–Haldane ......................................................................... 23 2.3.3 ΢εκαζία ηεο ζηαζεξάο Michaelis–Menten (km) .......................................... 25 2.3.4 Γξαθηθή παξάζηαζε ησλ θηλεηηθψλ δεδνκέλσλ ......................................... 25 2.3.5 ΢πκπεξάζκαηα αμηνιφγεζεο ηεο εμίζσζεο Michaelis-Menten ................... 27 2.4 Αλαζηνιή ελδπκηθψλ αληηδξάζεσλ ................................................................... 28 2.4.1 Αληηζηξεπηή αλαζηνιή ............................................................................... 29 2.4.1.1 ΢πλαγσληζηηθή αλαζηνιή ..................................................................... 29 2.4.1.2 Με ζπλαγσληζηηθή αλαζηνιή ............................................................... 31 2.4.2 Με αληηζηξεπηή αλαζηνιή ......................................................................... 33 3. ΚΔΦΑΛΑΗΟ 3 ΚΑΣΑΛΑ΢Δ΢ ................................................................................... 34 3.1 Δηζαγσγή.......................................................................................................... 34 3.2 Καηεγνξίεο ελδχκσλ «θαηαιάζεο» ................................................................... 35 3.3 Ο ξφινο ηεο θαηαιάζεο .................................................................................... 36 3.4 Κηλεηηθέο ........................................................................................................... 37 3.4.1 Η θαηαιπηηθή δηάβαζε ................................................................................ 37 3.4.2 Η ππεξνμεηδηθή δξαζηηθφηεηα ησλ θαηαιαζψλ ........................................... 41 6 3.5 Έιεγρνο απφ NADPH : Η "πξφζζεηε" δηάβαζε ................................................ 43 3.6 Η θαηαιπηηθή δξαζηηθφηεηα ησλ θαηαιάζσλ–ππεξνμεηδαζψλ .......................... 46 3.7 Μεραληζκφο ηεο θαηαιπηηθήο αληίδξαζεο ......................................................... 48 3.7.1 ΢ρεκαηηζκφο ηεο έλσζεο Ι ......................................................................... 48 3.7.2 Αλαγσγή ηεο έλσζεο Ι ............................................................................... 52 4. ΚΔΦΑΛΑΗΟ 4 Τπεξνμεηδάζεο .............................................................................. 55 4.1 Δηζαγσγή.......................................................................................................... 55 4.2 Καηαζηάζεηο νμείδσζεο ηεο νηθνγέλεηαο ηεο ππεξνμεηδάζεο ............................ 58 4.3 Καηαιπηηθή πεξηνρή ηεο νηθνγέλεηαο ησλ ππεξνμεηδαζψλ ................................ 59 4.4 Βάζε δεδνκέλσλ ππεξνμεηδαζψλ (PeroxiBase) ............................................... 61 5. ΚΔΦΑΛΑΗΟ 5 ΤΠΔΡΟΞΔΗΓΑ΢Ζ ΑΓΡΗΟΡΑΠΑΝΟΤ (Horseradish Peroxidase) 64 5.1 Δηζαγσγή.......................................................................................................... 64 5.2 Πεξηγξαθή ηνπ ελδχκνπ .................................................................................... 66 5.2.1 Γεληθά ραξαθηεξηζηηθά ............................................................................... 66 5.2.2 Σξηζδηάζηαηε δνκή ..................................................................................... 70 5.2.3 HRP θαη ηεο ππεξνηθνγέλεηαο θπηηθψλ ππεξνμεηδαζψλ ............................. 71 5.3 Μεραληζκφο δξάζεο ......................................................................................... 72 5.3.1 Λεηηνπξγηθφο ξφινο .................................................................................... 72 5.3.2 Καηαιπηηθφο κεραληζκφο ............................................................................ 73 5.4 Σν δήηεκα ηνπ ηζνέλδπκνπ, ηεο ππεξνεηδάζεο ηνπ αγξηνξάπαλνπ θαη νη Arabidopsis ππεξνμεηδάζεο ........................................................................................ 75 5.4.1 Η νηθνγέλεηα ηνπ ηζνέλδπκνπ ηεο ππεξνμεηδάζεο ηνπ αγξηνξάπαλνπ ........ 75 ΠΔΗΡΑΜΑΣΗΚΟ ΜΔΡΟ΢ ................................................................................................ 77 6. ΚΔΦΑΛΑΗΟ 6 Πνζνηηθή θαη πνηνηηθή πεξηγξαθή ηεο ζπζρέηηζεο ηωλ δνκηθώλ ραξαθηεξηζηηθώλ ηωλ κνξίωλ κε ηελ ππό κειέηε δξαζηηθόηεηα/ηδηόηεηα. ............................................................................................................................... 78 6.1 Δηζαγσγή.......................................................................................................... 78 6.2 Μέζνδνο ........................................................................................................... 79 7 6.2.1 ΢ηάδην 1. Αλάπηπμε κνληέινπ πνζνηηθήο ζπζρέηηζεο δνκήο– δξαζηηθφηεηαο/ηδηνηήησλ ........................................................................................ 79 6.2.2 ΢ηάδην 2. ΢ρεδηαζκφο λέσλ κνξίσλ ........................................................... 81 6.2.3 ΢ηάδην 3. ΢χλζεζε θαη αμηνιφγεζε–Αλαηξνθνδφηεζε ηεο βάζεο δεδνκέλσλ ................................................................................................................... 82 6.3 Δπίιπζε πξνβιεκάησλ .................................................................................... 83 6.4 Δθαξκνγέο ηνπ κνληέινπ ή αλάπηπμε κνληέινπ QSAR ζηελ ππεξνμεηδάζε αξγηνξάπαλνπ ............................................................................................................ 84 6.4.1 Δηζαγσγή ................................................................................................... 84 6.4.2 QSAR ζε βηνινγηθά κφξηα π. ρ. έλδπκα ...................................................... 84 6.4.2.1 Πξνζδηνξηζκφο ηνπ km θαη kCAT ............................................................ 87 6.4.2.2 ΢ρέζεηο κεηαμχ ηεο ζηαζεξάο αλαινγίαο ηεο Αληίδξαζεο θαη ησλ κνξηαθψλ δνκψλ ηνπ Τπνζηξψκαηνο ................................................................. 87 6.4.2.3 Πνζνηηθή απφθιηζε απφ ην κνληέιν kCAT/EHOMO: Μνξηαθφο φγθνο (VM). ...........................................................................................................
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