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Ġstanbul Ünġversġtesġ Fen Bġlġmlerġ Enstġtüsü ĠSTANBUL ÜNĠVERSĠTESĠ FEN BĠLĠMLERĠ ENSTĠTÜSÜ YÜKSEK LĠSANS TEZĠ ASETĠLKOLĠNESTERAZ’IN BAZI TIBBĠ BĠTKĠLER TARAFINDAN ĠNHĠBĠSYONU Kimyager Nayat ORAK Kimya Anabilim Dalı Biyokimya Programı DanıĢman Prof.Dr. Refiye YANARDAĞ Ocak, 2011 ĠSTANBUL ĠSTANBUL ÜNĠVERSĠTESĠ FEN BĠLĠMLERĠ ENSTĠTÜSÜ YÜKSEK LĠSANS TEZĠ ASETĠLKOLĠNESTERAZ’IN BAZI TIBBĠ BĠTKĠLER TARAFINDAN ĠNHĠBĠSYONU Kimyager Nayat ORAK Kimya Anabilim Dalı Biyokimya Programı DanıĢman Prof.Dr. Refiye YANARDAĞ Ocak, 2011 ĠSTANBUL Bu çalıĢma Ġstanbul Üniversitesi Bilimsel AraĢtırma Projeleri Yürütücü Sekreterliği’nin T-3366 numaralı projesi ile desteklenmiĢtir. ÖNSÖZ Lisans ve yüksek lisans öğrenimim sırasında ve tez çalıĢmalarım boyunca gösterdiği her türlü destek ve yardımdan dolayı çok değerli hocam Sayın Prof. Dr. Refiye YANARDAĞ’a en içten dileklerimle teĢekkür ederim. Bu çalıĢma boyunca yardımlarını esirgemeyen Sayın Doç.Dr. Özlem SAÇAN’a teĢekkür eder, gösterdikleri ilgi ve anlayıĢ için Yrd. Doç. Dr. Sevim TUNALI, Ar. Gör. Bertan Boran BAYRAK ve Ar. Gör. Ġsmet Burcu TÜRKYILMAZ’a teĢekkürü bir borç bilirim. Hayatım boyunca benden maddi, manevi desteklerini esirgemeyen ve her zaman yanımda olan çok sevgili aileme en içten duygularımla teĢekkür ederim. ÇalıĢmamın uygulama kısmını destekleyen Ġstanbul Üniversitesi Bilimsel AraĢtırma Projeleri Koordinasyon Birimi’ne teĢekkür ederim. Ocak, 2011 Kimyager Nayat ORAK i ĠÇĠNDEKĠLER ÖNSÖZ i ĠÇĠNDEKĠLER ......................................................................................... ii ġEKĠL LĠSTESĠ ........................................................................................ iv TABLO LĠSTESĠ ......................................................................................vi SEMBOL LĠSTESĠ ................................................................................. vii ÖZET viii SUMMARY ................................................................................................ x 1. GĠRĠġ ...................................................................................................... 1 2. GENEL KISIMLAR ............................................................................... 4 2.1. ENZĠMLER ............................................................................................................ 4 2.1.1. Enzimlerin Genel Özellikleri ....................................................................... 4 2.1.2. Enzim Ġnhibisyonu ve Aktivasyonu ............................................................ 5 2.1.3. Enzimlerin Adlandırılması .......................................................................... 8 2.2. ASETĠLKOLĠNESTERAZ ENZĠMĠ ............................................................... 9 2.2.1. Asetilkolinesteraz Enziminin Biyolojik Önemi ........................................ 10 2.2.2. Asetilkolinesteraz Enziminin Moleküler Formlerı ve Moleküler Yapı- Aktivite ĠliĢkisi ............................................................................................. 13 2.3. ASETĠLKOLĠNESTERAZ ĠNHĠBĠTÖRLERĠ ............................................ 16 2.3.1. Alzheimer Hastalığı ve Alzheimer Hastalığında Kullanılan Reversibl Asetilkolinesteraz Ġnhibitörleri .................................................................. 17 2.3.2. Ġrreversibl Asetilkolinesteraz Ġnhibitörleri (Organofosfatlar) ............... 23 2.3.2.1. İnsektisitler……………………………………………………………………...24 2.3.2.2. Sinir Gazları....………………………………………………………………....25 3. MALZEME VE YÖNTEM ................................................................. 28 ii 3.1. DENEYLERDE KULLANILAN ALET VE CĠHAZLAR ................................ 28 3.2. DENEYLERDE KULLANILAN KĠMYASAL MADDELER ........................ 28 3.3. ENZĠM ĠNHĠBĠSYONU TAYĠNLERĠNDE KULLANILAN BĠTKĠ MATERYALĠ ....................................................................................................... 29 3.3.1. Sulu Ekstrelerin Hazırlanması ................................................................. 30 3.3.2. Etil Alkollü, Asetonlu ve Etil Asetatlı Ekstrelerin Hazırlanması ........... 30 3.4. ENZĠM ĠNHĠBĠSYONU TAYĠNLERĠNDE KULLANILAN KĠMYASAL MADDELER ........................................................................................................ 30 3.5. ASETĠLKOLĠNESTERAZ ĠNHĠBĠSYON ETKĠSĠNĠN ĠNCELENMESĠ .... 33 4. BULGULAR ......................................................................................... 35 4.1. BĠTKĠ EKSTRELERĠNĠN ASETĠLKOLĠNESTERAZ ÜZERĠNE ĠNHĠBĠTÖR ETKĠLERĠ ...................................................................................... 35 4.2. KĠMYASAL MADDELERĠN ASETĠLKOLĠNESTERAZ ÜZERĠNE ĠNHĠBĠTÖR ETKĠLERĠ ...................................................................................... 57 5. TARTIġMA VE SONUÇ ..................................................................... 63 KAYNAKLAR .......................................................................................... 79 ÖZGEÇMĠġ ............................................................................................ 100 iii ġEKĠL LĠSTESĠ ġekil 2.1.2.1 : YarıĢmalı (kompetitif) inhibisyonun reaksiyon Ģeması........................ ..6 ġekil 2.1.2.2 : YarıĢmasız (nonkompetitif) inhibisyonun reaksiyon Ģeması ............... ..7 ġekil 2.1.2.3 : Yarı yarıĢmalı (ankompetitif) inhibisyonun reaksiyon Ģeması ............. ..7 ġekil 2.2.1.1 : Asetilkolinin sentez reaksiyonu............................................................ 11 ġekil 2.2.1.2 : Sinir hücresinin yapısı .......................................................................... 11 ġekil 2.2.1.3 : Nöronların diğer nöronlara ya da kas veya salgı bezleri gibi nöron olmayan hücrelere mesaj iletimine olanak tanıyan özelleĢmiĢ bağlantı noktaları olan sinapsların gösterimi .......................................................... 12 ġekil 2.2.1.4 : Asetilkolinin yıkım reaksiyonu ................................................................ 13 ġekil 2.2.2.1 : Asetilkolinesterazın; (a) üç boyutlu yapısı, (b) kristal yapısı ............... 14 ġekil 2.2.2.2 : Asetikolinin katalitik bölge tarafından hidrolizasyonunun mekanizması ......................................................................................... 15 ġekil 2.2.2.3 : Asetilkolinesteraz molekülünü karakterize eden bölgelerin genel gösterimi ............................................................................................... 16 ġekil 2.3.1 : Asetilkolinesteraz inhibitörlerinin saldırı mekanizmaları ......................... 17 ġekil 2.3.1.1 : Alzheimer hastalığında görülen beyin atrofisi ..................................... 18 ġekil 2.3.1.2 : Alzheimer hastalığına yol açtığı düĢünülen amiloid plaklar ve nörofibriler yumaklar ........................................................................... 18 ġekil 2.3.2.1 : Organofosfatların genel kimyasal yapısı .............................................. 23 ġekil 3.5.1.2 : Ellman yönteminde gerçekleĢen renk reaksiyonu ................................ 33 ġekil 4.1.1 : Adaçayının sulu ekstresinin % inhibisyon grafiği .................................... 39 ġekil 4.1.2 : Kaparinin sulu ekstresinin % inhibisyon grafiği ....................................... 39 ġekil 4.1.3 : Oğul otunun sulu ekstresinin % inhibisyon grafiği ................................... 40 ġekil 4.1.4 : Soğanın sulu ekstresinin % inhibisyon grafiği .......................................... 40 ġekil 4.1.5 : Biberiyenin etil alkollü ekstresinin % inhibisyon grafiği ......................... 44 ġekil 4.1.6 : Muzun etil alkollü ekstresinin % inhibisyon grafiği ................................. 44 ġekil 4.1.7 : Sakız ağacının etil alkollü ekstresinin % inhibisyon grafiği ..................... 45 ġekil 4.1.8 : ġahtere otunun etil alkollü ekstresinin % inhibisyon grafiği .................... 45 ġekil 4.1.9 : Havucun asetonlu ekstresinin % inhibisyon grafiği .................................. 49 ġekil 4.1.10 : Isırgan otunun asetonlu ekstresinin % inhibisyon grafiği .................... 49 ġekil 4.1.11 : Sarımsağın asetonlu ekstresinin % inhibisyon grafiği ......................... 50 ġekil 4.1.12 : YeĢil çayın asetonlu ekstresinin % inhibisyon grafiği ......................... 50 ġekil 4.1.13 : Baklanın etil asetatlı ekstresinin % inhibisyon grafiği ......................... 54 ġekil 4.1.14 : Muzun etil asetatlı ekstresinin % inhibisyon grafiği ............................ 54 ġekil 4.1.15 : Soğanın etil asetatlı ekstresinin % inhibisyon grafiği .......................... 55 ġekil 4.1.16 : ġahtere otunun etil asetatlı ekstresinin % inhibisyon grafiği ............... 55 ġekil 4.2.1 : β-Karotenin % inhibisyon grafiği ............................................................. 60 ġekil 4.2.2 : (+)-α-Lipoik asidin % inhibisyon grafiği .................................................. 61 ġekil 4.2.3 : Edaravonun % inhibisyon grafiği ............................................................. 61 ġekil 4.2.4 : L-Prolinin % inhibisyon grafiği ................................................................ 62 iv ġekil 5.1 : Sinir hücresinin dıĢında topaklanma özelliği gösteren βA1-42 peptidleri .............................................................................................. 66 ġekil 5.2 : Asetilkolin sentezi ..................................................................................... 72 ġekil 5.3 : Adaçayında bulunan monoterpenoid yapıdaki güçlü asetilkolinesteraz inhibitörleri ........................................................................................... 75 v TABLO LĠSTESĠ Tablo 2.2.1 : Asetilkolinesteraz substratları ve bunların
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