臺灣博碩士論文加值系統

蛋白質的轉譯後修飾反應是指胺基酸與親電性分子形成加成物改變蛋白質的結構、性質產生變化。硝化脂肪酸在轉譯後修飾反應中會與硫醇進行Michael addition 反應，這個過程可以發揮保護人體及抗發炎的功能，被認為有利於治療各種疾病，像是糖尿病、腎損傷及內發毒血症等。如同硝化脂肪酸一樣，15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2)也是屬於第二型烯烴(Type-2 alkene)。15d-PGJ2 是PPARγ 的活化劑，具有抗發炎及抗癌的效果。上述所提到的這些具
有生物活性的親電性物質以及殘留基的反應及加成物，我們使用密度泛函理論進行研究。除了具有生物活性的硫醇之外，含有生物活性的胺類分子與親電性物質所形成的Schiff base 加成物也是我們研究的重點。

另外我們研究數種不同的第二型烯烴， 例如:α,β-unsaturated carbonyl compounds (α,β 未飽和羰基化合物)，這些物質被認為經由與Cysteine 硫醇的鍵結會產生神經毒性。我們比較第二型烯烴與親電性物質的反應性，從我們的結果顯示第二型烯烴的毒性是因為它們更能夠放熱，換句話說這些加成物更不具有可逆性質。

The post-translational modification of protein refers that amino acid, such as thiol groups of cysteine, imidazole moiety of histidine and the ε-amino group of
lysine residues, form adducts with electrophiles, and modify protein’s structures and functions. Nitro-fatty acids (NO2-FA) exert protective and anti-inflammatory via
Michael addition to thiol groups in post-translational modifications, they have been shown to be beneficial in treating diseases such as diabetes, renal injury, and
endotoxemia. Similar to NO2-FA, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is also Type-2 alkene . 15d-PGJ2 is PPARγ agonist that has anti-inflammatory and
significant anti-cancer effect. The adduct formations of these reactions of these biologyical electro-philes with the residues mentioned above are investigated using
density functional theory. In addition to biological thiols, the adduct formations of biological amines with the electrophiles via Schiff base formation is also investigated.

Furthermore, we investigated several Type-2 alkenes, i.e., α,β-unsaturated carbonyl compounds, which have been identified to be neurotoxicity via forming adducts with sulfhydrl groups of Cysteine residue. We have compared the reactivity of Type-2 alkenes with the electrophiles, our computations reveal that the toxicity of Type-2 al-kenes are attributed to their more exergonic, i.e., less reversible adduct formations.

目錄
摘要................................................................................................................................ I
Abstract ......................................................................................................................... II
目錄.............................................................................................................................. III
Figure 目錄 .................................................................................................................. V
Scheme 目錄 ............................................................................................................... IX
第1 章 緒論........................................................................................................ 1
1-1 第二型烯烴化合物 ......................................................................................... 1
1-1-1 硝化脂肪酸 ..................................................................................................... 2
1-1-2 15-deoxy-Δ12,14-prostaglandin J2 ................................................................. 5
1-1-3 α,β 未飽和羰基化合物 ................................................................................... 6
1-2 轉譯後修飾反應 ............................................................................................. 7
第2 章 理論計算方法........................................................................................ 9
第3 章 結果與討論.......................................................................................... 10
3-1 第二型烯烴與含硫分子的研究 ................................................................... 10
3-1-1 第二型烯烴小型分子模型的研究 ............................................................... 12
3-1-2 第二型烯烴與Cysteine 衍生物的研究 ....................................................... 23
3-2 第二型烯烴與Histidine 的反應 .................................................................. 50
3-2-1 小型分子 ....................................................................................................... 51
3-2-2 Histidine 與第二型烯烴反應機制的探討 ................................................... 55
3-2-3 Histidine 與第二型烯烴的反應 ................................................................... 59
3-3 第二型烯烴與Lysine 的反應 ...................................................................... 79
3-3-1 Lysine 結構的探討 ....................................................................................... 79
3-3-2 Lysine 與第二型烯烴的反應機制 ............................................................... 81
3-3-3 Lysine 與第二型烯烴的反應探討 ............................................................... 86
第4 章 結論.................................................................................................... 103
參考文獻.................................................................................................................... 105

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