利用化學結合法修飾蛋白質為目前研究蛋白質體學（proteomics）的關鍵技術之一，並且有助於探討蛋白質聯絡網，協助拼湊複雜的生物機制。利用光親和性基團位向專一性地修飾於蛋白質活性中心附近，建構蛋白質探針，將蛋白質探針丟入未知複雜系統中，當未知蛋白質與蛋白質探針因具親和力互相結合後，經由不破壞其作用力之溫和照光便可將蛋白質探針與未知蛋白質交聯，藉此探討蛋白質探針與未知蛋白質間的交互關係。
本論文合成了AGD（affinity-guided DMAP）-甘露醣探針，利用甘露醣與刀豆凝集素之間親和力成功將生物素選擇性地修飾於刀豆凝集素的活性中心附近。
另外，還合成了不同長度的乳糖三級胺催化劑與一級胺探針，結合CDMT的化學，活化蛋白質的羧基，成功將生物素標記於蓖麻凝集素活性中心附近，利用帶有鏈黴親和素的固相載體將之純化，並且經由照光將修飾於蛋白質上的光敏化斷裂基團光解，將蓖麻凝集素從固相載體上釋放，最後利用CuAAC反應再一次修飾生物素。
另一方面，本論文將光親和性基團修飾於蓖麻凝集素的活性中心附近，利用帶有單元抗生物素蛋白的磁珠固相載體將蛋白質純化，建構凝集素探針。最後，利用蛋白質探針與醣蛋白-卵清蛋白光照交聯，並將此系統應用於蛋白質池與大腸桿菌溶解產物中，於單純系統與複雜系統中均得到交聯之產物。

Protein labeling probes not only become a powerful tool for protein trafficking but also provide a route to elucidate protein-protein interactions. By assembling a photoactive group near the binding site of the protein probe, the unknown interacting protein(s) with high affinity toward the protein probe can be captured under mild photo-activation without disturbing protein structure.
In this thesis, We synthesized dimethylaminopyridine (AGD)-mannose probe to label Concanavalin A (Con A) with a biotin at the place near the ligand binding site with high selectivity because of the affinity between mannose and ConA.
We also synthesized the lactose-tethered tertiary amine with different lengths of linkers and primary amine probes for Ricinus communis Agglutinin (RCA120) labeling using CDMT chemistry approach which activated the carboxylate group. The biotinylated RCA120 was purified by agarose streptavidin beads and then photocleaved the o-nitrobenzyl ether tether to release the labeled protein from the solid support and the resulting biotinylated RCA120 was further modified by click reaction.
Moreover, we constructed RCA120 lectin probe by labeling the photoaffinity group at the place near the lactose binding site and the purification of labeled protein was achieved by using monomeric avidin magnetic beads. We photocrosslinked our RCA120 lectin probe to glycoprotein-Ovalbumin (OVA) and applied this system to the protein pool and E. Coli. cell lysates. We successfully got the photocrosslinked product in both the pure buffer condition and mixture condition.

第一章　緒論 1
1.1 前言 1
1.2 蛋白質間交互作用（protein-protein interactions） 1
1.2.1 蛋白質間作用力之種類 3
1.2.2 研究蛋白質間作用力之方法 4
1.2.2.1 免疫沉澱法（immunoprecipitation）與蛋白質沉澱法（pull down assay） 5
1.2.2.2 遠端西方墨點法（Far-Western Blot） 7
1.2.2.3 雙雜交（two-hybrid）系統 9
1.2.2.4 分子影像法（molecular image） 11
1.2.2.5 化學交聯法（chemical crosslinking） 12
1.2.2.6 標記轉移法（label transfer） 18
1.3 蛋白質修飾（protein modification） 24
1.3.1 融合蛋白（fusion protein） 25
1.3.2 胜肽鏈（peptide） 26
1.3.2.1 組胺酸標籤（His tag） 27
1.3.2.2 四半胱胺酸標籤（tetracysteine, FlAsH） 28
1.3.2.3 Sortase A 28
1.3.2.4 硫辛酸連接酶（lipoic acid ligase, LplA） 29
1.3.3 化學結合法 30
1.3.3.1 殘基專一性（residue-specific） 30
1.3.3.2 位相專一性（site-specific） 32
1.3.3.2.1 生物正交結合法（bioorthogonal chemistry） 33
1.3.3.2.2 配位基導向標記法（Ligand-directed labeling method）35
1.4 光親和性官能基（Photoaffinity group） 39
1.5 光敏化斷裂官能基（photocleavage group） 42
1.6 半乳醣凝集素（Galectin） 44
1.6.1 Galectin-1與漿細胞（plasma cell）的關係 45
1.7 研究動機與目的 47
第二章　親和力導向DMAP催化（AGD）探針合成與凝集素標記 49
壹. 親和力導向DMAP催化（AGD）探針的設計與機制 49
貳. 親和力導向DMAP催化（AGD）探針的實驗結果與討論 50
2.1 Sugar-tethered DMAP（STD）的合成 50
2.1.1. 4-(methylamino)pyridine的合成 50
2.1.2. 乳醣配位基探針的合成 52
2.1.3. 甘露醣配位基探針的合成 53
2.2 Acyl donor的合成 55
2.2.2. 光親和性基團acyl donor 57
2.2.3. 生物素（biotin）acyl donor 59
2.3 Acyl donor穩定度測試 60
2.4 AGD 探針應用於不同蛋白質的標記 62
2.5 AGD探針於蛋白質池中標記ConA與RCA120 71
參. 總結 74
第三章　三級胺（TA）探針的合成與凝集素標記之蛋白質間作用力的研究 75
壹. 三級胺（Tertiary amine, TA）探針的設計與機制 75
貳. 三級胺（Tertiary amine, TA）探針的實驗結果與討論 77
2.1 Sugar-tethered tertiary amine（STTA）的合成 77
2.1.1. 短鏈STTA的合成 81
2.1.2. 中鏈與長鏈STTA的合成 82
2.1.3. N-乙醯乳糖胺（N-acetyl-lactosamine，LacNAc）STTA合成 85
2.2 Primary amine tag的合成 86
2.2.1. 螢光primary amine tag的合成 87
2.2.2. 光解primary amine tag的合成 88
2.2.2.1 化合物44的合成 89
2.2.2.2 化合物48的合成 90
2.2.2.3 化合物52的合成 90
2.2.3. 光親和性基團primary amine tag的合成 91
2.3 三級胺（TA）探針之初步應用 92
2.3.1 三級胺（TA）探針螢光標記於RCA120 92
2.3.2 三級胺（TA）探針生物素標記於Galectin-1 98
2.4 光解primary amine tag標記於RCA120之應用 99
2.4.1 光解primary amine tag標記RCA120之純化 101
2.4.2 光解primary amine tag標記RCA120之光解 103
2.4.3 光解primary amine tag標記RCA120之生物結合修飾 107
2.5 光親和性基團primary amine tag標記於RCA120之應用 109
2.5.1 光親和性基團primary amine tag標記RCA120之效率 111
2.5.2 光親和性基團primary amine tag標記RCA120之純化 112
2.6 蛋白質探針在單純環境中進行蛋白質間交聯反應之研究 116
2.7 蛋白質探針在複雜環境中進行蛋白質間交聯反應之研究 127
參. 總結 130
第四章　結論 132
第五章　實驗部分 134
參考文獻及資料 184
附錄 196

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