神經節苷脂為一類富含唾液酸的醣神經鞘脂，主要存在於神經細胞表面，參與神經系統的發育及分化、軸突與髓鞘之間的作用以及細胞間訊息傳遞。部分神經節苷脂也被發現大量表現於癌細胞表面，幫助癌細胞生長以及躲避免疫系統的攻擊。由於神經節苷脂參與許多生理作用，因此具有發展治療神經退化疾病藥物與癌症疫苗之潛力。
為發展抗癌疫苗以及探討 Siglecs 與醣體間作用力，本論文利用酵素方法階段性一鍋化合成神經節苷脂醣體 GM3、GM2、GM1、GD1a、GT1a、GD3、GD2、GT1b、GT3、GT2、GA2、GA1與GM1b，並以核苷再生系統合成 GD1b 以及 GT1c。此外，利用不同來源的α2,6-唾液酸轉移酶 (Pd2,6ST 與 Psp2,6ST) 催化 GD1a 進行α2,6-唾液酸化反應，發現兩者具有不同反應位置選擇性，得到 GT1aα 與神經節苷脂系列之外的醣體。本論文亦成功合成末端唾液酸九號羥基修飾為O-乙醯基與N-乙醯基之 GD2，將來可用於開發抗癌疫苗之研究。

Gangliosides, a subclass of glycosphingolipids, comprise a structurally diverse set of sialylated glycans that are found in most cells but are particularly abundant in nervous system. Many gangliosides involve in brain development, axon-myelin interaction, and cell signal transduction. In addition, some of them are well-known tumor associated antigens. Since gangliosides are involved in many biological processes, they are considered as potential candidates for treating neurodegenerative diseases and cancer immunotherapies. Therefore, synthesis of these sialoglycans for further research is essential.
In this thesis, multiple enzymes from various sources were used to synthesize o-, a-, b- and c-series gangliosides successfully. Most of the enzymatic syntheses were conducted by a sequential one-pot manner while some of them were performed by using UDP-sugar nucleotide regeneration system in order to simplify the purification of intermediates. During the α2,6-sialylation of GD1a glycan, we found that α2,6-sialyltransferases from different species (Pd2,6ST and Psp2,6ST) showed different selectivity to acceptors with galactosyl configuration. Moreover, the synthesis of OAcGD3 was achieved by using 9-O-acetyl-sialic acid as a donor precursor, which was obtained by acetylation of sialic acid using serine esterase BPN’. A β-1,4-N-acetylgalactosaminylation was applied to assemble GalNAc on OAcGD3 to successfully yielded OAcGD2, a potential carbohydrate antigen for improvement of previous GD2-based anti-cancer vaccine.

摘要 I
Abstract II
目錄 III
圖目錄 VI
表目錄 X
流程目錄 XII
縮寫表 XV
單醣中英文名稱與代表符號 XVII
酵素中英文名稱對照表 XVIII
第一章、緒論 1
1.1 酵素於醣體合成的重要性 1
1.2 唾液酸 (Sialic Acid) 3
1.3 神經節苷脂 (Ganglioside) 5
1.2.1 神經相關神經節苷脂 9
1.2.2 癌症相關神經節苷脂 11
1.4 唾液酸免疫球蛋白凝集素 19
1.3.1 Siglec-4 (MAG) 24
1.3.2 Siglec-7 25
1.5 醣激酶與醣基轉移酶 26
1.5.1 醣激酶 (GalK、NahK、FKP) 28
1.5.2 磷酸醣核苷轉移酶 (GlmU、AtUSP、CSS) 30
1.5.3 醣基轉移酶 35
1.5.4 唾液酸轉移酶 (PmST1、PdST、PspST、CstI、CstII、NgST) 44
1.6 研究目標與動機 60
第二章、實驗結果與討論 62
2.1 以大腸桿菌誘導表現目標蛋白 62
2.1.1 勝任細胞 62
2.1.2 目標酵素純化與表現分析 63
2.1.3酵素表達分析 68
2.2 酵素系統合成神經節苷脂醣體 89
2.2.1 a-series醣體合成 89
2.2.2 b-series 和 c-series 醣體合成 109
2.2.3 o-series 醣體合成 122
2.3 結論 127
第三章、未來展望 129
第四章、實驗材料與方法 130
4.1 Materials 130
4.1.1 General 130
4.1.2 Machines 131
4.1.3 Enzymes 132
4.1.4 Vectors 132
4.2 General procedure of overexpression and purification of target enzymes 133
4.2.1 General procedure of enzyme overexpression 133
4.2.2 Purification of target enzymes 134
4.3 Synthetic procedures and characterization 136
第五章、參考文獻 182
附錄 205
附錄目錄 207

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