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研究生： 陳昱心
Chen, Yu-Hsin
論文名稱： 建立細胞或酵素之試驗方法以分析人類疾病相關之聚醣代謝
Establishment of the cell- or enzyme-based approaches to analyze disease-associated human glycan metabolism
指導教授： 鄭偉杰
Cheng, Wei-Chieh
共同指導教授: 周鶴軒
Chou, Ho-Hsuan
學位類別： 碩士
Master
系所名稱： 理學院 - 化學系
Department of Chemistry
論文出版年： 2019
畢業學年度： 107
語文別： 英文
論文頁數： 129
中文關鍵詞： 溶小體儲積症 、第二型黏多醣症 、己醛糖酸鹽硫酸酶 、肝黏醣硫酸鹽 、酸水解甲基化法 、小分子酵素穩定劑 、高程度甘露醣聚醣 、高基氏體甘露醣酶 、寡醣受質 、選擇性抑制劑
外文關鍵詞： LSDs, MPS II, GAGs, Iduronate-2-sulfatase, heparan sulfate, methanolysis, High-mannose type glycan, hGMII, Oligosccharide-based substrate, Selective inhibitor
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    • 聚醣是一種在人體中必需的生物材料，其功能為調節人體中細胞或是訊息傳遞等生理功能，像是細胞與細胞之連結與傳遞訊息之橋樑以及細胞與周邊胞內間質的交互作用。聚醣包括了寡醣或是多醣存在於人體中，而這些醣類的生合成以及代謝在特定疾病中扮演了可能誘發致病的重要角色。本篇論文主要分為兩個部分，第一部分講述了罕見疾病-溶小體儲積症，其致病機制為遺傳基因的缺陷造成特定的溶小體酵素失去正常功能，導致其受質大量堆積於溶小體中，使得細胞功能異常並更進一步造成組織以及器官無法正常運作。現行的溶小體儲積症的治療方法包括了酵素取代療法、藥理小分子伴護療法以及小分子穩定劑共同治療等。然而在溶小體儲積症中，其中又以黏多醣症的小分子藥物開發最為艱困，原因為現行平台不夠完備以致無法有效率地進行分子庫的篩選。本篇論文將以第二型黏多醣症為主要的研究方向，第二型黏多醣症又稱作韓特氏症，其致病機制為病患體中缺乏了己醛糖酸鹽硫酸酶，導致其受質皮膚素硫酸鹽及肝黏醣硫酸鹽兩種多醣類的代謝異常並堆積。為了要建立小分子檢測平台作為治療第二型黏多醣症的藥物開發，我們嘗試開發酵素以及細胞之檢測平台並且針對酵素標靶或是受質致病表徵的改變來檢測小分子的潛在應用。另外，瞭解黏多醣症病人與正常人之間的差異也是一個重要的指標來判斷小分子的效果，因此我們建立了黏多醣症病人或正常人的酵素平台對於酵素的熱穩定性與細胞內的酵素活性實驗來針對小分子酵素穩定劑作評估。另一方面，觀察其受質致病表徵也是一種評判小分子效果的方法，主要目的為判斷其大量累積的受質在小分子參與下是否能夠減少以達到治療效果，但其受質為大分子多醣在藥物研究中其難以檢測，因此我們嘗試了化學標誌方法以及酸水解甲基化法。然而在開發化學標誌方法中，我們尚須在製備艾杜醣醛酸的標準品以及樣品的前處理中進行可行性的評估。同時，我們成功利用酸水解甲基化法藉由液相串聯式質譜儀評估肝黏醣硫酸鹽在正常人與黏多醣症病人細胞中的差異。在此初步成果中，希望此酵素與細胞試驗在未來能夠運用在分子庫檢測以利開發治療黏多醣症的小分子藥物。
    在第二部分中，高程度甘露醣聚醣在癌症細胞或是正常細胞中扮演著細胞增生的重要角色。人類高基氏體甘露醣酶是一種水解酵素並且是一個藥物開發中已知的癌症標靶，而目前已知具有抗癌活性的天然物苦馬豆素是一種強力的高基氏體甘露醣酶抑制劑，但同時也會抑制溶小體甘露醣酶而造成了高程度甘露醣聚醣無法正常代謝並累積在溶小體中並在藥物臨床開發中造成負面影響。為了克服苦馬豆素對於高基氏體甘露醣酶與溶小體甘露醣酶的不良選擇性，其具有潛力的選擇性抑制劑會透過人工螢光受質試驗篩選出來。然而在簡易版的人工螢光受質試驗無法精確的探討抑制劑在酵素與真實受質的結合情況。因此我們嘗試建立以寡醣作為真實受質的檢測平台，來更進一步確認具有潛力之選擇性抑制劑的抑制效果。最後我們成功利用酵素化學合成法製備螢光標定的寡醣作為高基氏體甘露醣酶與溶小體甘露醣酶的受質。與此同時，我們也建立寡醣受質檢測方法來評估了具有潛力的高基氏體甘露醣酶抑制劑的選擇性抑制能力，並且更進一步利用此平台來探討酵素動力學之抑制模式。最後我們發現利用了不同受質的檢測平台來評估具有潛力之抑制劑確實會觀察到不同的抑制效果，並且也會在酵素動力學研究中造成不同抑制模式。針對此結果，我們提供了真實的寡糖受質檢測平台來幫助未來在高基氏體甘露醣酶選擇性抑制劑的開發。

    Glycans are necessary bio-materials for physiological function regulating like cell-cell communication or cell-matrix interaction. Moreover, the balance of biosynthesis and metabolism toward the many oligo- or polysaccharides is very important and relates to diseases.
    The first part described lysosomal storage diseases (LSDs), a kind of rare inherited diseases caused by genetic deficiency. The major pathogenic mechanism is the abnormal accumulation of the substrates in the lysosomes, resulting in progressive cellular and multi-organ dysfunction. Nowadays, the treatments of LSD include enzyme replacement therapy, pharmacological chaperone, and small molecule enzyme stabilizer. However, the small molecule drug discovery of mucopolysaccharidosis (MPS) is the most challenging among all the LSDs, because the assay platform for screening is incomplete to screening the library efficiently. In this work, we focus on the mucopolysaccharidosis type II (LSDs), is also called Hunter syndrome, which is caused by the deficiency of iduronate-2-sulfatase to lead the substrate accumulation of glycosaminoglycans (GAGs). To establish the assay platform for small molecule screening in the drug discovery, we attempt to develop the enzyme- and cell-based assays to observe the variation of specific target or phenotype. Besides, differentiation of the level of substrates toward the normal person and MPS patient is crucial information to judge the potency of the small molecule. Thus, we established the enzymatic bio-assays include the thermal stability and enzyme activity in the cell-based assay to evaluate the property of small molecules. Also, the observation of the pathological phenotype of the substrate accumulation is a direct approach to link with the potency of the small molecule. Because the substrate of polysaccharides is difficult to detect, so we attempt to use the methods of tag chemicals and methanolysis. Unexpectedly, in the development of tag chemical method, we still need to evaluate the feasibility of the preparation of standard and sample pretreatments. At the same time, we successfully established the method of methanolysis in the cell-based assay to evaluate the differentiation of HS levels by LCMS/MS toward the normal person and MPS patient. In our efforts of this work, we hope these established assay platforms include the enzyme- and the cell-based assay can apply in the small molecules screening for the drug discovery of MPS.
    The second part is the topic about the high mannose-type glycan, a key role in the cell-cell communication toward cell proliferation in normal cell and cancer cell. Human Golgi α-mannosidase II (hGMII) is a glycosyl hydrolase, and also is a pharmaceutical target for the anticancer therapies. A well-known potent inhibitor of hGMII called Swainsonine, a natural product which has the anti-tumor activity but co-inhibition of human lysosomal α-mannosidase (hLM) cause the accumulation of high-mannose oligosaccharides in lysosomes which limits the application in the clinical trials. To overcome the challenge arising from poor selective inhibition between hGMII and hLM, the potential small molecules have been analyzed the selective inhibition through the common used fluorometric assay by the artificial substrate. However, the artificial substrate is not the insight to express the binding situation of the inhibitor between the real substrate and enzyme. Thus, we attempt to establish the real oligosaccharide-based assay to characterize the potency of the selective inhibitors. On the other hand, we successfully prepared the labeled oligosaccharides and the real substrate of hGMII by chemoenzymatic synthesis. By using the oligosaccharide-based substrate, we establish the assay platform to evaluate the potential selective inhibitors and the binding mode in the enzyme kinetic studies.

    中文摘要 I Abstract III Acknowledgment V Table of Contents VI Index of Figures IX Index of Tables XII Index of Schemes XII Chapter 1 Develop the analytical platform toward mucopolysaccharidosis type II 1 Part A. Establish enzyme-based assays for small molecules evaluation 1 1A.1 Introduction 1 1A.1.1 Lysosomal storage diseases 1 1A.1.2 Mucopolysaccharidoses 2 1A.1.3 Glycosaminoglycans 4 1A.1.4. The characterization of iduronate-2-sulfatase 5 1A.1.5. Treatments of Mucopolysaccharidosis type II 7 1A.1.6 Chaperone and Stabilizer 8 1A.1.7. The fluorimetric enzyme assay for IDS 11 1A.1.8 Motivation 12 1A.2. Results and discussions 13 1A.2.1 The initial enzyme-based assay 13 1A.2.2. Enzyme activity of cell-based assay 18 1A.2.3. Small molecule evaluation 20 1A.3 Sub-summary 23 Part B. Establish cell-based assays for metabolic processing toward the normal and MPS patient cell. 25 1B.1 Introduction 25 1B.1.1 GAGs as the biomarker of MPS 25 1B.1.2 The assay platforms of GAGs detection by LC or LCMS/MS 27 1B.1.3 Derivatization of carbohydrates for analysis 30 1B.1.4 Motivation 31 1B.2. Results and discussions 32 1B.2.1 Design 32 1B.2.2 Tag chemistry to enhancing the sensitivity 34 1B.2.3 Comparison of the normal and patient cell by methanolysis 41 1B.2.4 Demonstration of the assay platform for small molecule evaluation 46 1B.3 Sub-summary 50 Chapter 2 Characterization and inhibition studies of human Golgi α-mannosidase II and lysosomal α-mannosidase with oligosaccharides-based substrates 53 2.1 Introduction 53 2.1.1 Glycoprotein biosynthesis 53 2.1.2 The differentiated functions of N-acetylglucosaminyltransferases 54 2.1.3 A commonly recognized drug target: Golgi α-mannosidase II 55 2.1.4 The binding pocket of Golgi mannosidase II 57 2.1.5 The commercial substrate of preliminary screening 58 2.1.6 Preliminary data in house 59 2.1.7 Motivation 60 2.2. Results and discussions 61 2.2.1 Preparation of the labeled oligosaccharide-based substrates 61 2.2.2 Chemoenzymatic synthesis of hGMII substrate 62 2.2.3 UPLC-based enzyme activity studies 64 2.2.4 Characterization of the potential inhibitor against hGMII by O2AB substrate 67 2.2.5 Comparison of the enzyme kinetic assay about the different substrates 69 2.3. Sub-summary 72 Chapter 3 Experimental Section 74 3.1 Abbreviation 74 3.2 General information 75 3.3 Procedures of Chapter 1 76 3.4 Preparation and characterization of compounds Chapter 1 83 3.5 Procedures of Chapter 2 89 3.6 Preparation and characterization of compounds Chapter 2 90 References 92 Appendix 102

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