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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 邱繼輝 | |
| dc.contributor.author | Arwen Lee | en |
| dc.contributor.author | 李雅雯 | zh_TW |
| dc.date.accessioned | 2021-06-13T02:22:02Z | - |
| dc.date.available | 2007-02-01 | |
| dc.date.copyright | 2007-02-01 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-01-29 | |
| dc.identifier.citation | (1) Corbett, E. L., Watt, C. J., Walker, N., Maher, D., Williams, B. G., Raviglione,
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(2006) Development of a quantitative assay for mycobacterial endogenous arabinase and ensuing studies of arabinase levels and arabinan metabolism in Mycobacterium smegmatis. Appl Environ Microbiol 72, 2601-5. (115) Harvey, D. J., Bateman, R. H., and Green, M. R. (1997) High-energy collision-induced fragmentation of complex oligosaccharides ionized by matrix-assisted laser desorption/ionization mass spectrometry. J Mass 158 Spectrom 32, 167-87. (116) Spina, E., Sturiale, L., Romeo, D., Impallomeni, G., Garozzo, D., Waidelich, D., and Glueckmann, M. (2004) New fragmentation mechanisms in matrix-assisted laser desorption/ionization time-of-flight/time-of-flight tandem mass spectrometry of carbohydrates. Rapid Commun Mass Spectrom 18, 392-8. (117) Hancock, I. C., Carman, S., Besra, G. S., Brennan, P. J., and Waite, E. (2002) Ligation of arabinogalactan to peptidoglycan in the cell wall of Mycobacterium smegmatis requires concomitant synthesis of the two wall polymers. Microbiology 148, 3059-67. (118) Domon, B., and Costello, C. E. (1988) Structure elucidation of glycosphingolipids and gangliosides using high-performance tandem mass spectrometry. Biochemistry 27, 1534-43. (119) Lee, R. E., Li, W., Chatterjee, D., and Lee, R. E. (2005) Rapid structural characterization of the arabinogalactan and lipoarabinomannan in live mycobacterial cells using 2D and 3D HR-MAS NMR: structural changes in the arabinan due to ethambutol treatment and gene mutation are observed. Glycobiology 15, 139-51. (120) Kall, L., Krogh, A., and Sonnhammer, E. L. (2004) A combined transmembrane topology and signal peptide prediction method. J Mol Biol 338, 1027-36. (121) Alderwick, L. J., Radmacher, E., Seidel, M., Gande, R., Hitchen, P. G., Morris, H. R., Dell, A., Sahm, H., Eggeling, L., and Besra, G. S. (2005) Deletion of Cg-emb in corynebacterianeae leads to a novel truncated cell wall arabinogalactan, whereas inactivation of Cg-ubiA results in an arabinan-deficient mutant with a cell wall galactan core. J Biol Chem 280, 32362-71. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/30943 | - |
| dc.description.abstract | 阿拉伯聚醣 (arabinan) 是結核桿菌細胞壁重要的多聚醣體之一， 分別銜接起半乳聚醣 (galactan) 或是脂化甘露聚醣 (lipomannan) 來形成兩個複雜的大分子- 阿拉伯半乳聚醣 (arabinogalactan, AG) 和脂化阿拉伯甘露聚醣 (lipoarabinomannan, LAM)。 一般結核菌 ( Mycobacterium sp.) 都含有這兩個多醣體。常見的致病性結核菌會引起兩個嚴重的法定傳染病包括了肺結核 (tuberculosis) 以及痲瘋 (leprosy)。 現有的抗結核病用藥中， 胺丁醇（Ethambutol）， 被認為是可抑制阿拉伯醣聚合化酵素 (arabinan transferases) 基因 embCAB。 此基因分別的是去影響阿拉伯醣化的形成 (arabinosylation)。 近年來利用一快速生長的結核桿菌Mycobacterium smegmatis 所進行的一些遺傳和基因缺陷的實驗中， 顯示由 embCAB 所轉錄的基因產物， EmbB/A 和 EmbC 蛋白質， 可分別調控 AG 和 LAM 的阿拉伯醣聚合化。 儘管AG 和LAM 的阿拉伯聚醣結構相似，生化實驗分析結果指示， 相較於AG 的支鏈結構， LAM 明顯的多了直鏈結構式的阿拉伯聚醣鏈末端， 且可能是由 EmbC 蛋白質所調控或轉錄。 從EmbC 缺陷菌種中得到的結果發現它已經不能合成正常菌種的LAM， 取而代之的是類似AG 的結構產生。到目前為止， 也還不能很清楚的了解這種結果發生的原因以及阿拉伯聚醣生合成的分子機制。
進一步的去了解阿拉伯醣聚合化過程是一迫切需要的事， 這有利於我們去對抗此全球性的疾病的蔓延。 本論文將是要朝向去鑑定一個完整的阿拉伯聚醣初始化、 延伸、 分支、 最後終結及末端甘露糖 (Mannose) 修飾等等的機制。 在結構分析上， 首先我們去建立起一關鍵性技術: 有效的應用一內切性阿拉伯聚醣酵素 (endogenous arabinannase) 去水解複雜的阿拉伯聚醣而獲得如同過去所推測的由之22 個阿拉伯糖組成的大分子片斷。 配合各種俱高解析度、精準度且敏感的質譜設備去快速的分析結構與定序。 在此， 分別的去分析來自於各種不同結核桿菌屬像是M. smegmatis、 M. leprae、 M. tuberculosis Rv37、 Emb-resistant M. tuberculosis clinical isolates CSU20等的阿拉伯半乳聚醣 (arabinogalactan, AG) 和脂化阿拉伯甘露聚醣 (lipoarabinomannan, LAM) 結構並做比較。 最後可以將所獲得的結果配合上目前我們對於結核桿菌所的知識做一有系統的整合， 以了解細胞壁的整個結構功能以及生合成之始末原由。 由質譜數據分析證明了來自於 AG 上的阿拉伯聚醣結構是由18 個阿拉伯單糖所組成的且俱有高度分支狀， 符合於過去文獻所推測； 而 LAM 上的阿拉伯聚醣主要是直鏈狀所延伸的結構且變異度高。 在一些慢速生長的且俱致病性的結核菌種中， 半乳糖氨化 (galactosaminylation) 是修飾於AG 上 3,5 鍵結的阿拉伯單糖上面的C-2 位置。 運用基因突變缺陷的技術去建構一可能是影響 LAM 阿拉伯醣聚合化的其中一轉化酵素之轉錄基因末端缺陷的突變株 (embC)。 在基因缺陷實驗所得知的結果中， LAM的阿拉伯聚醣已經形成較為接近 AG 形式的阿拉伯聚醣， 此基因被證明確實影響 LAM 的阿拉伯醣聚合化。 在慢速生長的結核菌種中 (H37Rv、 CSU20 以及leprae)， 皆為有甘露糖 (mannose) 末端修飾種類的阿拉伯聚醣 (ManLAM)， 且各有不同程度的結構複雜度。 我們定義了過去不被報告過的結構及一個更大可能的模型， 且認為雖然這些菌種的阿拉伯聚醣變異性很高， 但應該都是經由一個共通性的結構所組成的。 | zh_TW |
| dc.description.abstract | D-arabinofurans are unique polymers present in the mycobacterial cell wall, attached either to a galactofuran or a mannan. Studies on D-arabinofurans from arabinogalactan (AG) and lipoarabinomannan (LAM) have been hampered because of the complexity of the structure, and unavailability of sufficient tools to aid analyses. The main thrust of this thesis work is the development of refined analytical methodology using a newly available endogenous arabinanase to release intact large fragments of arabinan oligomers from mycobacterial AG and LAM for high sensitivity structural motif mapping and sequencing by a combination of low and high collision energy induced dissociation (CID) tandem mass spectrometry.
Collectively, the data demonstrated that the arabinans of AG are highly branched and structured into a well defined 18 mers, whereas those of LAM may be further extended with linear chains, giving rise to a highly heterogeneous ensemble. Significantly, evidence was obtained for the first time which validated the linkages and branching pattern of the previously inferred Ara22 structural motif of AG, on which the preferred cleavage sites of the novel arabinanase could be localized. The established linkage-specific MS/MS fragmentation characteristics further led to identification of a galactosamine substituent on the C-2 position of a portion of the internal 3,5-branched Ara residue of the AG of M. tuberculosis, but not that of the nonpathogenic, fast growing M. smegmatis. Similar analysis on LAM arabinan isolated from the genetic mutants of M. smegmatis showed that C-terminal truncation of the EmbC gene encoding for the putative arabinan transferase specific for LAM halts LAM-specific linear extension from an AG-like inner arabinan core structure. Collectively, the data reveal a new model, which implicates an inner branched Ara-(18 –22)-mer core structure as a common structural motif for both LAM and AG. However, direct structural analyses of the mannose-capped LAMs from M. tuberculosis and M. leprae showed them to be distinct from that of the fast growing, non-pathogenic species, a feature which was not previously recognized. Man4Ara10 and Man6Ara13 were identified as distinct terminal motifs whereas Man2Ara7 probably represents an internal repeat motif variably found in various strains of M. tuberculosis and M. leprae. The new insights on the arabinan structure provided by the current analysis lead us to a broader perspective on the assembly and biogenesis of the mycobacterial arabinan never before realized and addressed. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T02:22:02Z (GMT). No. of bitstreams: 1 ntu-96-D89242002-1.pdf: 7913765 bytes, checksum: e7338ad4c8cfd475892016766fd53824 (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | Chapter 1 Introduction ……………………….…………………………………1~26 1.1 Tuberculosis and immunity …………….…………………………………………1 1.2 Classification …...…………………………...……………………….…………....2 1.3 D-Arabinofurans structure ………………………………………………………...5 1.4 Mycobacterial cell wall …………………………………………………………...6
(1) Peptidoglycan structure ……….………..…………………………...………...7 (2) Mycolic acid structure ……...……………………………………...…….…....7 (3) Arabinogalactan (AG) structure ……………………………………...………..8 (4) Lipoarabinomannan (LAM) structure ………………………………………..10 1.5 The immunomodulatory activities of LAM …………………………………..…13 1.6 Biosynthesis of mycobacterial D-arabinofurans ……………………………...…14 1.7 D-Arabinanase enzyme ………………………………………………………….17 1.8 Strategy for structural analysis of polysaccharides …………………………….18 1.9 Mass spectrometry ……………………………………………………………….19 1.10 History of structural analysis of AG and LAM arabinan ………………………20 Chapter 2 Objective ……………………………………………………..……..27~29 Chapter 3 Materials and instruments ………………………………………30~31 3.1 Reagent ….……………………………………………………………………….30 3.2 Strains ……………………………………………………………………………30 3.3 Instruments and apparatus ….……………………………………………………30 Chapter 4 Methods ………………………………………………………..……32~39 4.1 Preparation of soluble arabinogalactan and lipoarabinomannan ………………32 4.2 Purification of endogenous arabinanase …………………………………………33 4.3 Arabinanase activity assay and arabinan digestion ……………………………33 4.4 Fractionation and desalting ……………………………………………………34 4.5 Digestion with α-mannosidase …………………………………………………35 4.6 Digestion with Endoarabinanase ………………………………………………35 4.7 Chemical derivatization ………………………………………………………… 35 (1) Permethylation ……………………………………………………….………35 (2) Peracetylation .……...………………………………………………..………36 (3) Reduction …………………………………………………………………….36 4.8 Sep-Pak C18 ……………………………………………………………..………36 4.9 Zip-Tip C18 ………………………………………………………………...……37 4.10 Phenol-sulfuric acid assay ……………………………………………...………37 4.11 Sugar composition analysis …………………………………………………….37 4.12 Gel electrophoresis ……………………………………………………………..38 4.13 Mass spectrometry analysis …………………………………………………….38 (1) MALDI-TOF and MALDI-Q-TOF ………………………………………….38 (2) MALDI-TOF/TOF ……………………………………………………….…..39 Chapter 5 Preparation of arabinan and determination of its high-energy CID MS/MS fragmentation pattern ………………………………………..……40~54 5.1 General workup strategy ……………………………………………………….40 5.2 Msm-arabinanase ………………………………………………………………41 5.3 Separation of arabinan …………………………………………………………...42 (1) Size exclusion HPLC …………………………………………………...……42 (2) Bio-Gel P-10 column ……………………………………………………...…43 (3) PGC (porous graphitized carbon) column …………………………...………43 5.4 Rule of fragmentation in high-energy CID MS/MS ……………………………..43 5.5 Discussion ………………………………………………………….……………46 Chapter 6 Mycobacterium smegmatis AG ………………………….………55~71 6.1 Mass spectra of Mycobacterium smegmatis AG-arabinan ………………………55 6.2 Characterization of arabinan in low-energy CID ……………………..…………56 (1) Characterization of Ara7 by low-energy CID MS/MS ……………………….57 (2) Characterization of Ara8 by low-energy CID MS/MS …………….…………57 (3) Characterization of Ara11,12 by low-energy CID MS/MS ……………………58 (4) Characterization of Ara18 by low-energy CID MS/MS ……………………58 6.3 High-energy CID in MALDI TOF-TOF..…………………………………...……59 (1) Characterization of Ara18 by high-energy CID MS/MS ……………………..59 (2) Characterization of Ara7 and Ara12 by high-energy CID MS/MS …………...60 6.4 Characterization of Ara19/Ara20 by low and high-energy CID MS/MS …………61 6.5 Discussion ………………………………………………………………….……61 Chapter 7 M. tuberculosis CSU20AG and Leprae AG …………………..…72 ~91 7.1 Mass spectra of M. tuberculosis CSU20AG-arabinan ………………………..72 7.2 Characterization of GalN by high-energy CID MS/MS………………………….75 (1) Characterization of Ara13-GalN (m/z 2374) …………………………………75 (2) Characterization of Ara6-GalN (m/z 1238) …………………………………..76 (3) Characterization of Ara18,20-GalN (m/z 3174, 3494) in high-energy CID …...77 7.3 Mass spectra of M. Leprae AG-arabinan ………………………………...………78 7.4 Discussion ……………………………………………………………………….79 Chapter 8 LAM from M. smegmatis and EmbC mutants ………….………92~110 8.1 Mass spectra of M. smegmatis LAM-arabinan …………………………………..92 8.2 Characterization of LAM-Ara18 by high-energy CID ………………………...…92 8.3 EmbC and C-terminal mutation LAM-arabinan ………………………..….……93 8.4 Mass Spectra of LAM-arabinan derived from EmbC C-terminal mutants ……...94 8.5 Characterization of Msm- and EmbCΔ358c –LAM arabinans by low-energy CID…………………………………………………………………………………...96 8.6 Discussion …………………………………………………………….…………99 Chapter 9 M. tuberculosis and M. leprae LAM ………………………….…111~131 9.1 The evidence of SDS-PAGE in LAM ……………………………….…………111 9.2 Mass Spectra of M. tuberculosis CSU20LAM-arabinan ……………………….111 9.3 Characterization of CSU20LAM-arabinan by high-energy CID MS/MS …...…113 9.4 Mass spectra of M. tuberculosis RvLAM-arabinan …………………………….114 9.5 Characterization of RvLAM by high-energy CID MS/MS …………………….115 9.6 Mass spectra of LepLAM-arabinan …………………………………………….116 9.7 Characterization of LepLAM-arabinan by high-energy CID ………..…………117 9.8 MS/MS comparison of LAM-Ara10, 13 …………………………………………118 9.9 Discussion ………………………………………………………………...……119 Chapter 10 Discussion……………………………………………………..…132~147 References…………………………………..………………………….…..…148~158 Publications …..……………………………...……………………………….159~185 List of Figures and Supplementary I. Figures Figure 1.1 A schematic diagram of bacterial cell wall ………………………………23 Figure 1.2 A chemical model of the mycobaterial cell wall …………………………23 Figure 1.3 Structure of arabinogalactan (AG) ……………………………………….24 Figure 1.4 Structural mode of AG-arabinan …………………………………………25 Figure 1.5 Structural model of mycobacterial LAM ……………………...…………26 Figure 1.6 A cartoon representing how the Emb proteins function ………………….26 Figure 5.1 A flow chart for the characterization of arabinan structure……………….49 Figure 5.2 Purification of crude Msm-arabinanase and examination of enzymatic activity ……………………………………………………………………………….50 Figure 5.3 Separation of the arabinan oligomers by Superdex peptide HPLC ……...51 Figure 5.4 Fractionation of AG digestion by Bio-gel ……………….…………….....52 Figure 5.5 High-energy MALDI CID MS/MS spectrum of Ara4 standard ……….…53 Figure 5.6 High-energy MALDI CID MS/MS spectrum of Ara5 standard ………….54 Figure 5.7 High-energy MALDI CID MS/MS spectrum of Ara6 standard ………….54 Figure 6.1 MALDI-MS spectra of Msm-arabinanase digested MsmAG-arabinan .…64 Figure 6.2 MALDI MS/MS of permethylated Ara7, Ara8, Ara11, and Ara12 from MsmAG …………...…………………………………………………………………65 Figure 6. 3 MALDI MS/MS spectrum of permethylated Ara18 ………………….…..66 Figure 6.4 Expanded high-energy CID MS/MS spectrum of permethylated Ara18 …67 Figure 6.5 A complete assignment of the high-energy CID MS/MS fragment ions given by the Ara18 structure ………………………………………………………….68 Figure 6.6 MALDI MS/MS spectra of permethylated Ara7 and Ara12 ………………69 Figure 6.7 MALDI MS/MS analysis of permethylated Ara19, and Ara20 ……………70 Figure 6.8 The major components of MsmAG-arabinan released by Msm-arabinanase ……………………………………………………………………71 Figure 7.1 MALDI MS spectra of CSU20AG-arabinan …………………………….82 Figure 7.2 Mass spectra of permethylated CSU20 AG-arabinan after sub-fractionation ……………………………………………………………………..83 Figure 7.3 Mass spectra of permethylated, reduced arabinan in HPLC fractions ...…84 Figure 7.4 MALDI MS spectra of the permethyl derivatives of HPLC fraction D after further digestion by endoarabinanase …………..……………………………………85 Figure 7.5 MALDI MS/MS spectrum of permethylated Ara13-GalN and Ara6-GalN .86 Figure 7.6 MALDI MS/MS spectrum of permethylated Ara18, 20-GalN ……….……87 Figure 7.7 MALDI MS spectrum of the permethyl derivatives of LepAG-arabinan ..88 Figure 7.8 MALDI MS/MS spectrum of permethylated reduced Ara7 from LepAG-arabinan ……………………………..………………………………………89 Figure 7.9 MALDI MS/MS spectrum of permethylated reduced Ara18 from LepAG-arabinan …………..…………………………………………………………90 Figure 7.10 GalN-containing arabinan of Msm-arabinanase digestion product from CSU20AG …………………………………………………………………………...91 Figure 8.1 MALDI MS spectrum of permethylated derivatives of MsmLAM-arabinan …………………………………………………………...……101 Figure 8.2 High-energy CID MS/MS spectrum of permethylated reduced Ara18 from MsmLAM ……………………………………………………………………..……102 Figure 8.3 Predicted TM-topology of MsmEmbC ………………………………....103 Figure 8.4 Analysis of LAM and LM of Msm wild-type and the mutants by SDS-PAGE …………………………………………………………………………104 Figure 8.5 MALDI-MS spectra of permethyl derivatives of arabinan from EmbC C-terminal mutants of Msm ……………………………………………………..…105 Figure 8.6 Low-energy CID MALDI-MS/MS analysis of arabinosyl oligomers derived from Msm-arabinanase digestion ………………………………….………106 Figure 8.7 Low energy CID MALDI MS/MS analysis of arabinosyl oligomers derived from Msm-arabinanase digestion …………………………………………………..107 Figure 8.8 Low-energy CID MALDI-MS/MS analysis of arabinosyl oligomers derived from Msm-arabinanase digestion ………………………………………… 108 Figure 8.9 Arabinan structure deduced from low energy CID MS/MS analysis ..…109 Figure 8.10 High-energy CID MS/MS spectrum of permethylated reduced Ara18 derived from EmbCΔ358cLAM ……………………………………………………110 Figure 9.1 Evaluation of the degree of LAM digestion by gel electrophoresis ……121 Figure 9.2 Evaluation of Microspin efficiency …………………………………….121 Figure 9.3 MALDI MS spectra for the permethyl derivatives of CSU20LAM-arabinan …………………………………………………………...…122 Figure 9.4 MALDI MS/MS spectrum of permethyl derivatives of CSU20LAM Man4Ara10 ……..……………………………………………………………………123 Figure 9.5 MALDI MS/MS spectrum of permethyl derivatives of CSU20LAM Man6Ara13 …………………………………………………………………………..124 Figure 9.6 MALDI MS spectra of the permethyl derivatives of RvLAM-arabinan .125 Figure 9.7 MALDI MS/MS spectrum of permethyl derivatives of H37RvLAM Man2Ara7 ……………………………………………………………………….…..126 Figure 9.8 MALDI-MS spectrum of permethylated, reduced LepLAM-arabinan …127 Figure 9.9 MALDI MS/MS spectrum of permethylated, reduced Man2Ara10 from LepLAM and CSU20LAM ……………………………………………………...…128 Figure 9.10 MALDI MS/MS spectrum of permethylated reduced Ara10 of LAM …129 Figure 9.11 MALDI MS/MS spectrum of permethylated reduced Ara13 of LAM ....130 Figure 9.12 Summary of ManLAM arabinan motifs ………………………………131 Figure 10.1 Models for assembly of AG ……...……………………………………144 Figure 10.2 Model for assembly of LAM ………………………………………….145 Figure 10.3 Model for assembly of ManLAM ……………………………………..146 Figure 10.4 Summary of arabinan structures, model and arabinosylation …………147 II. Supplementary Table1 Table of nominal, monoisotopic, and average mass of arabinofuranose …...186 | |
| dc.language.iso | en | |
| dc.subject | 質譜儀 | zh_TW |
| dc.subject | 結核桿菌 | zh_TW |
| dc.subject | 阿拉伯聚醣 | zh_TW |
| dc.subject | MS/MS | en |
| dc.subject | and Glycan sequencing | en |
| dc.subject | Mass spectrometry | en |
| dc.subject | Mycobacterium | en |
| dc.subject | Arabinan | en |
| dc.title | 結核桿菌細胞壁多醣體結構之研究 | zh_TW |
| dc.title | Sequencing of Arabinans from Mycobacterial Cell Wall Arabinogalactan and Lipoarabinomannan by Advanced Tandem Mass Spectrometry | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 方俊民,陳水田,楊文彬,華國媛 | |
| dc.subject.keyword | 阿拉伯聚醣,結核桿菌,質譜儀, | zh_TW |
| dc.subject.keyword | Arabinan,Mycobacterium,Mass spectrometry,MS/MS,and Glycan sequencing, | en |
| dc.relation.page | 186 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2007-01-30 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科學研究所 | zh_TW |
| 顯示於系所單位： | 生化科學研究所 | |
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