胃幽門螺旋桿菌26695菌株之phosphoheptose isomerase由 hp0857基因所表現之特性研究

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研究生：	游忠凱 Yu, Chung Kai
論文名稱：	胃幽門螺旋桿菌26695菌株之phosphoheptose isomerase由 hp0857基因所表現之特性研究 Identification and characterization of Helicobacter pylori 26695 phosphoheptose isomerase encodedby hp0857
指導教授：	高茂傑 Kao, Mou-Chieh
口試委員:	殷献生蘇慧敏
學位類別：	碩士 Master
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2011
畢業學年度：	99
語文別：	中文
論文頁數：	79
中文關鍵詞：	胃幽門螺旋桿菌
相關次數：	點閱：2 下載：0
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Helicobacter pylori is a gram-negative spiral-shaped microaerophilic bacterium which infects 50% human population and is associated with chronic gastritis, peptic ulcer, gastroduodenal ulcer, gastric adenocarcinoma and mucosa-associated lymphatic tissue (MALT) lymphoma. Because of the appearance of antibiotic resistance, it is essential to develop new antibiotics against this notorious bacterium.
Lipopolysaccharide (LPS) plays significant roles in pathogenesis of H. pylori infection. This phosphorylated lipoglycan maintains the structural integrity of bacterial outer membrane and provides a protective barrier against the entry of toxic hydrophobic compounds like bile salts, detergents and lipophilic antibiotics into the bacterial cell. It is composed of lipid A, core oligosaccharide and O-chain polysaccharide.
In this study, we identified that the H. pylori open reading frame (ORF) hp0857 codes for a phosphoheptose isomerase which catalyzes the isomerization of D-Sedoheptulose 7-phosphate into D-glycero-D-manno-heptose 7-phosphate and is involved in inner core biosynthesis of lipopolysaccharide. We cloned hp0857 and overexpressed it in Eschericha coli. The recombinant protein was purified to homogeneity with the subunit molecular weight of 23.2 kDa. The gel filtration and analytical ultracentrifugation studies indicated that HP0857 protein has a native molecular mass of 40.5 ± 2.2 kDa and 49.0 ± 0.1 kDa, respectively, suggesting that HP0857 protein is likely a dimer under the present experimental conditions. The result of circular dichroism spectrum analysis indicated that HP0857 contains 67.8 ± 6.8% α-helix and 2.7 ± 0.8% β-strand. The results of the enzymatic activity assay indicated that the purified protein could convert the D-Sedoheptulose 7-phosphate into D-glycero-D-manno-heptose 7-phosphate. Moreover, a HP0857 knockout mutant was constructed and its phenotypic properties was characterized. The HP0857 knockout mutant showed a truncated LPS structure, a reduced growth rate, a weak motility and more susceptible to detergent Triton X-100 and antibiotic novobiocin. In addition, the AGS cells infected by the HP0857 knockout mutant were unable to display a classic hummingbird phenotype. Complementation of the HP0857 in the knockout mutant was found to restore most of these phenotypic changes. In conclusion, we demonstrated that HP0857 protein is essential for LPS inner core biosynthesis of H. pylori and is a potential target for developing new antimicrobial agents against H. pylori infection.

Abstract    i
中文摘要    iii
Table of contents    v
Abbreviations    viii
Introduction    1
Materials and methods    13
Results    26
Identification and the bioinformation of HP0857    26
Molecular cloning of hp0857 gene and hp0860 gene    27
Overexpression and affinity purification of HP0857, HP0858 and HP0860 protein    27
H. pylori HP0857 steady-state kinetic analysis    28
Molecular weight determination of HP0857 protein    29
Circular dichroism of HP0857 protein    30
The confirmation of HP0857 knockout and its complement mutant strains by genomic DNA PCR    30
The effects of HP0857 knockout mutant on LPS expression    31
The growth curve analysis of wild type H. pylori strain, HP0857 knockout mutant and its complement mutant strain    32
The effects of HP0857 mutations on detergent (SDS, Triton X-100) and antibiotic novobiocin resistance    32
The motility comparison of wild type strain and HP0857 knockout mutant    33
The effects of HP0857 mutation on host cell morphology and bacterial adhesion    34
Discussion    35
Reference    40
Tables    51
Table 1. Sequences of the primers used in this study:    51
Table 2. Sequence comparison of H. pylori HP0857 protein with homologues from other gram-negative bacteria    52
Table 3. The summary of steady state kinetic parameters of purified HP0857 (GmhA) protein determined by the malachite green phosphate detection assay    53
Table 4. Comparison of biochemical properties of GmhA homologues from different species    53
Table 5. Minimal Inhibitory Concentrations (MICs) of H. pylori strains to antibiotics (Novobiocin) and detergent (Triton X-100 and SDS)    54
Table 6. Motility comparison of H. pylori strains on Brucella-serum semi-solid agar after 6 days culture    54
Figures    55
Figure 1. The genomic bioinformations of HP0857 in H. pylori 26695 strain    55
Figure 2. Amino acid sequence alignment of the H. pylori 26695 phosphoheptose isomerase (HP0857) with its homologues    56
Figure 3. Analysis of transmembrane and hydrophobicity profiles of the HP0857 protein    57
Figure 4. The chemical structure of the saccharide moiety of H. pylori 26695 LPS    58
Figure 5. The proposed mechanism for ADP-heptose biosynthetic pathway in H. pylori    58
Figure 6. Molecular cloning of hp0857 gene and hp0860 gene    59
Figure 7. Purification of HP0857 protein with the metal-chelated affinity column using an increasing gradient of imidazole    60
Figure 8. Heterogeneous expression and purification of HP0857    61
Figure 9. Heterogeneous expression and purification of HP0858    62
Figure 10. Heterogeneous expression and purification of HP0860    63
Figure 11. (A) The proposed mechanism for ADP-heptose biosynthetic pathway in H. pylori (B) The reaction scheme of phosphate detection used in this study    64
Figure 12. The evaluation of the specificity of the assay    65
Figure 13. Steady state kinetic analysis of H. pylori HP0857 with S7P as substrate    66
Figure 14. The subunit molecular weight of HP0857 determined by MALDI-TOF mass spectrometry    67
Figure 15. Determination of the native molecular weight of the recombinant HP0857 by gel filtration    68
Figure 16. The native molecular weight of recombinant HP0857 was determined by analytical ultracentrifugation    69
Figure 17. The secondary structure of H. pylori HP0857    70
Figure 18. Molecular cloning of hp0857 knockout plasmid    71
Figure 19. The construction of the hp0857 knockout complement plasmid    72
Figure 20. Schematic representation of the construction of HP0857 knockout and its complement mutants.    73
Figure 21. The confirmation of HP0857 knockout and its complement mutant strains by genomic DNA PCR    74
Figure 22. LPS profile analysis    75
Figure 23. The growth curve analysis of the wild type H. pylori strain, HP0857 knockout mutant and its complement mutant    76
Figure 24. Effects of HP0857 mutations on novobiocin resistance and detergent susceptibility of H. pylori    77
Figure 25. Effects of HP0857 mutations on AGS cell morphological changes after infection    78
Figure 26. Comparison of adherence levels of the H. pylori strains to AGS cells    79

                                

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