Biogenesis of lipoarabinomannan in mycobacteria

分枝杆菌中阿拉伯脂甘露聚糖的生物合成

• 批准号: 7886053
• 负责人: Mary Jackson
• 金额: $ 46.34万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886053
• 关键词: 1,2-diacylglycerol; Abbreviations; Actinobacteria class; Actinomyces; Acyltransferase; Anabolism; Bacillus (bacterium); Bacteria; Biochemical; Biochemistry; Biogenesis; Bioinformatics; Biological Assay; Blood capillaries; Candidate Disease Gene; Cell Wall; Cell membrane; Cell surface; Cells; Characteristics; Chemicals; Chromosomes; Complex; Development; Diglycerides; Dissection; Drug resistance; Electrophoresis; Electrospray Ionization; Enzymes; Event; Family; Fatty Acids; Funding; Genes; Genetic; Genome; Genus Mycobacterium; Glycerol; Glycolipids; Human Development; Hydroxyl Radical; Infection; Inositol; Intervention; Knock-out; Knowledge; Laboratories; Lead; Leprosy; Libraries; Ligands; Link; Lipids; Location; Mannose; Mannosides; Mannosyltransferases; Mass Spectrum Analysis; Measures; Membrane; Modeling; Molecular; Mono-S; Mycobacterium tuberculosis; Nature; Nomenclature; Open Reading Frames; Organism; PIM1 gene; Pathogenesis; Pathway interactions; Phagocytes; Pharmaceutical Preparations; Phosphatidylinositols; Physiology; Play; Polysaccharides; Process; Recombinants; Research; Research Personnel; Role; Screening procedure; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure; Structure-Activity Relationship; Surface; Therapeutic Intervention; Thin Layer Chromatography; Time; Trifluoroacetic Acid; Tuberculosis; Vaccines; Work; acyl group; arabinomannan; base; capillary; cell envelope; deoxycholate; design; enzyme pathway; genetic manipulation; genome sequencing; glycoprotein biosynthesis; glycosyltransferase; in vivo; interest; lipoarabinomannan; lipomannan; lipooligosaccharide; mutant; mycobacterial; new therapeutic target; novel; overexpression; periplasm; phosphatidylinositol mannoside; protein protein interaction; public health relevance; response; sugar; tuberculosis drugs; tuberculosis treatment

DESCRIPTION (provided by applicant): Biogenesis of lipoarabinomannan in mycobacteria Summary Phosphatidylinositol mannosides (PIM) and their multiglycosylated counterparts, lipomannan (LM) and lipoarabinomannan (LAM) are complex glycolipids and lipoglycans found in the envelopes of all mycobacterial species. They play various essential although poorly defined roles in mycobacterial physiology and are important immunomodulatory molecules in the course of tuberculosis and leprosy as well as key ligands promoting the entry of mycobacteria into phagocytic and non-phagocytic cells. Although much progress has been made over the last 20 years in elucidating the structures of these molecules, knowledge of the pathways leading to their biosynthesis, assembling and transport to the cell surface is still incomplete. The elucidation of these pathways, in addition to providing fundamental knowledge about the biochemistry of Mycobacterium tuberculosis, is expected to lead to the discovery of essential enzymes and transporters that could represent interesting targets for novel anti-TB drugs. The availability of recombinant mycobacterial strains accumulating biosynthetic precursors of these molecules would facilitate structure-function relationship studies and that of defined M. tuberculosis mutants deficient in various aspects of PIM, LM and LAM synthesis would allow a precise assessment of the contribution of these molecules to the immunopathogenesis of tuberculosis in vivo. Following an integrated approach in the form of bioinformatics, genetics and biochemistry, we propose to pursue our work on the identification and functional characterization of the enzymes involved in the elongation and assembling of PIM, LM and LAM and to further extend this work to the characterization of the transporters responsible for the translocation of biosynthetic intermediates and end products across the different layers of the cell envelope. Abbreviations: AM, arabinomannan; AcylT, acyltransferase; Araf, arabinofuranosyl; AraT, arabinosyltransferase; CZE, capillary zone electrophoresis; DOC, deoxycholate; ESI, electrospray ionization; GT, glycosyltransferase; LAM, lipoarabinomannan; LM, lipomannan; MALDI-TOF, Matrix-Assisted Laser desorption/ionization time of flight; Manp, mannopyranosyl; ManT, mannosyltransferase; MPI, mannosylated phosphatidylinositol; MS, mass spectrometry; myo-Ins, myo-inositol; ORF, open reading frame; investigator, phosphatidyl-myo-inositol; PIM, phosphatidyl-myo-inositol mannosides; TFA, trifluoroacetic acid; TLC, thin-layer chromatography. Nomenclature: PIM is used to describe the global family of phosphatidylinositol mannosides that carries one to four fatty acids (attached to the glycerol, inositol and/or mannose) and one to six mannose residues. In AcXPIMY, x refers to the number of acyl groups esterified to available hydroxyls on the mannose or myo-inositol residues, y refers to the number of mannose residues; e.g. Ac1PIM1 corresponds to the phosphatidylinositol mono-mannoside PIM1 carrying two acyl groups attached to the glycerol (the diacylglycerol substituent) and one acyl group esterified to the mannose residue. PUBLIC HEALTH RELEVANCE: Dissection of the PIM, LM and LAM pathways in Mycobacterium tuberculosis will lead to the discovery of novel classes of essential enzymes and transporters that may represent attractive targets for therapeutic intervention. In addition, the mutants defective in some aspects of PIM, LM or LAM synthesis will help define the precise role of these molecules in immunopathogenesis.

描述（由申请人提供）：分枝杆菌中脂脂瘤的生物发生，即磷脂酰肌醇甘露糖苷（PIM）及其多糖基化的Lipomannan（LM）和脂肪Arlabinomannan（LAM）（LAM）（LAM）（LAM）（LAM）是复杂的Glycolipids and Lipobipans and lipobys and Mimycans rialials and Mimycans。它们在分枝杆菌生理学中发挥了各种必不可少的作用，但在结核病和麻风病过程中是重要的免疫调节分子，以及促进分枝杆菌进入吞噬细胞和非斑点细胞的关键配体。尽管在过去的20年中，在阐明这些分子的结构方面取得了很多进展，但对导致其生物合成，组装和运输到细胞表面的途径的了解仍然不完整。除了提供有关结核分枝杆菌生物化学的基本知识外，这些途径的阐明还预计还会导致发现必需酶和转运蛋白，这些酶和转运蛋白可能代表了新型抗TB药物的有趣靶标。这些分子积累的重组分枝杆菌菌株的可用性将促进结构 - 连接关系研究，以及在PIM，LM和LAM合成的各个方面缺乏的定义结核分枝杆菌突变体的研究将允许精确评估这些分子对ImmunoPopo of tuimunopopo of tubercoles of tubercopo的贡献。遵循生物信息学，遗传学和生物化学形式的综合方法，我们建议在涉及PIM，LM和LAM伸长和组装的酶的识别和功能表征上追求我们的工作，并进一步将其扩展到该启发量的运输量，以使其跨越型号的插入式构成互动式互动和最终。缩写：Am，Arabinomannan；酰基，酰基转移酶； Araf，阿拉伯呋喃糖基； ARAT，阿拉伯糖基转移酶； CZE，毛细管区电泳； DOC，脱氧胆酸； ESI，电喷雾电离； GT，糖基转移酶；林，脂肪动物群； LM，Lipomannan； MALDI-TOF，基质辅助激光解吸/电离时间； manp，mannopyranosyl; Mant，甘露糖基转移酶； MPI，甘露糖基化的磷脂酰肌醇； MS，质谱； myo-Ins，肌醇； ORF，开放阅读框；研究者，磷脂酰 - 甲醇； PIM，磷脂酰 - 甲状腺醇甘露糖苷； TFA，三氟乙酸； TLC，薄层色谱。命名法：PIM用于描述全球磷脂酰肌醇甘露糖苷的全球家族，该家族携带一种至4种脂肪酸（附着于甘油，肌醇和/或甘露糖）和一到六个甘露糖残基。在Acxpimy中，X指在甘露糖或肌醇残基上被酯酯酯酯酯酯的数量，y是指甘露糖残基的数量。例如AC1PIM1对应于载有两个附着在甘油（二酰基甘油取代基）的酰基基团的磷脂酰肌醇单糖苷PIM1和1酰基基团与甘露糖残基上的酰基。 公共卫生相关性：分枝杆菌中PIM，LM和LAM途径的解剖会导致发现新型必需酶和转运蛋白的新型基本酶和转运蛋白，这些酶可能代表了治疗性干预的有吸引力的靶标。此外，在PIM，LM或LAM合成的某些方面有缺陷的突变体将有助于定义这些分子在免疫发作中的精确作用。