Structure of LAM in Relation to Biology and Biosynthesis

LAM 结构与生物学和生物合成的关系

• 批准号: 6544799
• 负责人: DELPHI CHATTERJEE
• 金额: $ 24.44万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6544799
• 关键词: CD1 molecule; Mycobacterium tuberculosis; T lymphocyte; bacterial antigens; carbohydrate biosynthesis; carbohydrate receptor; carbohydrate structure; cell free system; cell wall; cellular immunity; chemical structure function; galactans; infrared spectrometry; macrophage; mannans; mass spectrometry; receptor sensitivity; structural biology

DESCRIPTION (provided by applicant): The re-emergence of tuberculosis as a public health problem has been complicated by the lack of effective chemotherapeutic agents and the development of new antibiotics. The cell wall of its causative agent, Mycobacterium tuberculosis, is known to be a target of some of the most effective antimycobacterial drugs including ethambutol which has been known to inhibit the biosynthesis of arabinan of the cell wall proper and associated lipoarabinomannan (LAM). A diverse range of biological studies over a decade has collectively provided compelling evidence implicating LAM as a key surface molecule in host-pathogen interactions. The finding of immature LAM or truncated LAM as a consequence of natural and laboratory induced resistance to ethambutol, and embC gene knockout events provide invaluable model compounds for both structural and functional studies aiming at defining the relevance of LAM in pathogenesis. Specifically, with the availability of new enzymes, advanced chemical, NrvIR and mass spectrometric tools can be combined to yield the fine details of the arabinan assembly and the mode and site(s) of arabinan attachment to the mannan core. Enzymatically modified structural arabinan motifs positively correlating with particular biological attributes of clinical isolates will be derived from LAM, and neoarabinolipids will be generated for functional studies. Efforts will be given in resolving the heterogeneity in LAM and relate it to biology. CD1 restricted recognition of LAM by T cells will be examined in the context of cell mediated immunity in tuberculosis and its concomitant induction of cytokine secretion. Finally, gene knock-out mutants, cell-free assays and synthetic arabinofuranosyl acceptors will be utilized to establish the metabolic events involved in the arabinan assembly of LAM about which almost nothing is known, followed by identification of proteins (transferases) involved. Thus, the unifying theme of this Research Proposal is the structural analysis and manipulation of LAM, supplemented by genetic and biosynthetic studies leading to a better understanding of its biology and biosynthesis.

描述（由申请人提供）：缺乏有效的化学治疗剂和新抗生素的发展使结核病作为公共卫生问题的重新出现变得复杂。已知其致病剂分枝杆菌结核病的细胞壁是某些最有效的抗菌药物的靶标，包括埃achambutol，已知已知可以抑制细胞壁的生物合成和适当的脂肪兰贝诺曼南（LAM）的生物合成。十年来，各种各样的生物学研究都提供了令人信服的证据，这暗示着LAM作为宿主 - 病原体相互作用中的关键表面分子。由于天然和实验室诱导的乙酰胺醇的抗性以及EMBC基因敲除事件的结果，未成熟的LAM或截短的LAM的发现为结构和功能研究提供了宝贵的模型化合物，旨在定义LAM在发病机理中的相关性。 具体而言，可以将新酶，高级化学，NRVIR和质谱工具的可用性组合在一起，以产生阿拉伯装配的细节以及阿拉伯人在曼南核心的模式和位置​​（S）。酶修改的结构性阿拉伯基序与临床分离株的特定生物学属性正相关，将从LAM中得出，并将为功能研究生成新赤胆脂。在解决LAM中的异质性并将其与生物学联系起来时将做出努力。 T细胞对CD1对LAM的限制识别将在结核病中的细胞介导的免疫力及其随之诱导的细胞因子分泌的背景下进行检查。最后，将利用基因敲除突变体，无细胞测定和合成阿拉伯透明素的受体来建立与LAM的阿拉伯式组装中有关的代谢事件，几乎一无所知，其次是鉴定涉及的蛋白质（转移酶）。 因此，该研究建议的统一主题是对LAM的结构分析和操纵，并补充了遗传和生物合成研究，从而更好地理解了其生物学和生物合成。

项目成果

Altered composition and functional profile of high-density lipoprotein in leprosy patients.

麻风病患者高密度脂蛋白的组成和功能谱发生改变。

• DOI: 10.1371/journal.pntd.0008138
• 发表时间: 2020
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Lemes,RoberthaMarianaR;Silva,CarlosAdrianodeME;Marques,MariaÂngeladeM;Atella,GeorgiaC;Nery,JoséAugustodaC;Nogueira,MariaRenataS;Rosa,PatriciaS;Soares,CléversonT;De,Prithwiraj;Chatterjee,Delphi;Pessolani,MariaCristina
• 通讯作者: Pessolani,MariaCristina