MOLECULAR BIOLOGY OF UNIQUE WALL LIPIDS OF MYCOBACTERIA

结核分枝杆菌和相关的致病分枝杆菌有很大的 在细胞壁中有大量独特的脂质。 其中一些独特的 脂质是致病分枝杆菌的表面抗原， 可用于鉴别、诊断和治疗。 这些脂质 构成屏障，使细菌能够抵抗自然 宿主的防御，抵抗抗微生物药物，并帮助在体内繁殖 主持人 目前使用的抗分枝杆菌药物是针对 对分枝菌酸的生物合成，一类独特的 脂质。 对这些药物的耐药性已成为一个主要问题。 其他独特脂质的生物合成可能是新的合适靶点。 抗分枝杆菌药物。 多甲基支链极长链脂肪酸 酸，例如分枝蜡酸和β-二醇，邻苯二甲酸和 这些酸被酯化的苯硫基蜡醇是独特的 缓慢生长的病原菌的细胞壁脂质成分 分枝杆菌 即使是分枝杆菌的脂肪酸合成酶， 催化脂肪酸从头合成和 链伸长以产生所述化合物的非常长链的酸前体。 独特的分枝杆菌脂质。 了解生物化学和 这些独特脂质的分子生物学可以帮助设计新药。 为此，我们建议实现以下具体目标：1. 确定真菌蜡酸是如何从真菌蜡酸中引导出来的 合成酶转化为细胞壁结构中的苯硫代蜡醇和苯硫代蜡醇。 2. 破坏枝蜡酸合成酶基因， 对细胞壁结构易感性和毒力的影响。3. 确定负责真菌蜡酸合成酶的结构域， 甲基丙二酰辅酶A的选择性掺入，以产生多个 甲基分支细胞壁脂质。 4. 阐明途径，酶学 和参与苯硫代蜡醇生物合成的基因的结构， 苯硫基二甲酚。5. 阐明结构关系， 真菌蜡酸合成酶和脂肪酸合成酶，并阐明 分枝杆菌脂肪酸独特能力的分子基础 合成酶催化脂肪酸从头合成和链 伸长率 这是可能的，提出的独特过程的解释， 致病性分枝杆菌可能导致新的方法来识别和 诊断每年导致数百万人死亡的分枝杆菌感染 并对抗结核病和其他分枝杆菌的死灰复燃 美国艾滋病患者的感染率。

Mycobacterium tuberculosis and related pathogenic mycobacteria have large amounts of unique lipids in their cell walls. Some of these unique lipids are surface antigens of the pathogenic mycobacteria and can be useful in identification, diagnosis and treatment. These lipids constitute barriers that allow the bacteria to resist the natural defenses of the host, resist antimicrobial drugs and help multiply within the host. The antimycobacterial drugs currently in use are directed against the biosynthesis of mycolic acids, one class of the unique lipids. Resistance against these drugs has become a major problem. Biosynthesis of other unique lipids could be suitable targets for new antimycobacterial drugs. Multiple methyl branched very long chain fatty acids such as mycocerosic acids and the beta-diols, phthiocerol and phenolphthiocerol, to which these acids are esterified, are unique constituents of the cell wall lipids of the slow growing pathogenic mycobacteria. Even the fatty acid synthase of mycobacteria has the unique ability to catalyze both de novo synthesis of fatty acids and chain elongation to generate the very long chain acid precursors of the unique mycobacterial lipids. Understanding of the biochemistry and molecular biology of these unique lipids could help design new drugs. To this end, we propose to pursue the following specific objectives: 1. Determine how mycocerosic acids are channeled from mycocerosic acid synthase to phthiocerol and phenolthiocerol in the cell wall structure. 2. Disrupt the mycocerosic acid synthase gene and determine the consequences on the cell wall structure susceptibility and virulence. 3. Determine the domains in mycocerosic acid synthase responsible for the selective incorporation of methylmalonyl-CoA to generate the multiple methyl branched cell wall lipids. 4. Elucidate the pathway, enzymology and structure of the gene involved in the biosynthesis of phthiocerol and phenolphthiocerol. 5. Elucidate the structural relationship between mycocerosic acid synthase and the fatty acid synthase and elucidate the molecular basis of the unique capability of mycobacterial fatty acid synthase to catalyze both de novo fatty acid synthesis and chain elongation. It is possible that the proposed elucidation of unique processes in pathogenic mycobacteria could lead to novel methods to identify and diagnose mycobacterial infections that kill millions of people annually and to combat the resurgence of tuberculosis and other mycobacterial infections in AIDS patients in the United States.