Brennan P J
Department of Microbiology, B308 Microbiology Building, Colorado State University, Fort Collins, CO 80523, USA.
Tuberculosis (Edinb). 2003;83(1-3):91-7. doi: 10.1016/s1472-9792(02)00089-6.
Much of the early structural definition of the cell wall of Mycobacterium spp. was initiated in the 1960s and 1970s. There was a long period of inactivity, but more recent developments in NMR and mass spectral analysis and definition of the M. tuberculosis genome have resulted in a thorough understanding, not only of the structure of the mycobacterial cell wall and its lipids but also the basic genetics and biosynthesis. Our understanding nowadays of cell-wall architecture amounts to a massive "core" comprised of peptidoglycan covalently attached via a linker unit (L-Rha-D-GlcNAc-P) to a linear galactofuran, in turn attached to several strands of a highly branched arabinofuran, in turn attached to mycolic acids. The mycolic acids are oriented perpendicular to the plane of the membrane and provide a truly special lipid barrier responsible for many of the physiological and disease-inducing aspects of M. tuberculosis. Intercalated within this lipid environment are the lipids that have intrigued researchers for over five decades: the phthiocerol dimycocerosate, cord factor/dimycolyltrehalose, the sulfolipids, the phosphatidylinositol mannosides, etc. Knowledge of their roles in "signaling" events, in pathogenesis, and in the immune response is now emerging, sometimes piecemeal and sometimes in an organized fashion. Some of the more intriguing observations are those demonstrating that mycolic acids are recognized by CD1-restricted T-cells, that antigen 85, one of the most powerful protective antigens of M. tuberculosis, is a mycolyltransferase, and that lipoarabinomannan (LAM), when "capped" with short mannose oligosaccharides, is involved in phagocytosis of M. tuberculosis. Definition of the genome of M. tuberculosis has greatly aided efforts to define the biosynthetic pathways for all of these exotic molecules: the mycolic acids, the mycocerosates, phthiocerol, LAM, and the polyprenyl phosphates. For example, we know that synthesis of the entire core is initiated on a decaprenyl-P with synthesis of the linker unit, and then there is concomitant extension of the galactan and arabinan chains while this intermediate is transported through the cytoplasmic membrane. The final steps in these events, the attachment of mycolic acids and ligation to peptidoglycan, await definition and will prove to be excellent targets for a new generation of anti-tuberculosis drugs.
分枝杆菌属细胞壁的许多早期结构定义始于20世纪60年代和70年代。之后有很长一段时间没有进展，但最近核磁共振和质谱分析的发展以及结核分枝杆菌基因组的定义，使人们不仅对分枝杆菌细胞壁及其脂质的结构，而且对其基本遗传学和生物合成有了透彻的了解。如今我们对细胞壁结构的认识是一个庞大的“核心”，它由肽聚糖通过连接单元（L-鼠李糖-D-葡萄糖胺-P）共价连接到线性半乳呋喃糖，半乳呋喃糖又连接到几条高度分支的阿拉伯呋喃糖链，阿拉伯呋喃糖链再连接到分枝菌酸。分枝菌酸垂直于细胞膜平面排列，形成了一个真正特殊的脂质屏障，这与结核分枝杆菌的许多生理和致病方面有关。插入在这种脂质环境中的是那些让研究人员着迷了五十多年的脂质：结核硬脂酸二霉菌酸酯、索状因子/双霉菌酸海藻糖、硫脂、磷脂酰肌醇甘露糖苷等。它们在“信号传导”事件、发病机制和免疫反应中的作用的相关知识现在正在逐渐浮现，有时是零散的，有时是有组织的。一些更有趣的观察结果表明，分枝菌酸可被CD1限制的T细胞识别，结核分枝杆菌最强大的保护性抗原之一抗原85是一种霉菌酸转移酶，并且当脂阿拉伯甘露聚糖（LAM）被短甘露糖寡糖“封端”时，它参与结核分枝杆菌的吞噬作用。结核分枝杆菌基因组的定义极大地帮助了确定所有这些奇特分子的生物合成途径：分枝菌酸、霉菌酸、结核硬脂醇、LAM和聚异戊二烯磷酸酯。例如，我们知道整个核心的合成始于一个十聚异戊二烯-P与连接单元的合成，然后在这个中间体通过细胞质膜运输时，半乳聚糖和阿拉伯聚糖链同时延伸。这些事件的最后步骤，即分枝菌酸的附着和与肽聚糖的连接，还有待确定，并且将被证明是新一代抗结核药物的极佳靶点。
