耻垢分枝杆菌（Mycobacterium smegmatis）EmbC蛋白C端的功能探讨
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摘要
结核分枝杆菌(Mycobacterium tuberculosis)是引起结核病(tuberculosis，TB)的病原体。近年来，由于多耐药性(muti-drug resistant，MDR)结核分枝杆菌突变株的出现，使得结核病卷土重来。结核分枝杆菌能够在机体免疫系统功能正常的情况下生存于感染宿主的巨噬细胞内，不但未被消灭，反而受其保护，这关键在于分枝杆菌具有独特的细胞壁结构。
由D-呋喃型阿拉伯糖(D-Araf)构成的聚阿拉伯糖(Arabinan)是分枝杆菌细胞壁中聚阿拉伯糖半乳糖(arabinogalactan，AG)和聚阿拉伯糖甘露糖脂(lipoarabinomannan，LAM)的主要组成成分。AG和LAM中的聚阿拉伯糖的还原端均由α-(1→5)连接的阿拉伯糖残基构成，但聚阿拉伯糖非还原末端的模序(motif)结构不同，AG中只含有分支的阿拉伯六糖(Ara_6)，[β-D-Araf-(1→2)-α-D-Araf-(1→)]_2→(3，5)-α-D-Araf-(1→5)-α-D-Araf；而LAM中既含有与AG相同的分支Ara_6，又含有线性的阿拉伯四糖(Ara_4)，β-D-Araf-(1→2)-α-D-Araf-(1→5)-α-D-Araf-(1→5)-α-D-Araf。分枝菌酸—聚阿拉伯糖聚半乳糖—肽聚糖(mycolic acid-arabinogalactan-peptidoglycan，mAGP)构成了分枝杆菌细胞壁的骨架；而LAM则通过磷酸肌醇锚定物非共价连接于细胞膜上，其中聚阿拉伯糖连接于聚甘露糖并延伸至细胞壁骨架之外，结核分枝杆菌中的聚阿拉伯糖非还原末端具有甘露糖残基构成的帽子结构，是分枝杆菌与宿主细胞相互作用的关键因子。
抗结核病的一线药物之一乙胺丁醇具有抑制AG和LAM中聚阿拉伯糖合成的作用，其可能的作用靶标为Emb蛋白，包括EmbC，EmbA和EmbB蛋白。Emb蛋白是跨膜蛋白，N端含有12-14个跨膜区，而C端位于细胞膜外，呈球形。在不同的分枝杆菌中，Emb蛋白质具有保守性。在embA或embB基因敲除的耻垢分枝杆菌(Mycobacterium smegmatis)突变株中，AG中阿拉伯糖的含量明显减少，结构分析表明聚阿拉伯糖非还原末端Ara_6中以3，5连接的α-D-Araf残
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has infected the human being for thousands years. In recent years, the impressive emergence and wide distribution of multidrug-resistant (MDR) strains of M. tuberculosis has a significant impact for the increased incidence of TB. M. tuberculosis is an extraordinarily successful pathogen with the remarkable ability to persist and replicate within the normally hostile environment of macrophages. An important key to the success of pathogenic M. tuberculosis is likely to be its unusual cell wall structure and its interactions with the immune system.
D-Arabinans, composed of D-arabinofuranose (D-Araf), dominate the structure of mycobacterial cell walls in two settings, as part of lipoarabinomannan (LAM) and arabinogalactan, each with markedly different structures and functions. The arabinan in AG and LAM has the same reducing α-(1→5) arabinosyl chain, but different terminal motif. The nonreducing end of the arabinan in AG is terminated by branched Ara_6,[β -D-Araf-(1→2)-α-D-Araf-(1→)]_2→(3,5)-α-D-Araf-(1→5)-α-D-Araf, while the nonreducing end of the arabinan in LAM is terminated by both Ara_6, the same as in AG, and linear Ara_4, β -D-Araf-(1→2)-α-D-Araf-(1→5)-α-D-Araf-(1→5)-α-D-Araf. Mycolic acid arabinogalactan - peptidoglycan (mAGP) composed of the backbone of the mycobacterial cell wall. LAM consists of arabinan, mannan and phosphatidyl -myo- inositol anchor, and the arabinan and mannan are non-covalently attached to the plasma membrane through the phosphatidyl-myo-inositol anchor. The arabinan is extend to the exterior of the cell wall backbone, and the non-reducing ends of the arabinan are capped with mannose residues responsible for much of their biological roles relating to host pathogen interaction.
Little is known about the synthesis of the arabinan in AG and LAM. EmbA,
由D-呋喃型阿拉伯糖(D-Araf)构成的聚阿拉伯糖(Arabinan)是分枝杆菌细胞壁中聚阿拉伯糖半乳糖(arabinogalactan，AG)和聚阿拉伯糖甘露糖脂(lipoarabinomannan，LAM)的主要组成成分。AG和LAM中的聚阿拉伯糖的还原端均由α-(1→5)连接的阿拉伯糖残基构成，但聚阿拉伯糖非还原末端的模序(motif)结构不同，AG中只含有分支的阿拉伯六糖(Ara_6)，[β-D-Araf-(1→2)-α-D-Araf-(1→)]_2→(3，5)-α-D-Araf-(1→5)-α-D-Araf；而LAM中既含有与AG相同的分支Ara_6，又含有线性的阿拉伯四糖(Ara_4)，β-D-Araf-(1→2)-α-D-Araf-(1→5)-α-D-Araf-(1→5)-α-D-Araf。分枝菌酸—聚阿拉伯糖聚半乳糖—肽聚糖(mycolic acid-arabinogalactan-peptidoglycan，mAGP)构成了分枝杆菌细胞壁的骨架；而LAM则通过磷酸肌醇锚定物非共价连接于细胞膜上，其中聚阿拉伯糖连接于聚甘露糖并延伸至细胞壁骨架之外，结核分枝杆菌中的聚阿拉伯糖非还原末端具有甘露糖残基构成的帽子结构，是分枝杆菌与宿主细胞相互作用的关键因子。
抗结核病的一线药物之一乙胺丁醇具有抑制AG和LAM中聚阿拉伯糖合成的作用，其可能的作用靶标为Emb蛋白，包括EmbC，EmbA和EmbB蛋白。Emb蛋白是跨膜蛋白，N端含有12-14个跨膜区，而C端位于细胞膜外，呈球形。在不同的分枝杆菌中，Emb蛋白质具有保守性。在embA或embB基因敲除的耻垢分枝杆菌(Mycobacterium smegmatis)突变株中，AG中阿拉伯糖的含量明显减少，结构分析表明聚阿拉伯糖非还原末端Ara_6中以3，5连接的α-D-Araf残
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has infected the human being for thousands years. In recent years, the impressive emergence and wide distribution of multidrug-resistant (MDR) strains of M. tuberculosis has a significant impact for the increased incidence of TB. M. tuberculosis is an extraordinarily successful pathogen with the remarkable ability to persist and replicate within the normally hostile environment of macrophages. An important key to the success of pathogenic M. tuberculosis is likely to be its unusual cell wall structure and its interactions with the immune system.
D-Arabinans, composed of D-arabinofuranose (D-Araf), dominate the structure of mycobacterial cell walls in two settings, as part of lipoarabinomannan (LAM) and arabinogalactan, each with markedly different structures and functions. The arabinan in AG and LAM has the same reducing α-(1→5) arabinosyl chain, but different terminal motif. The nonreducing end of the arabinan in AG is terminated by branched Ara_6,[β -D-Araf-(1→2)-α-D-Araf-(1→)]_2→(3,5)-α-D-Araf-(1→5)-α-D-Araf, while the nonreducing end of the arabinan in LAM is terminated by both Ara_6, the same as in AG, and linear Ara_4, β -D-Araf-(1→2)-α-D-Araf-(1→5)-α-D-Araf-(1→5)-α-D-Araf. Mycolic acid arabinogalactan - peptidoglycan (mAGP) composed of the backbone of the mycobacterial cell wall. LAM consists of arabinan, mannan and phosphatidyl -myo- inositol anchor, and the arabinan and mannan are non-covalently attached to the plasma membrane through the phosphatidyl-myo-inositol anchor. The arabinan is extend to the exterior of the cell wall backbone, and the non-reducing ends of the arabinan are capped with mannose residues responsible for much of their biological roles relating to host pathogen interaction.
Little is known about the synthesis of the arabinan in AG and LAM. EmbA,
引文
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