结核分枝杆菌UDP-N-乙酰葡糖胺生物合成及抗结核药物靶标

Biosynthesis of UDP-GlcNAc in Mycobacterium tuberculosis and drug targets of anti-tuberculosis

关键词:  结核病  结核分枝杆菌  UDP-N-乙酰葡糖胺  GlmM  GlmU

Key words:  tuberculosis  Mycobacterium tuberculosis  UDP-GlcNAc  GlmM  GlmU

摘要:

结核分枝杆菌是结核病的致病菌。UDP-N-乙酰葡糖胺是结核分枝杆菌细胞壁的重要糖基供体及前体分子，其生物合成由三种酶催化的四步反应完成。磷酸葡糖胺变位酶GlmM催化第二步反应，GlmU双功能酶催化最后两步反应。glmM及glmU基因敲除分别导致细菌细胞壁受损、细菌裂解及死亡，因此，GlmM和GlmU可作为研发抗结核新药的作用靶标。建立GlmM及GlmU酶活性检测方法、揭示其酶学特性、解析GlmU的晶体结构，便于人们筛选及定向设计酶抑制剂，以期发现新一代抗结核药物。

Abstract:

Mycobacterium tuberculosis is a pathogen causing tuberculosis. UDP-N-acetylglucosamine (UDP-GlcNAc) is an important sugar donor and precursor in the cell wall of M. tuberculosis. The biosynthetic pathway of UDP-GlcNAc includes four steps which are catalyzed by three enzymes. Phosphoglucosamine mutase (GlmM) catalyzes the second reaction and a bifunctional enzyme GlmU with glucosamine-1-phosphate acetyltransferase and N-acetylglucosamine-1-phosphate uridyltransferase activities catalyzes the last two sequential steps in the formation of UDP-GlcNAc. The gene knockout of GlmM and GlmU results in cell wall destruction, bacterial lysis and death. Therefore, GlmM and GlmU are drug targets for developing anti-tuberculosis. Development of GlmM and GlmU enzyme assays and characterization of GlmM and GlmU enzymes as well as determination of crystal structure of GlmU will be helpful for screening and designing inhibitors of GlmM and GlmU to develop new drugs of anti-tuberculosis.