Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major
Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major
复制标题
DOI：
10.1042/bj20051886
复制
发表时间：
2006-06-01
影响因子：
4.1
通讯作者：
Smith, Deborah F.
中科院分区：
文献类型：
--
作者：
Panethymitaki, Chrysoula;Bowyer, Paul W.;Smith, Deborah F.
真核酶NMT（肉豆蔻酰辅酶A：蛋白N-肉豆蔻酰转移酶）已在从酿酒酵母到智人的一系列物种中得到表征。NMT对于许多人类病原体的生存能力至关重要，包括真菌白色念珠菌和新型隐球菌，以及寄生原虫大型利什曼原虫和布氏锥虫。我们已经纯化了利什曼原虫和T.将布鲁氏菌NMT作为活性重组蛋白，并对其必需脂肪酸供体肉豆蔻酰-CoA和特异性肽底物进行动力学分析。针对真菌种属中的NMT的许多抑制性化合物已针对体外寄生虫酶和体内活寄生虫进行了测试。这些化合物中的两种抑制TbNMT的IC 50值< 1 μ M，并且对哺乳动物寄生虫阶段也有活性，ED 50（允许50%细胞生长的有效剂量）值为16-66 μ M，并且对鼠巨噬细胞具有低毒性。这些结果表明，靶向NMT可能是一种有效的方法，用于开发针对非洲昏睡病和Nagana等传染病的化疗药物。
The eukaryotic enzyme NMT (myristoyl-CoA:protein N-myristoyltransferase) has been characterized in a range of species from Saccharomyces cerevisiae to Homo sapiens. NMT is essential for viability in a number of human pathogens, including the fungi Candida albicans and Cryptococcus neoformans, and the parasitic protozoa Leishmania major and Trypanosoma brucei. We have purified the Leishmania and T. brucei NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and specific peptide substrates. A number of inhibitory compounds that target NMT in fungal species have been tested against the parasite enzymes in vitro and against live parasites in vivo. Two of these compounds inhibit TbNMT with IC50 values of < 1 mu M and are also active against mammalian parasite stages, with ED50 (the effective dose that allows 50 % cell growth) values of 16-66 mu M and low toxicity to murine macrophages. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against infectious diseases including African sleeping sickness and Nagana.