Analysis of the regulation, expression, and localisation of the isocitrate lyase from Aspergillus fumigatus, a potential target for antifungal drug development
Analysis of the regulation, expression, and localisation of the isocitrate lyase from Aspergillus fumigatus, a potential target for antifungal drug development
复制标题
DOI：
10.1016/j.fgb.2006.01.015
复制
发表时间：
2006-07-01
影响因子：
3
通讯作者：
Brock, Matthias
中科院分区：
文献类型：
--
作者：
Ebel, Frank;Schwienbacher, Monika;Brock, Matthias
侵袭性曲霉病是由烟曲霉菌引起的免疫功能低下患者的严重全身感染。需要新的药物靶点，因为治疗性治疗经常失败，并受到抗真菌药物严重副作用的阻碍。乙醛酸旁路的酶是潜在的靶点，因为它们在人类中不存在，但对于曲霉菌在产生C2的碳源上的生长是必需的。关键酶异柠檬酸裂解酶（ICL）可以抑制3-硝基丙酸，无论是作为一个纯化的酶和完整的细胞内，而后者的抑制上调ICL启动子活性。ICL被发现在不同的亚细胞结构内生长的菌丝，但只有在条件下需要ICL活性。相反，ICL组成型分生孢子中发现，这表明在萌发过程中的特定作用。在分生孢子和巨噬细胞中检测到脂质作为潜在底物。此外，在巨噬细胞内萌发的分生孢子含有ICL，这表明乙醛酸分流可能是开发抗真菌剂的相关靶点。(c)2006年爱思唯尔公司All rights reserved.
Invasive aspergillosis, caused by Aspergillus fumigatus, is a severe systemic infection in immunocompromised patients. New drug targets are required, since therapeutic treatment often fails and is hampered by severe side effects of antifungals. Enzymes of the glyoxylate bypass are potential targets, since they are absent in humans, but required for growth of Aspergillus on C2-generating carbon sources. The key enzyme isocitrate lyase (ICL) can be inhibited by 3-nitropropionate, both as a purified enzyme and within intact cells, whereas the latter inhibition upregulates ICL promoter activity. ICL was found in distinct subcellular structures within growing hyphae, but only under conditions requiring ICL activity. In contrast, ICL was constitutively found in conidia, suggesting a specific role during germination. Lipids, as potential substrates, were detected in conidia and macrophages. Additionally, germinating conidia within macrophages contain ICL, suggesting that the glyoxylate shunt might be a relevant target for development of antifungals. (c) 2006 Elsevier Inc. All rights reserved.