对于抗菌活性和有效的离子结合,需要在非阿克丁宏循环中交替的立体化学模式
Brian R Kusche1, Adrienne E Smith, Michele A McGuirl
1Department of Chemistry and Biochemistry, University of Montana, 32 Campus Drive, Missoula, Montana 59812-1656, USA.
Journal of the American Chemical Society
|November 12, 2009
概括
作为抗生素离子体的诺纳克丁的自然立体化学是其抗菌活性和运输离子的能力的关键. 对于nonactin的功能来说,需要使用nonactin酸的两个反体.
科学领域:
- 生物化学 生物化学
- 微生物学 微生物学
- 化学生物学 化学生物学
背景情况:
- 诺纳克丁是一种多基类抗生素,也是Streptomyces griseus产生的选择性离子体.
- 它具有S4对称性,并且是阿基拉性,是两个 (+) - 非酸和两个 (-) - 非酸单体的循环四.
- 诺纳克的自然立体化学对于其生物活性至关重要,但其反体成分的确切作用尚未完全阐明.
研究的目的:
- 为了研究氨酸离子和抗菌性能的 (+) - 和 (-) - 非酸离子体的必要性.
- 为了比较天然诺纳克丁的结合亲和力和运输能力,与其由单个诺纳克丁酸反体组成的二聚同体进行比较.
主要方法:
- 合成两种非天然的双立体异构体:全-(+) - 非actin和全-(-) - 非actin.
- 确定抗菌活性对抗阳性生物体的测定.
- 异热定位热量计用于量化结合热力学 (K(a),DeltaG,DeltaH,DeltaS) 与K(+),Na(+) 和NH(4)(+).
- 皮克拉特分离试验,以评估通过有机溶剂的离子运输.
- 计算建模用于分析离子-连接体复合体内的固态相互作用.
主要成果:
- 与天然的无活性蛋白相比,非天然的类异构体对阳性细菌的活性降低了500倍.
- 自然的诺纳克对K的结合亲和力比所有-(-) -诺纳克高880倍.
- 不同于nonactin,all-(-) -nonactin无法将K(+) 离子分解成有机溶剂.
- 建模表明,在all-(-) - nonactin-K(+) 综合体中存在固体阻碍,防止紧密结合.
结论:
- 无论是 (+) - 还是 (-) - - 非酸反体的存在,对于生物活性非酸的形成是不可或缺的.
- 诺纳克丁的特定立体化学决定了其作为离子体的有效性及其抗菌性质.
- 了解立体化学要求可以了解离子运输和抗生素作用的机制.
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