Baceridin, a Cyclic Hexapeptide from an Epiphytic Bacillus Strain, Inhibits the Proteasome
Baceridin, a Cyclic Hexapeptide from an Epiphytic Bacillus Strain, Inhibits the Proteasome
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DOI：
10.1002/cbic.201300778
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发表时间：
2014-05-05
期刊：
影响因子：
3.2
通讯作者：
Kalesse, Markus
中科院分区：
文献类型：
--
作者：
Niggemann, Jutta;Bozko, Przemyslaw;Kalesse, Markus
从一株与植物共生的芽孢杆菌属菌株的培养基中分离得到一个新的环状六肽--杆菌肽（1）。通过HR-HPLC-MS和1D和2D NMR实验解析了1的结构，并通过相应线性六肽2的ESI MS/MS序列分析证实了1的结构。衍生化后用GC-MS法和Marvelt法测定氨基酸残基的绝对构型。环肽1部分由非核糖体衍生的D-和allo-D-构型氨基酸组成。通过两种可能的立体异构体的全合成来指定序列环（-L-Trp-D-Ala-D-allo-Ile-L-Val-D-Leu-L-Leu-）内的D-和L-亮氨酸残基的顺序。测试了杆菌肽（1）的抗微生物和细胞毒性活性，显示出中等细胞毒性（1-2 gmL（-1））以及对金黄色葡萄球菌的弱活性。然而，它被鉴定为一种蛋白酶体抑制剂，通过p53非依赖性途径抑制细胞周期进程并诱导肿瘤细胞凋亡。
A new cyclic hexapeptide, baceridin (1), was isolated from the culture medium of a plant-associated Bacillus strain. The structure of 1 was elucidated by HR-HPLC-MS and 1D and 2D NMR experiments and confirmed by ESI MS/MS sequence analysis of the corresponding linear hexapeptide 2. The absolute configurations of the amino acid residues were determined after derivatization by GC-MS and Marfey's method. The cyclopeptide 1 consists partially of nonribosomal-derived D- and allo-D-configured amino acids. The order of the D- and L-leucine residues within the sequence cyclo(-L-Trp-D-Ala-D-allo-Ile-L-Val-D-Leu-L-Leu-) was assigned by total synthesis of the two possible stereoisomers. Baceridin (1) was tested for antimicrobial and cytotoxic activity and displayed moderate cytotoxicity (1-2 gmL(-1)) as well as weak activity against Staphylococcus aureus. However, it was identified to be a proteasome inhibitor that inhibits cell cycle progression and induces apoptosis in tumor cells by a p53-independent pathway.