We have developed a syringolin-based chemical probe and explored its utility for the profiling of metabolite extracts as potent inhibitors of the 20S proteasome. Activity-guided fractionation by competitive labeling allowed us to isolate and identify glidobactin A and C as well as luminmycin A from a Burkholderiales strain. The natural products exhibited unique subunit specificities for the proteolytic subunits of human and mouse constitutive and immunoproteasome in the lower nanomolar range. In particular, glidobactin C displayed an unprecedented β2/β5 coinhibition profile with single-digit nanomolar potency in combination with sufficiently high cell permeability. These properties render glidobactin C a promising live cell proteasome inhibitor with potent activity against human breast cancer cell lines and comparably low immunotoxicity.

中文翻译：

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天然产物的竞争性代谢产物分析揭示了20S蛋白酶体的亚基特异性抑制剂。

我们已经开发出一种基于丁香酚素的化学探针，并探索了其作为20S蛋白酶体有效抑制剂的代谢物提取物谱分析的实用性。通过竞争性标记进行活性导向的分级分离，使我们能够从Burkholderiales菌株中分离和鉴定格列杆菌素A和C以及发光素A。天然产物在较低的纳摩尔范围内对人和小鼠组成型和免疫蛋白酶体的蛋白水解亚基表现出独特的亚基特异性。特别地，葡糖杆菌素C显示出前所未有的β2/β5共抑制谱，具有单位数纳摩尔的效力以及足够高的细胞渗透性。这些特性使glidobactin C成为有前途的活细胞蛋白酶体抑制剂，对人乳腺癌细胞系具有有效的活性，并且免疫毒性相对较低。