Groll Michael, Schellenberg Barbara, Bachmann André S, Archer Crystal R, Huber Robert, Powell Tracy K, Lindow Steven, Kaiser Markus, Dudler Robert
Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstrasse 4, Garching D-85747, Germany.
Nature. 2008 Apr 10;452(7188):755-8. doi: 10.1038/nature06782.
Pathogenic bacteria often use effector molecules to increase virulence. In most cases, the mode of action of effectors remains unknown. Strains of Pseudomonas syringae pv. syringae (Pss) secrete syringolin A (SylA), a product of a mixed non-ribosomal peptide/polyketide synthetase, in planta. Here we identify SylA as a virulence factor because a SylA-negative mutant in Pss strain B728a obtained by gene disruption was markedly less virulent on its host, Phaseolus vulgaris (bean). We show that SylA irreversibly inhibits all three catalytic activities of eukaryotic proteasomes, thus adding proteasome inhibition to the repertoire of modes of action of virulence factors. The crystal structure of the yeast proteasome in complex with SylA revealed a novel mechanism of covalent binding to the catalytic subunits. Thus, SylA defines a new class of proteasome inhibitors that includes glidobactin A (GlbA), a structurally related compound from an unknown species of the order Burkholderiales, for which we demonstrate a similar proteasome inhibition mechanism. As proteasome inhibitors are a promising class of anti-tumour agents, the discovery of a novel family of inhibitory natural products, which we refer to as syrbactins, may also have implications for the development of anti-cancer drugs. Homologues of SylA and GlbA synthetase genes are found in some other pathogenic bacteria, including the human pathogen Burkholderia pseudomallei, the causative agent of melioidosis. It is thus possible that these bacteria are capable of producing proteasome inhibitors of the syrbactin class.
致病细菌常常利用效应分子来增强毒力。在大多数情况下，效应分子的作用方式仍不为人知。丁香假单胞菌丁香致病变种（Pss）的菌株在植物体内分泌丁香菌素A（SylA），它是一种由混合的非核糖体肽/聚酮化合物合成酶产生的产物。在此，我们确定SylA为一种毒力因子，因为通过基因破坏获得的Pss菌株B728a中的SylA阴性突变体在其宿主菜豆上的毒力明显降低。我们表明，SylA不可逆地抑制真核蛋白酶体的所有三种催化活性，从而将蛋白酶体抑制作用添加到毒力因子的作用方式列表中。酵母蛋白酶体与SylA复合物的晶体结构揭示了一种与催化亚基共价结合的新机制。因此，SylA定义了一类新的蛋白酶体抑制剂，其中包括来自伯克霍尔德菌目一个未知物种的结构相关化合物格利多菌素A（GlbA），我们证明其具有类似的蛋白酶体抑制机制。由于蛋白酶体抑制剂是一类有前景的抗肿瘤药物，发现一类新的抑制性天然产物（我们称之为syrbactins）可能也对抗癌药物的开发具有启示意义。在包括人类病原体类鼻疽伯克霍尔德菌（类鼻疽的病原体）在内的一些其他致病细菌中发现了SylA和GlbA合成酶基因的同源物。因此，这些细菌有可能能够产生syrbactin类的蛋白酶体抑制剂。
