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Groll M Schellenberg B Bachmann AS Archer CR Huber R Powell TK Lindow S Kaiser M Dudler R 《Nature》2008,452(7188):755-758
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. 相似文献
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HYPERKALAEMIC periodic paralysis (HYPP) is an autosomal dominant disease that results in episodic electrical inexcitability and paralysis of skeletal muscle. Electrophysiological data indicate that tetrodotoxin-sensitive sodium channels from muscle cells of HYPP-affected individuals show abnormal inactivation. Genetic analysis of nine HYPP families has shown tight linkage between the adult skeletal muscle sodium channel alpha-subunit gene on chromosome 17q and the disease (lod score, z = 24; recombination frequency 0 = 0), strongly suggesting that mutations of the alpha-subunit gene cause HYPP. We sequenced the alpha-subunit coding region isolated from muscle biopsies from affected (familial HYPP) and control individuals by cross-species polymerase chain reaction-mediated complementary DNA cloning. We have identified an A----G substitution in the patient's messenger RNA that causes a Met----Val change in a highly conserved region of the alpha-subunit, predicted to be in a transmembrane domain. This same change was found in a sporadic case of HYPP as a new mutation. We have therefore discovered a voltage-gated channel mutation responsible for a human genetic disease. 相似文献
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E. N. Powell A. C. Morrill R. R. Bidigare 《Cellular and molecular life sciences : CMLS》1989,45(2):198-200
Vesicomyid and lucinid clams and tubeworms from Gulf of Mexico petroleum seeps, all of which bear symbiotic sulfide-oxidizing bacteria, have much lower catalase activities than shallow-water species lacking symbionts. A petroleum seep mussel bearing methane-oxidizing bacteria is unusual in having catalase activities as high as shallow-water bivalves. Unlike sulfide-dependent meiofauna from shallow-water marine sands, catalase from all petroleum seep species was inhibited by 3-amino-1,2,4-triazole.Acknowledgments. We thank S. McDonald and the crew of R/V Gyre for assistance in animal collection. This research was funded by NSF grant OCE-8219792 to EP and NSF grant OCE-83-01538 and funds from the Offshore Operators Committee to J. Brooks. We appreciate this support. 相似文献
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