Cyclic di-AMP metabolism and functions in Streptomyces

链霉菌中环二腺苷的代谢和功能

• 批准号: 314855492
• 负责人: Professorin Dr. Natalia Tschowri
• 金额: --
• 依托单位: Institut für Mikrobiologie (ifmb)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/314855492?language=en
• 关键词: Cyclic; di; AMP; metabolism; functions

The Gram-positive soil bacteria streptomycetes belong to natures most competent natural product factories and are an important source of diverse antibiotics and other bioactive molecules for medical, veterinary and agricultural use. The production of these secondary metabolites is temporally and genetically coordinated with a complex developmental life cycle involving growth as vegetative mycelium of branching hyphae and dispersion via spores formed on specialized reproductive structures called aerial hyphae. We have recently shown that in Streptomyces venezuelae the diadenylate cyclase (DAC) domain-containing protein DisA produces the nucleotide second messenger cyclic di-AMP which controls the levels of the cell wall lytic enzyme RpfA by binding to a riboswitch in the 5-untranslated leader region (UTR) of the rpfA gene. However, our knowledge about the biosynthesis, turnover and functions of c-di-AMP in the physiology of streptomycetes is still very limited. The aim of the proposed work within the SPP 1879 is to analyse and characterise in molecular detail the roles of DisA and c-di-AMP in S. venezuelae. We will determine the conditions under which DisA is expressed and active and define how this protein and c-di-AMP contribute to differentiation and stress survival strategies employed by Streptomyces spp. Since streptomycetes do not contain any of the already characterised c-di-AMP-binding proteins, we will perform a global screen for c-di-AMP effector proteins, which will allow us to identify a potentially novel type of c-di-AMP-degrading phosphodiesterases and a new class of effectors. Further, in our previous, unpublished studies we found, that S. venezuelae produces an up to now uncharacterised cyclic di-nucleotide. Detailed analysis and characterisation of this compound will lead to the discovery of a novel type of nucleotide-based second messengers in bacteria. Altogether, this work will greatly improve our understanding of the physiology and stress survival mechanisms in Streptomyces spp. and contribute to a better knowledge of c-di-AMP signalling in a new physiological context involving multicellular differentiation and secondary metabolite production.

革兰氏阳性土壤细菌链霉菌属于自然界最有能力的天然产物工厂，并且是用于医疗、兽医和农业用途的多种抗生素和其他生物活性分子的重要来源。这些次级代谢产物的产生在时间上和遗传上与复杂的发育生命周期相协调，所述发育生命周期涉及作为分支菌丝的营养菌丝体的生长和通过在称为气生菌丝的专门生殖结构上形成的孢子的分散。我们最近已经表明，在委内瑞拉链霉菌的二腺苷酸环化酶（DAC）结构域的蛋白质DisA产生的核苷酸第二信使环二-AMP控制水平的细胞壁裂解酶RpfA的5-非翻译前导区（UTR）的rpfA基因的核糖开关结合。然而，我们对链霉菌中c-di-AMP的生物合成、周转和生理功能的了解仍然非常有限。在SPP 1879中提出的工作的目的是在分子上详细分析和阐明DisA和c-di-AMP在S.委内瑞拉。我们将确定条件下，DisA的表达和活性，并定义如何这种蛋白质和c-di-AMP有助于分化和应力生存策略所采用的链霉菌。由于链霉菌不包含任何已经表征的c-di-AMP结合蛋白，我们将进行c-di-AMP效应蛋白的全球筛选，这将使我们能够识别一种潜在的新型c-di-AMP降解磷酸二酯酶和一类新的效应物。此外，在我们以前未发表的研究中，我们发现，S。委内瑞拉生产一种迄今为止尚未表征的环状二核苷酸。对这种化合物的详细分析和表征将导致在细菌中发现一种新型的基于核苷酸的第二信使。总之，这项工作将大大提高我们对链霉菌生理和逆境生存机制的理解。并有助于在涉及多细胞分化和次级代谢产物产生的新生理背景下更好地了解c-di-AMP信号传导。