Structural and biochemical characterization of Class I and Class III adenylyl cyclases from microbial pathogens

微生物病原体的 I 类和 III 类腺苷酸环化酶的结构和生化特征

• 批准号: 161714577
• 负责人: Professor Dr. Clemens Steegborn
• 金额: --
• 依托单位: Arbeitsgruppe Biochemie I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/161714577?language=en
• 关键词: Structural; biochemical; characterization; Class; III

Adenylyl cyclases (ACs) synthesize the ubiquitous second messenger cyclic AMP (cAMP) from ATP. In pathogenic microbes, cAMP is often involved in the regulation of virulence mechanisms. Microbes contain AC enzymes of the Class I and Class III subfamilies. Several microbial ACs of the structurally well studied Class III have been confirmed as drug targets, and the low conservation within this family renders specific inhibition of individual Class III enzymes possible. No structural information is yet available for the AC Class I, which is unique to bacterial organisms and thus enables even more specific inhibition of signaling systems of bacterial pathogens.We propose to study the structural details that differentiate CyaB, a confirmed drug target in the pathogen Pseudomonas aeroginosa, from Class III ACs of its human host. Using this information, modifications improving existing inhibitors as well as completely novel compounds will be identified. Further, we propose to solve the first crystal structure of a Class I AC as a representative of this conserved family. The structural data will again be used for the development of inhibitors, which should result in drugs affecting only the Class I AC-carrying pathogen with little side effects on the human host.

腺苷酸环化酶（AC）从ATP合成普遍存在的第二信使环AMP（cAMP）。在病原微生物中，cAMP通常参与毒力机制的调节。微生物含有I类和III类亚科的AC酶。结构上研究良好的III类的几种微生物AC已被证实为药物靶标，并且该家族内的低保守性使得可能特异性抑制单个III类酶。没有结构信息是尚未获得的AC I类，这是唯一的细菌有机体，从而使更具体的抑制信号系统的细菌pathogenes.We建议研究的结构细节，区分CyaB，一个确认的药物靶标的病原体铜绿假单胞菌，从III类AC的人类宿主。使用这些信息，改进现有抑制剂的修饰以及全新的化合物将被鉴定。此外，我们建议解决的第一个晶体结构的I类AC作为这个保守的家庭的代表。结构数据将再次用于抑制剂的开发，这将导致药物仅影响携带AC的I类病原体，对人类宿主的副作用很小。