Replenishing the cyclic-di-AMP pool: regulation of diadenylate cyclase activity in bacteria
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- 作者：Thi Huong Pham ; Zhao-Xun Liang ; Esteban Marcellin ; Mark S. Turner
- 关键词：Cyclic ; di ; AMP ; Diadenylate cyclase ; Peptidoglycan ; DNA ; Regulation
- 刊名：Current Genetics
- 出版年：2016
- 出版时间：November 2016
- 年：2016
- 卷：62
- 期：4
- 页码：731-738
- 全文大小：1,035 KB
- 刊物类别：Biomedical and Life Sciences
- 刊物主题：Life Sciences
Microbial Genetics and Genomics
Microbiology
Biochemistry
Cell Biology
Plant Sciences
Proteomics - 出版者：Springer Berlin / Heidelberg
- ISSN：1432-0983
- 卷排序：62
文摘
Bacteria can sense environmental cues and alter their physiology accordingly through the use of signal transduction pathways involving second messenger nucleotides. One broadly conserved second messenger is cyclic-di-AMP (c-di-AMP) which regulates a range of processes including cell wall homeostasis, potassium uptake, DNA repair, fatty acid synthesis, biofilm formation and central metabolism in bacteria. The intracellular pool of c-di-AMP is maintained by the activities of diadenylate cyclase (DAC) and phosphodiesterase (PDE) enzymes, as well as possibly via c-di-AMP export. Whilst extracellular stimuli regulating c-di-AMP levels in bacteria are poorly understood, recent work has identified effector proteins which directly interact and alter the activity of DACs. These include the membrane bound CdaR and the phosphoglucosamine mutase GlmM which both bind directly to the membrane bound CdaA DAC and the recombination protein RadA which binds directly to the DNA binding DisA DAC. The genes encoding these multiprotein complexes are co-localised in many bacteria providing further support for their functional connection. The roles of GlmM in peptidoglycan synthesis and RadA in Holliday junction intermediate processing suggest that c-di-AMP synthesis by DACs will be responsive to these cellular activities. In addition to these modulatory interactions, permanent dysregulation of DAC activity due to suppressor mutations can occur during selection to overcome growth defects, rapid cell lysis and osmosensitivity. DACs have also been investigated as targets for the development of new antibiotics and several small compound inhibitors have recently been identified. This review aims to provide an overview of how c-di-AMP synthesis by DACs can be regulated.