Cyclic di-GMP

An intracellular signaling molecule in bacteria

Cyclic di-GMP (c-di-GMP) is a bacterial second messenger that plays a crucial role in the regulation of various cellular processes, including biofilm formation, motility, virulence, and cell cycle progression. It is a cyclic dinucleotide composed of two guanosine monophosphate (GMP) molecules linked by two phosphodiester bonds.

Structure and Synthesis

Cyclic di-GMP is synthesized from two molecules of GTP by the enzyme diguanylate cyclase (DGC), which contains a GGDEF domain. The reaction involves the formation of a phosphodiester bond between the 3' and 5' carbons of the ribose sugars of the two GMP molecules, resulting in the cyclic structure of c-di-GMP.

Degradation

The degradation of cyclic di-GMP is catalyzed by phosphodiesterases (PDEs) that contain either an EAL or HD-GYP domain. These enzymes hydrolyze c-di-GMP into linear pGpG or GMP, thereby reducing its intracellular concentration and modulating its signaling effects.

Function

Cyclic di-GMP is a key regulator of bacterial lifestyle transitions. High levels of c-di-GMP generally promote biofilm formation and sessility, while low levels favor motility and planktonic growth. This molecule influences various cellular processes through its interaction with specific receptor proteins, including:

• Biofilm Formation: c-di-GMP enhances the production of extracellular polymeric substances (EPS), which are essential for biofilm matrix formation.
• Motility: It inhibits flagellar motility by interacting with proteins that control flagellar motor function.
• Virulence: In some pathogenic bacteria, c-di-GMP modulates the expression of virulence factors.
• Cell Cycle: It can influence cell cycle progression and differentiation in certain bacterial species.

Receptors and Effectors

Cyclic di-GMP exerts its effects by binding to various receptor proteins, which can be classified into several types:

• PilZ Domain Proteins: These are the most well-characterized c-di-GMP receptors and are involved in regulating motility and biofilm formation.
• Riboswitches: Some bacteria use c-di-GMP-binding riboswitches to regulate gene expression at the level of transcription or translation.
• Enzymes and Transcription Factors: c-di-GMP can bind to enzymes and transcription factors, altering their activity and thereby influencing cellular processes.

Role in Pathogenesis

In pathogenic bacteria, c-di-GMP is often involved in the regulation of virulence factors. For example, in Pseudomonas aeruginosa, high levels of c-di-GMP promote biofilm formation, which is associated with chronic infections and increased resistance to antibiotics.

Research and Applications

Understanding the role of c-di-GMP in bacterial physiology and pathogenesis has significant implications for the development of novel antimicrobial strategies. Targeting c-di-GMP signaling pathways could lead to the development of drugs that disrupt biofilm formation or enhance bacterial clearance by the immune system.

Also see

• Biofilm
• Second messenger system
• Bacterial motility
• Virulence factor
• Guanosine triphosphate