Cyclic-di-GMP disodium is the disodium salt form of cyclic diguanylate monophosphate (c-di-GMP), a ubiquitous bacterial second messenger that regulates a multitude of physiological and developmental processes in prokaryotic organisms. Structurally, c-di-GMP consists of two guanine nucleotides connected via a 5'-3' cyclic phosphate linkage, forming a macrocyclic ring with two-fold symmetry. In aqueous physiological conditions, the molecule predominantly exists as a monomer, though it can also form dimeric complexes when bound to specific effector proteins.
Figure 1. Principle of c-di-GMP signaling. Its monomer has double symmetry, with the two GMP parts fused via a 5'-3' macrocycle[1].
Biosynthesis of c-di-GMP is catalyzed by diguanylate cyclases (DGCs), enzymes harboring conserved GGDEF domains, which facilitate the condensation of two GTP molecules into c-di-GMP. Conversely, phosphodiesterases (PDEs) with EAL or HD-GYP domains degrade c-di-GMP, thereby maintaining intracellular homeostasis. The antagonistic regulation by DGCs and PDEs enables bacteria to modulate c-di-GMP concentrations dynamically in response to environmental and cellular cues.
Alfa Chemistry offers reliable, high-purity cyclic-di-GMP disodium and related analogs for use by researchers exploring novel bacterial signaling pathways or seeking to exploit host-pathogen interactions for therapeutic benefit.
Cyclic-di-GMP plays a pivotal role in regulating bacterial motility, biofilm formation, cell cycle progression, and virulence. In species such as Caulobacter crescentus, c-di-GMP orchestrates developmental transitions during the cell cycle, promoting polar morphogenesis by regulating the formation of cellular appendages such as flagella and pili. Mutations that impair c-di-GMP synthesis lead to severe morphological abnormalities and the loss of polar structures.
Figure 2. Role of c-di-GMP in Caulobacter crescentus pole morphogenesis and cell cycle progression[1].
In most bacteria, high levels of c-di-GMP result in reduced motility and increased sessility, surface attachment and biofilm formation, which is often associated with chronic infection and persistence in the environment. For instance, in Escherichia coli and Salmonella enterica, c-di-GMP binds to the flagellar motor via the effector protein YcgR, which directly blocks its activity and results in loss of motility. The co-expression of specific PDEs counteracts this effect, offering a fine-tuned switch between motile and sessile states. In Pseudomonas aeruginosa, distinct diguanylate cyclases and effector proteins have been shown to function at different stages of biofilm formation, revealing the modularity and hierarchy of c-di-GMP signaling.
Beyond structural and behavioral control, c-di-GMP also modulates virulence in pathogenic bacteria by regulating secretion systems, surface adhesins, and toxin expression. In Clostridioides difficile, a pathogen responsible for antibiotic-associated diarrhea, c-di-GMP governs the switch from motility to surface adherence during intestinal colonization. This process is controlled by 16 riboswitches that respond to intracellular c-di-GMP levels, thereby regulating the expression of flagella, type IV pili, adhesion proteins, and virulence toxins such as TcdA and TcdB.
Figure 3. Role of c-di-GMP in the virulence of Clostridium difficile[1].
Curiously, these riboswitches have been classified as type I or off switches, and type II or on switches, to coordinate gene expression in response to c-di-GMP levels. This allows C. difficile to balance host colonization by encouraging biofilm and surface adherence under high c-di-GMP levels and downregulating these properties when c-di-GMP is low.
In addition to its role in prokaryotic signaling, cyclic-di-GMP has been found to have an immunostimulatory effect in mammalian systems as well. C-di-GMP is a member of a class of nucleotides known as cyclic dinucleotides (CDNs), which have been found to act as agonists of the STING (stimulator of interferon genes) pathway, a pathway that detects cytosolic DNA and causes induction of type I interferons. C-di-GMP binds to and activates the STING receptor and initiates downstream signaling through TBK1 and IRF3 to promote innate immune responses.
The finding of this cross-talk between bacterial CDNs and mammalian innate immunity has generated a novel therapeutic strategy for targeting innate immune activation. Alfa Chemistry provides high-purity cyclic-di-GMP disodium as a research chemical for applications including STING agonism in immuno-oncology and vaccine adjuvant design, as well as infectious disease modeling. C-di-GMP disodium has shown antiproliferative effects in cancer cell lines, as well as upregulation of CD4 receptor expression.
The enzymatic synthesis of c-di-GMP is tightly controlled at multiple levels. For instance, the diguanylate cyclase PleD from C. crescentus requires phosphorylation-induced dimerization to adopt a catalytically active conformation. Likewise, DgcZ from E. coli contains an N-terminal zinc-binding CZB domain, which acts as an allosteric inhibitor. Zinc binding prevents the proper alignment of the GGDEF domains, and only upon zinc release does the enzyme achieve a catalytically competent state.
This complex network of regulation allows bacteria to integrate a variety of environmental signals into a unified second messenger output. Such intricate control mechanisms reflect the essential and context-dependent functions of c-di-GMP in bacterial life.
Figure 4. General concepts of c-di-GMP signaling modules. (a) Evolutionary diagram of the incorporation of a new cellular process into an existing cyclic dinucleotide (CDN) network. (b, c) The network architecture that is involved in pathway-specific signaling. (d) c-di-GMP can control the same biological process at different levels[1].
Q1: Is cyclic-di-GMP disodium stable under physiological conditions?
Yes, cyclic-di-GMP disodium is stable as a monomer at physiological concentrations and does not readily dimerize unless bound to specific effector proteins.
Q2: Can c-di-GMP be used directly as a drug?
While it shows promising immunostimulatory and anti-cancer properties, c-di-GMP is currently limited to preclinical research and experimental therapeutic models due to delivery and stability challenges.
Q3: What makes c-di-GMP different from other second messengers like cAMP or cGMP?
Unlike cAMP and cGMP, which mainly function in eukaryotic cells, c-di-GMP is exclusive to prokaryotes and controls a much broader set of processes, including surface adaptation, virulence, and community behavior.
Q4: How is c-di-GMP delivered in experimental setups for STING activation?
Typically, c-di-GMP disodium is administered via liposomal carriers, nanoparticles, or direct microinjection, depending on the application and model system.
Q5: Is cyclic-di-GMP involved in antibiotic resistance?
Indirectly, yes. By promoting biofilm formation, c-di-GMP contributes to increased bacterial tolerance to antibiotics and immune evasion, complicating treatment strategies.
Q6: Can c-di-GMP be detected in clinical samples?
Currently, quantification is feasible using advanced techniques like LC-MS/MS, but clinical applications are still under investigation.
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