Roles of divalent metals in the regulation of cyclic di-GMP signaling in bacteria

Metals are essential co-factors that are important for the activity of many enzymes and, hence, bacterial life itself. Cyclic di-GMP (c-di-GMP) is an important signaling molecule that is prevalent across various bacterial phyla and involved in myriad physiological processes. The structure and function of diguanylate cyclase (DGCs) and phosphodiesterase (PDEs) domains that make and degrade c-di-GMP are also highly conserved. These enzymes are influenced by several signaling cues, such as temperature, oxygen, and small molecules, which determine the intracellular c-di-GMP levels and subsequent bacterial physiology. In this review, we summarize the current knowledge of the roles of divalent metals Mn²⁺, Mg²⁺, Zn²⁺, Ca²⁺, and Fe²⁺ in modulating the activity of DGCs and PDEs and c-di-GMP-related phenotypes. We describe the role of divalent metals in modulating DGC and PDE catalysis, and then discuss the examples of divalent metals as signals that modulate c-di-GMP levels. We also discuss how metals can influence the transcription of c-di-GMP catalytic enzymes. The review highlights the underexplored question of how metal availability shapes c-di-GMP signaling across diverse environmental contexts.