Emerging roles of pterins as signaling molecules in bacteria

Pterins are redox-active biomolecules with well-established functions as enzymatic cofactors in all domains of life. Examples of pterin cofactors include tetrahydrofolate, an essential carrier of one-carbon units, and the molybdenum cofactor (Moco)-composed of molybdopterin bound to molybdenum or tungsten-which supports a wide range of redox reactions for diverse enzymes. Pterins also play important roles outside of enzyme active sites where they serve as antioxidants and immune system modulators. Recently, a new role for pterins in bacteria has emerged through the discovery of a pterin-dependent regulator called DcpA that modulates the cytoplasmic second messenger cyclic-di-guanylate monophosphate (c-di-GMP) levels and biofilm formation in Agrobacterium tumefaciens, a model bacterial plant pathogen. The regulatory pathway involves the PruA pteridine reductase and a periplasmic pterin-binding protein termed PruR. This review provides an overview of each of the key players in this pathway and highlights the broad distribution of the respective genes that supports the presence of similar pterin-mediated regulatory pathways in diverse bacteria. In our current model for the A. tumefaciens pathway, PruA generates a tetrahydropterin species that is released to the periplasm where it binds to PruR. The pterin-PruR complex then interacts with the periplasmic domain of DcpA to promote c-di-GMP degradation. The decreased levels of cytoplasmic c-di-GMP disfavor attachment and limit biofilm formation. The redox active nature of pterins is likely a central facet of their signaling functions, where the different redox states of a given pterin species may reflect changing environmental conditions.