UC Berkeley

This past decade has witnessed an expanded diversity in the cast of nucleotide-based second messengers. The small lineup of cyclic AMP, cyclic di-GMP and ppGpp have been joined by new co-stars, including cyclic di-AMP, cyclic oligoA, and two flavors of cyclic AMP-GMP - with one possessing a unique 2’-5’ phosphodiester linkage specific to eukaryotes. As each new signaling pathway has been uncovered, new enzymes classes have been attached to each specific second messenger, suggesting rigid evolutionary pathways in the development of new signal transduction pathways.

We have begun to unravel this paradigm with the discovery of a subclass of GGDEF enzyme - previously associated only with cyclic di-GMP synthesis - responsible for synthesis of a different cyclic dinucleotide, cyclic AMP-GMP. Intriguingly, this enzyme behaves nothing like the other two. Our discovery of this new activity from an ancient enzyme class pinpoints a set of deltaproteobacteria that have this “hybrid promiscuous” GGDEF activity, which preliminary work suggests controls transient surface attachment in diverse bacterial lifestyles. Furthermore, we have begun to unravel how Nature has allowed this newfound activity to act separately from other GGDEF-related pathways to allow precise control over electron acceptor choice in Geobacter species. Our work suggests that there is further underappreciated potential for individual components of nucleotide second messenger signaling enzymes, and establishes a footing for engineering new bioorthogonal signaling functions into this venerable enzyme class.