Biosynthesis of guanidine-containing natural products in cyanobacteria

Cyanobacteria are prolific producers of structurally diverse and biologically potent natural products, a subset of which feature guanidino moieties. Introduction and modification of the guanidine group confer tuned basicity and enable extensive hydrogen bonding, cation-π, and electrostatic interactions, facilitating high-affinity binding to numerous biological targets. Although the enzymatic processes responsible for guanidine modifications in cyanobacterial pathways remain somewhat obscure, recent investigations have begun to clarify the biosynthetic machinery that mediates these distinctive transformations. In this review, we summarize these advances, with particular emphasis on the enzymatic steps responsible for guanidine installation and tailoring. These enzymatic transformations include N-prenylation, cyclization, and tricyclic guanidinium formation, representing rare or previously undescribed biosynthetic strategies in nature. This review provides new insights into the metabolic and enzymatic versatility of cyanobacteria and a foundation for future advances in enzyme engineering and therapeutic discovery. One-Sentence Summary: This review highlights recent advances in understanding how cyanobacteria enzymatically install and modify guanidino groups to produce bioactive natural products.