Deciphering the guanidine code: from core metabolism to biosynthesis of its derivatives

Guanidine is a chemically stable, nitrogen-rich moiety that constitutes a core structural element of numerous natural small molecules and is widely used in pharmaceuticals, animal feed, cosmetics, and related industries. In recent years, microbial cell factories have emerged as sustainable and efficient platforms for the production of guanidine derivatives. This review summarizes the central metabolic pathways of guanidine in microorganisms and provides critical insights for the metabolic engineering of guanidine derivatives. We highlight current biosynthetic strategies and recent advances in the production of representative guanidine derivatives, including L-arginine and its downstream products guanidinoacetate and agmatine. Finally, we discuss the key challenges limiting the efficient biosynthesis of guanidine and its derivatives and outline future directions toward industrially viable guanidine-based biomanufacturing.