Natural products with atypical atoms: unveiling structures, biosynthetic pathways, and bioactivities.

Covering: 1944-2025Nature's biosynthetic repertoire extends far beyond conventional CHON(S) chemistry and encompasses a rare but diverse array of natural products that incorporate atypical elements such as arsenic, selenium, fluorine, iodine, boron, and vanadium. These metabolites reveal how living systems have evolved to harness atypical atoms through both enzyme-mediated and spontaneous chemical strategies. Biological C-F and Se-C bond formation, SAM-dependent arsenic methylation, and non-enzymatic boron complexation exemplify nature's ingenuity in overcoming extreme energetic or coordination constraints. Despite their scarcity, these compounds play critical ecological and physiological roles in detoxification and redox regulation (As, Se), defense, and signaling (F, I, B), and in some cases, sustain global biogeochemical cycles (Mo, V). Structurally, they exhibit exceptional chemical stability, redox versatility, and metal-ligand diversity. Functionally, these findings expand our understanding of enzyme evolution, chemical defense strategies, and symbiotic metabolism in both marine and terrestrial ecosystems. Recent genomic and biochemical advances have uncovered new families of atypical natural products and the specialized enzymes responsible for their formation. Taken together, these discoveries define the limits of biogenic chemistry and highlight promising avenues for sustainable biocatalysis and drug discovery, particularly in the fluorination, selenation, and boronation pathways that bridge biological and synthetic chemistry.