The Essence of Nature Can be the Simplest (4)-Adenine: Powerful Reserve for Extracellular Fenton Chemistry.

Adenine has long been recognized for its critical roles in cellular metabolism and the storage of genetic information. However, the mechanism by which ATP, derived from adenine, outperforms nucleotides formed from other nucleobases as the primary energy currency remains unclear. In this study, we demonstrate that metabolism of all nucleobases produces hydrogen peroxide (H₂O₂), which serves as a key substrate for extracellular Fenton chemistry, a cellular energy mechanism that facilitates the increase of environmental temperature and the degradation of organic matter. Among the nucleobases, adenine metabolism generates the highest H₂O₂ levels, followed by guanine. Using thermophilic fungi as a model, we found that compared with the mutant without the extracellular Fenton reactions, wild-type strains with the extracellular Fenton chemistry showed downregulation of NTP synthesis and upregulation of nucleoside triphosphate degradation, resulting in H₂O₂ production. The function of nucleosides as crucial reserves for the extracellular Fenton reactions of organisms may offer insights into potential and natural functions of stop codons, poly(A) tails in RNA biosynthesis, junk DNA in the genome, tumor recurrence after chemotherapy or radiotherapy, shortening of telomerase genes with each cell division and the differentiation of long-lived keratinocyte stem cells with a high nucleus-to-cytoplasm ratio into short-lived enucleated keratinocytes.