Pyrroloquinoline quinone (PQQ) is a multifunctional natural coenzyme that plays important roles in innate immunity, nutritional physiology, and redox biology, including the activation of dual oxidases (DUOXs). Although native PQQ has been extensively studied, the biological consequences of its chemical modification remain poorly understood. Here, we synthesized several PQQ derivatives and identified PQQMe, a monomethyl ester derivative that activates DUOX more potently than native PQQ, even at low concentrations. PQQMe induced rapid lethality in C. elegans, as well as internal hatching resulting from severe defects in the egg-laying apparatus, a phenotype that occurred independently of DUOX. This outcome contrasted sharply with the lifespan-extending effects observed with native PQQ and its prodrug derivative, the acetone adduct ACTPQQ, indicating that esterification profoundly reshapes the biological activity spectrum of PQQ. Despite its pronounced biological effects, PQQMe exhibited greater tolerability than PQQ in mammalian cells and mice. Together, these findings identify PQQMe as a chemically modified PQQ derivative that enhances DUOX activation and induces a distinct lethal phenotype in C. elegans, suggesting that chemical modification of a multifunctional coenzyme is a useful strategy for inducing new biological functions.