Zinc deficiency in the human population, a major public health concern, can also be a consequence of nutritional deficiency in protein uptake. The discovery that tryptophan metabolites 3-hydroxykynurenine and xanthurenic acid are major zinc-binding ligands in insect cells establishes the kynurenine pathway as a regulator of systemic zinc homeostasis. Many biological processes influenced by zinc and the kynurenine pathway, including the regulation of innate and acquired immune responses to viral infections, have not been studied in light of the direct molecular links revealed in this study.
Zinc deficiency is commonly attributed to inadequate absorption of the metal. Instead, we show that body zinc stores in Drosophila melanogaster depend on tryptophan consumption. Hence, a dietary amino acid regulates zinc status of the whole insect—a finding consistent with the widespread requirement of zinc as a protein cofactor. Specifically, the tryptophan metabolite kynurenine is released from insect fat bodies and induces the formation of zinc storage granules in Malpighian tubules, where 3-hydroxykynurenine and xanthurenic acid act as endogenous zinc chelators. Kynurenine functions as a peripheral zinc-regulating hormone and is converted into a 3-hydroxykynurenine–zinc–chloride complex, precipitating within the storage granules. Thus, zinc and the kynurenine pathway—well-known modulators of immunity, blood pressure, aging, and neurodegeneration—are physiologically connected.