Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complex

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Abstract
The lipocalin protein Scn-Ngal is known to bind iron-chelating siderophores, leading to inhibition of bacterial growth. New results reveal that Scn-Ngal, in the absence of bacterial infection, can form a complex with catechol that binds and transports iron in vivo. The lipocalins are secreted proteins that bind small organic molecules. Scn-Ngal (also known as neutrophil gelatinase associated lipocalin, siderocalin, lipocalin 2) sequesters bacterial iron chelators, called siderophores, and consequently blocks bacterial growth. However, Scn-Ngal is also prominently expressed in aseptic diseases, implying that it binds additional ligands and serves additional functions. Using chemical screens, crystallography and fluorescence methods, we report that Scn-Ngal binds iron together with a small metabolic product called catechol. The formation of the complex blocked the reactivity of iron and permitted its transport once introduced into circulation in vivo. Scn-Ngal then recycled its iron in endosomes by a pH-sensitive mechanism. As catechols derive from bacterial and mammalian metabolism of dietary compounds, the Scn-Ngal–catechol–Fe(III) complex represents an unforeseen microbial-host interaction, which mimics Scn-Ngal–siderophore interactions but instead traffics iron in aseptic tissues. These results identify an endogenous siderophore, which may link the disparate roles of Scn-Ngal in different diseases.