Abstract
Dietary iron absorption is regulated by duodenal cytochrome b (Dcytb), an integral membrane protein that catalyzes reduction of nonheme Fe3+ by electron transfer from ascorbate across the membrane. This step is essential to enable iron uptake by the divalent metal transporter. Here we report the crystallographic structures of human Dcytb and its complex with ascorbate and Zn2+. Each monomer of the homodimeric protein possesses cytoplasmic and apical heme groups, as well as cytoplasmic and apical ascorbate-binding sites located adjacent to each heme. Zn2+ coordinates to two hydroxyl groups of the apical ascorbate and to a histidine residue. Biochemical analysis indicates that Fe3+ competes with Zn2+ for this binding site. These results provide a structural basis for the mechanism by which Fe3+ uptake is promoted by reducing agents and should facilitate structure-based development of improved agents for absorption of orally administered iron.
Highlights
Dietary iron absorption is regulated by duodenal cytochrome b (Dcytb), an integral membrane protein that catalyzes reduction of nonheme Fe3+ by electron transfer from ascorbate across the membrane
The three-dimensional structure of Dcytb reported in the current study addresses this deficiency by providing structural insight into the mechanism by which ascorbate reduction of Fe3+ is catalyzed to enable iron absorption
This recombinant Dcytb was crystallized in the lipidic cubic phase (LCP) in the absence of substrate
Summary
Dietary iron absorption is regulated by duodenal cytochrome b (Dcytb), an integral membrane protein that catalyzes reduction of nonheme Fe3+ by electron transfer from ascorbate across the membrane. This step is essential to enable iron uptake by the divalent metal transporter. Iron is recognized as an essential nutrient that is required for oxygen transport, energy production, and synthesis and metabolism of many bioactive compounds in all living organisms[3] Despite this long-standing medical use of iron, iron deficiency continues to affect 30% of the world population, is the most severe and widespread nutritional deficiency disorder, and remains the only nutritional deficiency disorder in industrialized countries[4,5]. Dcytb is an iron-regulated Fe3+ reductase that was first identified in the duodenal brush border of mice with systemic iron deficiency[12]
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