Iron Reductase Mechanisms in Cellular Iron Metabolism

Iron is vital for oxygen transport, DNA synthesis and cellular respiration, yet it is biologically available only after reduction from ferric (Fe3+) to ferrous (Fe2+) form. Membrane-bound ferric reductases catalyse this step, employing electron donors such as NADPH, ascorbate and flavin adenine dinucleotide (FAD) to transfer electrons across lipid bilayers. Key representatives include duodenal cytochrome b (Dcytb), which operates at the intestinal brush border to enable dietary iron absorption, and the STEAP (six-transmembrane epithelial antigen of the prostate) family, which couples an intracellular oxidoreductase domain to transmembrane heme centres for cellular iron uptake. These reductases interact closely with transporters, notably divalent metal transporter 1 (DMT1), and with ferroxidases in the extracellular space to maintain iron homeostasis. Dysregulation of ferric reductase activity underlies clinical conditions such as iron deficiency anaemia, neurodegenerative disorders and tumour progression, making these enzymes critical targets for therapeutic intervention and design of enhanced oral iron formulations.

Research from Nature Portfolio

Recent structural analysis of human duodenal cytochrome b has provided atomistic detail of its mechanisms. Crystallographic studies revealed that each homodimer contains cytoplasmic and apical heme groups flanked by discrete ascorbate-binding sites. A coordinated zinc ion in the apical site mimics ferric iron binding and has illuminated how ascorbate and Fe3+ compete for the same pocket. Kinetic and competition assays confirmed that ascorbate binding promotes efficient electron transfer to ferric substrates, elucidating the molecular basis for dietary iron reduction. These insights have informed structure-guided strategies to enhance the bioavailability of orally administered iron supplements.

Iron Reductase Mechanisms in Cellular Iron Metabolism publication trend

The graph below shows the total number of articles in iron reductase mechanisms in cellular iron metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Ferric reductase: Enzyme that catalyses reduction of Fe3+ to Fe2+ to facilitate cellular uptake.

Heme: Iron‐containing porphyrin cofactor involved in electron transfer.

Flavin adenine dinucleotide (FAD): Redox cofactor that mediates electron transfer from NADPH to substrate.

STEAP proteins: Six-transmembrane epithelial antigen proteins with oxidoreductase domains that mediate metal ion reduction.

Dcytb: Duodenal cytochrome b, a membrane-bound ferric reductase that uses ascorbate to reduce dietary iron.

Ascorbate: Reduced form of vitamin C, serving as electron donor in reductase reactions.

References

1. Mechanism of stepwise electron transfer in six-transmembrane epithelial antigen of the prostate (STEAP) 1 and 2. eLife (2023).
2. Spectral and Redox Properties of a Recombinant Mouse Cytochrome b561 Protein Suggest Transmembrane Electron Transfer Function. Molecules (2023).
3. Structural basis for promotion of duodenal iron absorption by enteric ferric reductase with ascorbate. Communications Biology (2018).