Iron uptake and transfer from ceruloplasmin to transferrin

Biochim Biophys Acta. 2014 Jun;1840(6):1771-81. doi: 10.1016/j.bbagen.2014.01.011. Epub 2014 Jan 11.


Background: Dietary and recycled iron are in the Fe(2+) oxidation state. However, the metal is transported in serum by transferrin as Fe(3+). The multi-copper ferroxidase ceruloplasmin is suspected to be the missing link between acquired Fe(2+) and transported Fe(3+).

Methods: This study uses the techniques of chemical relaxation and spectrophotometric detection.

Results: Under anaerobic conditions, ceruloplasmin captures and oxidizes two Fe(2+). The first uptake occurs in domain 6 (<1ms) at the divalent iron-binding site. It is accompanied by Fe(2+) oxidation by Cu(2+)D6. Fe(3+) is then transferred from the binding site to the holding site. Cu(+)D6 is then re-oxidized by a Cu(2+) of the trinuclear cluster in about 200ms. The second Fe(2+) uptake and oxidation involve domain 4 and are under the kinetic control of a 200s change in the protein conformation. With transferrin and in the formed ceruloplasmin-transferrin adduct, two Fe(3+) are transferred from their holding sites to two C-lobes of two transferrins. The first transfer (~100s) is followed by conformation changes (500s) leading to the release of monoferric transferrin. The second transfer occurs in two steps in the 1000-10,000second range.

Conclusion: Fe(3+) is transferred after Fe(2+) uptake and oxidation by ceruloplasmin to the C-lobe of transferrin in a protein-protein adduct. This adduct is in a permanent state of equilibrium with all the metal-free or bounded ceruloplasmin and transferrin species present in the medium.

General significance: Ceruloplasmin is a go-between dietary or recycled Fe(2+) and transferrin transported Fe(3+).

Keywords: Aceruloplasminemia; Iron-metabolism; Metal-transport; Multi-copper oxidase; Protein–protein adduct.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ceruloplasmin / chemistry*
  • Iron / chemistry*
  • Kinetics
  • Oxidation-Reduction
  • Spectrophotometry
  • Transferrin / chemistry*


  • Transferrin
  • Iron
  • Ceruloplasmin