Iron Oxidation and Core Formation in Recombinant Heteropolymeric Human Ferritins

Biochemistry. 2017 Aug 1;56(30):3900-3912. doi: 10.1021/acs.biochem.7b00024. Epub 2017 Jul 18.

Abstract

In animals, the iron storage and detoxification protein, ferritin, is composed of two functionally and genetically distinct subunit types, H (heavy) and L (light), which co-assemble in various ratios with tissue specific distributions to form shell-like protein structures of 24 subunits within which a mineralized iron core is stored. The H-subunit possesses a ferroxidase center (FC) that catalyzes Fe(II) oxidation, whereas the L-subunit does not. To assess the role of the L-subunit in iron oxidation and core formation, two human recombinant heteropolymeric ferritins, designated H-rich and L-rich with ratios of ∼20H:4L and ∼22L:2H, respectively, were employed and compared to the human homopolymeric H-subunit ferritin (HuHF). These heteropolymeric ferritins have a composition similar to the composition of those found in hearts and brains (i.e., H-rich) and in livers and spleens (i.e., L-rich). As for HuHF, iron oxidation in H-rich ferritin was found to proceed with a 2:1 Fe(II):O2 stoichiometry at an iron level of 2 Fe(II) atoms/H-subunit with the generation of H2O2. The H2O2 reacted with additional Fe(II) in a 2:1 Fe(II):H2O2 ratio, thus avoiding the production of hydroxyl radical. A μ-1,2-peroxo-diFe(III) intermediate was observed at the FC of H-rich ferritin as for HuHF. Importantly, the H-rich protein regenerated full ferroxidase activity more rapidly than HuHF did and additionally formed larger iron cores, indicating dual roles for the L-subunit in facilitating iron turnover at the FC and in mineralization of the core. The L-rich ferritin, while also facilitating iron oxidation at the FC, additionally promoted oxidation at the mineral surface once the iron binding capacity of the FC was exceeded.

Publication types

  • Comparative Study

MeSH terms

  • Apoferritins / chemistry
  • Apoferritins / genetics
  • Apoferritins / metabolism*
  • Catalytic Domain
  • Coenzymes / chemistry
  • Coenzymes / metabolism*
  • Electrophoresis, Capillary
  • Ferritins / chemistry
  • Ferritins / genetics
  • Ferritins / metabolism*
  • Heme / chemistry
  • Heme / metabolism*
  • Holoenzymes / chemistry
  • Holoenzymes / genetics
  • Holoenzymes / metabolism
  • Humans
  • Hydrogen Peroxide / metabolism
  • Iron / chemistry
  • Iron / metabolism*
  • Kinetics
  • Oxidation-Reduction
  • Oxidoreductases / chemistry
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Protein Multimerization
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism

Substances

  • Coenzymes
  • FTL protein, human
  • Holoenzymes
  • Recombinant Proteins
  • Heme
  • Ferritins
  • Apoferritins
  • Hydrogen Peroxide
  • Iron
  • FTH1 protein, human
  • Oxidoreductases