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#iron transport

3 public questions tagged with this topic.

Animal Tissue Culture 1

Which component provides iron transport in serum?

Iron necessity stems from essential cofactor roles in fundamental enzymes: ribonucleotide reductase small subunit R2 contains diferric tyrosyl radical centre essential for reducing ribonucleoside diphosphate to deoxyribonucleotide required for DNA replication and repair, cytochrome c oxidase complex IV contains heme a3 plus copper facilitating electron transport to oxygen, and aconitase iron-sulfur cluster catalyzing tricarboxylic acid cycle. Free ferric iron Fe3+ precipitates as insoluble Fe(OH)3 at neutral pH solubility product extremely low 10^-38, and participates in Fenton reaction Fe2+ plus H2O2 producing hydroxyl radical OH extremely reactive damaging DNA strand breaks and lipid peroxidation. Transferrin family 80 kDa bilobed glycoprotein synthesized by hepatocytes and secreted into plasma at 2 to 3 milligrams per ml, each lobe N and C lobe binds one Fe3+ ion plus synergistic carbonate anion coordinating octahedrally via two tyrosines, one histidine, one aspartate, forming complex with extremely low dissociation constant 10^-22 M keeping iron soluble and redox inert protected inside binding cleft.

Ref: Crichton Iron Metabolism 2016 transferrin Fe3+ transport 80 kDa; Alberts MBoC TfR1 clathrin endocytosis ribonucleotide reductase.

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Protein Sorting and Trafficking

What happens when the transferrin receptor is mutated and cannot bind Fe³⁺ at acidic pH?

Iron uptake in proliferating cells depends on transferrin receptor mediated endocytosis tightly coupled to endosomal acidification. At extracellular pH 7.4 holo transferrin carrying two ferric ions binds transferrin receptor 1 homodimer with nanomolar affinity, clusters via AP2 clathrin adaptor and internalizes into early endosomes. Vacuolar ATPase acidifies lumen to about pH 5.5, protonation of transferrin histidines and nearby receptor residues induces conformational opening of transferrin lobes, reducing Fe3+ affinity by orders of magnitude and releasing ferric iron while apo transferrin remains bound to receptor due to retained high affinity at acidic pH. Liberated Fe3+ reduced to Fe2+ by ferrireductase STEAP3, exported through divalent metal transporter DMT1 into cytosolic labile iron pool for use in heme, Fe S clusters or storage in ferritin. Recycling vesicles return complex to plasma membrane where neutral pH dissociates apo transferrin for reuse. If receptor mutation prevents iron release at low pH, transferrin stays iron locked, endosomal iron export fails, cytosol becomes deficient, IRP IRE system upregulates receptor and represses ferritin, but iron does not accumulate in mitochondria nor cause rapid receptor degradation.

Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 13: Endocytosis and Transferrin Iron Transport.

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Protein Sorting and Trafficking

During receptor-mediated endocytosis of iron, Fe³⁺ is transported into cells via:

Vertebrates transport ferric iron safely via transferrin family to avoid oxidative Fenton radical damage and precipitation. Hepatocytes secrete apo-transferrin 80 kDa bilobed glycoprotein serum loads two Fe3+ each coordinated synergistically bidentate carbonate anion plus four protein ligands two tyrosines histidine aspartate each lobe producing salmon pink complex termed ferrotransferrin diferric transferrin. Doubly loaded species binds transferrin receptor TfR1 homodimer dissociation constant 1-10 nM neutral pH versus 50-fold lower affinity monoferric negligible apo providing selection iron loaded species for uptake efficiency. After clathrin-mediated endocytosis acidification pH 5.5 protonates carbonate triggering iron release facilitated ferrireductase STEAP3 converting Fe3+ to Fe2+ transported via DMT1 SLC11A2 divalent transporter. Ferritin 24-subunit cytosolic cage storing 4500 atoms ferrihydrite mineral core storage not serum transport. Heme carries Fe2+ within protoporphyrin oxygen transport hemoglobin myoglobin. Lysosome degrades iron proteins not physiological carrier. Ferrotransferrin therefore represents circulating iron import form enabling receptor specificity regulated high-affinity uptake supporting erythropoiesis respiration enzyme activities and DNA synthesis.

Ref: Lodish et al., MCB Figure 14-29: Ferrotransferrin carries Fe3+ for uptake via transferrin receptor.

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