Atlas One · Atomic · Transition Metal / Redox Cofactor / Haem
Period 4, Group 8 — most biologically versatile redox metal
| Property | Value |
|---|---|
| Atomic mass | 55.85 Da |
| Key oxidation states | Fe²⁺ (ferrous); Fe³⁺ (ferric); Fe⁴⁺ (compound I of peroxidases) |
| Haem b | Protoporphyrin IX chelating Fe²⁺; in Hb, Mb, ETC cytochromes, catalase, peroxidase |
| Iron-sulfur clusters | [2Fe-2S] and [4Fe-4S] in ETC Complexes I/II/III; electron relay |
| Body distribution | Hb 65%, myoglobin 10%, ferritin/haemosiderin 20%, transferrin 1%, enzymes 4% |
| Dietary forms | Haem iron (meat/poultry/fish, ~40% of dietary iron, 15–35% absorbed); non-haem iron (plant sources, 1–10% absorbed) |
Biological Roles
Haem synthesis, oxygen transport, ETC electron relay, hepcidin regulation
Iron Absorption & Systemic Regulation
Duodenal lumen
│ Fe³⁺ ──DCYTB (Cybrd1)──► Fe²⁺ (acidic pH favours)
▼
DMT1 (SLC11A2) — apical enterocyte uptake (Fe²⁺)
│
▼ Intracellular: bound to ferritin (storage) or exported
Ferroportin (SLC40A1) — basolateral export (Fe²⁺ only)
│
▼ Hephaestin (GPI, Cu-dependent) + ceruloplasmin → Fe²⁺ → Fe³⁺
Plasma transferrin (Tf) — Fe³⁺ carrier (2 sites, Kd ~10⁻²³ M)
│
▼ TfR1-mediated endocytosis into erythroid precursors
STEAP3 reduces Fe³⁺ → Fe²⁺ in endosome
DMT1 exports Fe²⁺ into cytoplasm → mitochondria → haem synthesis
Systemic feedback:
↑ body iron / ↑ BMP6 → liver SMAD1/5/8 → ↑ HAMP → hepcidin ↑
Hepcidin binds ferroportin → ubiquitylation → degradation
→ ↓ iron export → ↓ plasma Fe (inflammation response / iron sequestration)
Haemoglobin and Oxygen Transport
Hb (α₂β₂ tetramer) contains four haem b groups. Cooperative O₂ binding (Hill coefficient ~2.8) via T→R allosteric transition. Bohr effect: H⁺ and CO₂ binding to Hb promotes O₂ release in tissues (rightward P50 shift). 2,3-BPG binds β-chain cleft in T state, ↓ O₂ affinity (P50 ~27 mmHg at pH 7.4, 37°C).
Electron Transport Chain
Complex I (NADH dehydrogenase): 8 Fe-S clusters relay electrons from FMNH₂ to ubiquinone. Complex II: [2Fe-2S], [4Fe-4S], [3Fe-4S] and haem b for succinate → ubiquinol. Complex III (cytochrome bc₁): haem b_L, b_H (Q cycle), Fe-S Rieske protein, haem c₁. Complex IV (CcO): haem a, haem a₃, and Cu centers.
Absorption & Metabolism
IRP/IRE post-transcriptional control balances uptake, storage, and export
When cellular iron is low, IRP1/IRP2 (iron regulatory proteins) bind IRE (iron-responsive elements) in mRNA. IRP binding to 5′-IRE of ferritin mRNA inhibits translation (↓ storage); IRP binding to 3′-IRE of TfR1 mRNA stabilises it (↑ uptake). High iron: Fe-S cluster assembly in IRP1 destroys IRE affinity; IRP2 is ubiquitylated/degraded.
| Form | Location | Amount | Notes |
|---|---|---|---|
| Haemoglobin iron | Erythrocytes | ~2.5 g | ~25 mg/day recycled by splenic macrophages (haem oxygenase-1) |
| Ferritin | Liver, spleen, BM | ~1 g | Serum ferritin 1 µg/L ≈ 8 mg storage iron; acute-phase reactant |
| Transferrin-bound | Plasma | ~3 mg | Transferrin saturation normal 20–45% |
| Myoglobin iron | Muscle | ~0.3 g | O₂ storage; P50 ~1 mmHg (high affinity) |
Deficiency & Toxicity
IDA is the world's most common nutritional deficiency; iron overload causes organ damage via ROS
| Status | Key Labs | Signs | Treatment |
|---|---|---|---|
| Iron deficiency anaemia (IDA) | Hb ↓, MCV ↓, ferritin <12 µg/L, TIBC ↑, Tsat <16% | Fatigue, pallor, pica, koilonychia, restless legs, impaired cognition | Oral ferrous sulfate; IV iron if malabsorption/inflammatory |
| Anaemia of chronic disease (ACD) | Ferritin ↑/normal, TIBC ↓, Tsat ↓, hepcidin ↑ | Normocytic or mildly microcytic anaemia; underlying inflammation/chronic illness | Treat underlying condition; IV iron + ESA if severe |
| Hereditary haemochromatosis (HH) | Tsat >45%, ferritin ↑↑, HFE C282Y homozygous | Liver cirrhosis, DM, cardiomyopathy, bronze skin, hypogonadism, arthropathy | Therapeutic phlebotomy (500 mL weekly → maintenance) |
| Transfusional iron overload | Ferritin >2500 µg/L; MRI T2* cardiac ↓ | Cardiac iron (arrhythmia, HF), liver fibrosis, endocrine failure | Deferasirox (oral chelator) or deferoxamine (subcutaneous infusion) |
| Acute iron poisoning | Serum Fe >90 µmol/L | GI haemorrhage, metabolic acidosis, shock, liver failure | IV deferoxamine; supportive care |
Clinical Use
| Application | Details |
|---|---|
| Oral iron supplements | Ferrous sulfate 325 mg (65 mg elemental Fe) TID; ascorbic acid enhances non-haem absorption; separates from Ca²⁺/tetracyclines |
| IV iron formulations | Ferric carboxymaltose, ferric derisomaltose, low-MW dextran — preferred in CKD, IBD, post-bariatric surgery, heart failure (AFFIRM-AHF trial: reduced HF hospitalisation) |
| ¹⁸F-FDH PET / iron MRI | MRI T2* quantifies hepatic and cardiac iron; used to guide chelation in thalassaemia |
| Erythropoiesis-stimulating agents | EPO/darbepoetin require adequate iron; functional iron deficiency common if Tsat <20% during ESA therapy |
Connections
References
- Ganz T. "Systemic iron homeostasis." Physiol Rev 2013;93:1721–1741.
- Andrews NC. "Disorders of iron metabolism." N Engl J Med 1999;341:1986–1995.
- Muckenthaler MU, Rivella S, Hentze MW, Galy B. "A red carpet for iron metabolism." Cell 2017;168:344–361.
- Camaschella C. "Iron-deficiency anemia." N Engl J Med 2015;372:1832–1843.
- Ponikowski P, et al. (AFFIRM-AHF). Lancet 2020;396:1895–1904.