Haemoglobin
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Haemoglobin
Structure
Haemoglobin (Hb) is a tetrameric protein found in red blood cells. Each molecule consists of:
- 4 globin chains - in adult Hb A: 2 alpha (α) and 2 beta (β) subunits
- 4 haem groups - one per subunit; each haem is a porphyrin ring with a central Fe²⁺ (ferrous iron) ion
The iron is anchored to the globin chain via the proximal histidine (His F8) on the F helix. When deoxygenated, Fe²⁺ sits slightly out of the plane of the porphyrin ring, pulling the proximal histidine and the attached helix with it. On O₂ binding, Fe²⁺ snaps into the plane, triggering a conformational shift that propagates across the whole tetramer - the structural basis of cooperative binding:
T and R States (Conformational States)
Haemoglobin exists in two interconvertible forms:
| State | Description | O₂ affinity |
|---|---|---|
| T (tense/deoxy) | Constrained by salt bridges between subunits | Low |
| R (relaxed/oxy) | Salt bridges broken after O₂ loading | High |
Cooperative binding means the affinity of haemoglobin for the last O₂ molecule bound is ~300 times greater than for the first.
The Oxygen-Dissociation Curve
- Haemoglobin curve: sigmoidal - reflects cooperative O₂ binding
- Myoglobin curve: hyperbolic - no cooperativity (monomeric)
- P50 (pO₂ at half-saturation): ~26 mm Hg for Hb vs. ~1 mm Hg for myoglobin
- In arterial blood (pO₂ ~95 mm Hg): Hb is ~97% saturated
- In venous blood at rest (pO₂ ~40 mm Hg): Hb is ~75% saturated
- Each 100 mL of blood contains ~15 g Hb; maximum O₂-carrying capacity ~20 mL/100 mL (20 vol%)
The steep portion of the sigmoid falls precisely in the range of tissue pO₂ values, so small drops in pO₂ trigger large release of O₂ - a feature a hyperbolic (myoglobin-like) curve could not provide.
Allosteric Effectors (Factors Shifting the Curve)
1. pH and CO₂ - the Bohr Effect
A fall in pH or a rise in pCO₂ shifts the curve right (decreases O₂ affinity, raises P50). This is the Bohr effect:
- Deoxyhemoglobin binds H⁺ more avidly than oxyhemoglobin via histidine side chains with a higher pKa in the deoxy state
- In active tissues, CO₂ is converted by carbonic anhydrase to H₂CO₃ → HCO₃⁻ + H⁺, lowering pH and favouring O₂ release
- Schematically: HbO₂ + H⁺ ⇌ HbH + O₂
2. 2,3-Bisphosphoglycerate (2,3-BPG)
2,3-BPG (also called 2,3-DPG) is the most abundant organic phosphate in RBCs. It:
- Binds in a positively charged pocket between the two β-globin chains of deoxyhemoglobin only
- Stabilises the T (deoxy) form, shifting the curve right
- Equation: HbO₂ + 2,3-BPG ⇌ Hb-2,3-BPG + O₂
Clinical relevance of 2,3-BPG:
- High altitude / chronic hypoxia / chronic anaemia: 2,3-BPG levels rise, shifting the curve right and enabling greater O₂ unloading in tissues
- Stored blood: 2,3-BPG is depleted in banked blood; transfused blood has abnormally high O₂ affinity and fails to deliver O₂ properly until 2,3-BPG is restored (6-24 hours). Large transfusions of stored blood can cause tissue hypoxia
- Thyroid hormones, growth hormone, androgens: raise 2,3-BPG → raise P50
- Acidosis: inhibits glycolysis → falls 2,3-BPG (partially offsetting the rightward Bohr shift)
3. Temperature
- Raised temperature (e.g. exercising muscle): curve shifts right → more O₂ released
- Lower temperature: curve shifts left → higher O₂ affinity
CO₂ Transport
Most CO₂ is carried as bicarbonate (after carbonic anhydrase reaction). A smaller fraction binds directly to terminal amino groups of haemoglobin forming carbaminohemoglobin, stabilising the T form and reducing O₂ affinity.
Carbon Monoxide (CO) Poisoning
- CO binds haemoglobin iron with 220× greater affinity than O₂
- CO binding shifts Hb into the R conformation, causing remaining heme sites to bind O₂ with high affinity → left shift of the dissociation curve → O₂ is not released to tissues
- Result: tissue hypoxia despite normal pO₂
- Treatment: 100% O₂ (or hyperbaric O₂) to competitively displace CO
Types of Haemoglobin
| Type | Chains | Where Found |
|---|---|---|
| Hb A | α₂β₂ | Normal adult (dominant) |
| Hb A₂ | α₂δ₂ | Normal adult (~2-3%) |
| Hb F (fetal) | α₂γ₂ | Fetus/newborn; higher O₂ affinity (binds 2,3-BPG poorly) |
| Hb S (sickle) | α₂β₂(Glu→Val) | Sickle cell disease |
| Hb C | α₂β₂(Glu→Lys) | Haemoglobin C disease |
| Methaemoglobin | Fe³⁺ (oxidised) | Cannot bind O₂; caused by oxidising drugs/toxins |
Fetal Hb has high O₂ affinity because its γ-chains bind 2,3-BPG poorly, keeping it in the R state - physiologically important for extracting O₂ from maternal blood across the placenta.
Normal Reference Values
| Measure | Normal Range |
|---|---|
| Haemoglobin (males) | 13.5-17.5 g/dL |
| Haemoglobin (females) | 12.0-16.0 g/dL |
| O₂-carrying capacity | ~20 mL O₂/100 mL blood |
| Arterial saturation (SaO₂) | ~97% |
| Venous saturation (SvO₂) | ~75% at rest |
| P50 | ~26 mm Hg |
Sources: Biochemistry, 8th ed. Lippincott Illustrated Reviews; Guyton and Hall Textbook of Medical Physiology; Ganong's Review of Medical Physiology, 26th ed.
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