Haemoglobin and respiration
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Haemoglobin and Respiration
1. Structure of Haemoglobin
Haemoglobin (Hb) is a tetrameric globular protein found exclusively in red blood cells. The adult form, HbA, consists of two α-chains and two β-chains (α₂β₂), each holding a heme prosthetic group - making four O₂ binding sites per molecule.
The Heme Group
Each heme unit is an iron-porphyrin compound: a planar ring of four pyrrole groups linked by methyne bridges, with a central Fe²⁺ ion. This deep-red chromophore gives blood its colour.
- The iron must remain in the ferrous (Fe²⁺) state to bind O₂. Oxidation to Fe³⁺ (forming methaemoglobin) abolishes oxygen-carrying capacity.
- The fifth coordination position of iron is bonded to the proximal histidine (His F8) of the globin chain.
- The distal histidine (His E7) lies on the opposite side and prevents CO₂ from irreversibly oxidising Fe²⁺ to Fe³⁺.
(Harper's Illustrated Biochemistry, 32nd Ed.)
T and R States (Cooperativity)
The haemoglobin tetramer exists in two conformations:
| State | Name | O₂ Affinity | Structure |
|---|---|---|---|
| T (Tense/Taut) | Deoxy-Hb | Low | Fe²⁺ pulled out of heme plane; ionic + H-bonds between αβ dimers |
| R (Relaxed) | Oxy-Hb | High | Fe²⁺ pulled into heme plane; polar bonds between dimers broken |
When the first O₂ binds, the Fe²⁺ pulls into the heme plane, moving the proximal histidine and triggering a conformational shift in adjacent subunits - increasing their O₂ affinity. This is positive cooperativity, producing the characteristic sigmoidal oxygen-dissociation curve (ODC).
(Lippincott's Biochemistry, 8th Ed.)
2. The Oxygen-Dissociation Curve (ODC)
Oxygen is carried in blood in two ways:
- Bound to haemoglobin (by far the dominant form - ~98%)
- Dissolved in plasma (very small amount, proportional to PO₂ by Henry's law)
The ODC plots % saturation of Hb with O₂ against partial pressure of O₂ (PO₂). Its S-shape reflects cooperative binding:
- At alveolar PO₂ ~100 mmHg: Hb is ~97-98% saturated (efficient O₂ loading)
- At tissue/venous PO₂ ~40 mmHg: Hb drops to ~75% saturated (efficient O₂ unloading)
- P₅₀ = PO₂ at which Hb is 50% saturated; normal ~26-27 mmHg in adults
Factors Shifting the ODC
Right shift = decreased O₂ affinity = more O₂ released to tissues (higher P₅₀)
| Factor | Direction | Physiological Meaning |
|---|---|---|
| ↑ PCO₂ | Right | Active tissues release more O₂ |
| ↓ pH (acidosis) | Right | Bohr effect (see below) |
| ↑ Temperature | Right | Exercising muscle gets more O₂ |
| ↑ 2,3-BPG | Right | High altitude adaptation |
| Left shift | ↑ affinity | Less O₂ released |
| ↓ PCO₂, ↑ pH | Left | In lungs - favours O₂ loading |
| Fetal Hb (HbF) | Left | P₅₀ = 18 mmHg (vs 27 mmHg adult) |
| HbS (sickle) | Right | Reduced affinity |
(Murray & Nadel's Textbook of Respiratory Medicine; Lippincott's Biochemistry)
3. The Bohr Effect
In metabolically active tissues, CO₂ production rises and pH falls. This causes a right shift of the ODC, promoting O₂ unloading exactly where it is needed most.
Mechanism:
- CO₂ + H₂O → H₂CO₃ → HCO₃⁻ + H⁺ (catalysed by carbonic anhydrase in RBCs)
- H⁺ binds to specific histidine residues (higher pKa in deoxyHb), forming ionic salt bridges that stabilise the T (deoxy) state
- This reduces O₂ affinity and promotes O₂ release
The equation:
HbO₂ + H⁺ ⇌ HbH⁺ + O₂
HbO₂ + H⁺ ⇌ HbH⁺ + O₂
Conversely, in the lungs, CO₂ is exhaled, pH rises, and the curve shifts left, favoring O₂ loading.
(Lippincott's Biochemistry, 8th Ed.)
4. Role of 2,3-Bisphosphoglycerate (2,3-BPG)
2,3-BPG is synthesised from a glycolytic intermediate in RBCs and is the most abundant organic phosphate in those cells (approximately equimolar with Hb).
- 2,3-BPG binds preferentially to the central cavity of deoxy-Hb (T state), forming ionic bonds with positively-charged residues of the β-chains
- This stabilises the T state, shifting the ODC right and reducing O₂ affinity
- At high altitude: hypoxia stimulates increased 2,3-BPG, right-shifting the ODC to enhance O₂ delivery to tissues
- Fetal Hb (HbF): has γ-chains instead of β-chains; γ-chains bind 2,3-BPG poorly, so HbF has higher O₂ affinity - ideal for extracting O₂ from maternal blood
(Lippincott's Biochemistry, 8th Ed.)
5. CO₂ Transport and the Haldane Effect
CO₂ is transported from tissues to lungs in three forms:
| Form | % of Total |
|---|---|
| As HCO₃⁻ (bicarbonate in plasma) | ~70% |
| Carbaminohaemoglobin (CO₂ bound to N-terminal amino groups of Hb) | ~20-25% |
| Dissolved in plasma | ~5-10% |
The Haldane Effect is the complement of the Bohr effect:
- Deoxygenated Hb binds CO₂ and H⁺ more avidly than oxygenated Hb
- At the tissues: Hb unloads O₂ → becomes better CO₂ carrier
- At the lungs: Hb loads O₂ → releases CO₂ and H⁺ for exhalation
This means O₂ loading in the lungs directly promotes CO₂ unloading - a beautifully coordinated reciprocal exchange.
(Murray & Nadel's Textbook of Respiratory Medicine)
6. Oxygen Cascade: Lungs to Mitochondria
The PO₂ falls progressively from air to the site of use:
| Location | PO₂ (mmHg) |
|---|---|
| Dry room air | ~159 |
| Humidified tracheal air | ~149 |
| Alveolar gas | ~100 |
| Arterial blood | ~95-100 |
| Mixed venous blood | ~40 |
| Mitochondria | <10 |
In a normal lung, blood transiting the pulmonary capillary (~0.75 seconds at rest) is fully oxygenated in the first one-third of capillary transit, providing substantial diffusion reserve. Under exercise or disease (thickened blood-gas barrier), this reserve may be exhausted and diffusion limitation can occur.
(Murray & Nadel's Textbook of Respiratory Medicine)
7. Variant Haemoglobins of Clinical Importance
| Haemoglobin | Feature | Clinical Significance |
|---|---|---|
| HbF (fetal) | γ-chains, low 2,3-BPG binding | High O₂ affinity; switches to HbA by ~6 months |
| HbS (sickle) | Glu→Val substitution β6 | Polymerises when deoxygenated → sickling, vaso-occlusion |
| HbA₂ | δ-chains | Elevated in β-thalassaemia trait |
| MetHb | Fe³⁺ (oxidised) | Cannot carry O₂; causes cyanosis |
| COHb | CO bound to Fe²⁺ | 250× affinity for CO vs O₂; left-shifts ODC (CO poisoning) |
(Murray & Nadel's; Tietz Laboratory Medicine, 7th Ed.)
Summary
Haemoglobin is the master molecule of respiratory gas transport. Its sigmoidal ODC - generated by cooperative binding across its four subunits - allows efficient O₂ loading in the lungs (high PO₂) and efficient O₂ unloading at active tissues (low PO₂, low pH, high CO₂, high temperature). The Bohr effect (pH/CO₂ shifting the ODC right) and Haldane effect (deoxygenation enhancing CO₂ carriage) are reciprocal mechanisms ensuring that wherever metabolism is highest, O₂ delivery is greatest and CO₂ removal is most efficient. 2,3-BPG provides an additional regulatory handle, particularly important at altitude or in chronic anaemia.
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