Haemoglobin Structure and Function
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Direct answer
Haemoglobin packs four haem-bearing subunits — two alpha chains of 141 residues and two beta chains of 146 residues — each haem holding ferrous iron (Fe2+) in a protoporphyrin IX ring coordinated to a histidine of the globin fold. Oxygen binding flips the tetramer from the tense (T) low-affinity state to the relaxed (R) high-affinity state, so binding at one haem eases binding at the rest: cooperativity, giving the sigmoid oxygen dissociation curve with a P50 near 26 millimetres of mercury. Three modulators shift the curve rightward — hydrogen ions and carbon dioxide (the Bohr effect, aiding unloading in tissue capillaries) and 2,3-bisphosphoglycerate, which binds the central cavity between beta chains. One gram of haemoglobin carries about 1.34 millilitres of oxygen.
What you must remember
- Chains and genes: alpha cluster on chromosome 16, beta cluster on chromosome 11; HbA is alpha2 beta2 (over 95 percent in adults), HbA2 alpha2 delta2 (up to about 3.5 percent), HbF alpha2 gamma2.
- Haem chemistry: iron must stay ferrous; methaemoglobin (Fe3+) cannot bind oxygen — maintained low by methaemoglobin reductase (NAD-dependent) and exploited by nitrates and dapsone.
- Cooperativity mathematics: Hill coefficient about 2.8 for haemoglobin versus 1.0 for myoglobin's hyperbolic curve; the tetramer behaves as a two-state allosteric machine.
- Bohr effect: protons stabilise the T state by protonating salt-bridge histidines; carbon dioxide also binds N-terminal valines as carbaminohaemoglobin — together unloading oxygen where metabolism is busiest.
- 2,3-BPG: produced in the Rapaport-Luebering shunt of glycolysis inside red cells; one molecule binds the beta cleft, lowering affinity — its failure to bind gamma chains explains HbF's higher oxygen affinity.
- Physiological numbers: P50 approximately 26-27 mmHg, oxygen capacity about 20 mL per 100 mL of blood, 1.34 mL oxygen per gram of haemoglobin.
- Carbon monoxide: binds with over 200 times the affinity of oxygen and shifts the curve left, making the small leftward-shifted curve of a smoker or poisoning case a classic pictorial question.
A typical curve-interpretation case
A neonate with severe hyaline membrane disease has a cyanosis-resistant hypoxia. Reason through the curve: maternal and fetal blood are separated by the placenta, so fetal blood must load oxygen at the mother's relatively low tissue oxygen tension — hence HbF's low 2,3-BPG binding and left-shifted curve (P50 near 19 mmHg). In adult chronic hypoxia, for instance at altitude or with cyanotic congenital heart disease common in Indian shunting lesions, the red cell responds oppositely: deoxyhaemoglobin raises 2,3-BPG, shifting the curve right so tissue unloading improves at the cost of loading. Same molecule, opposite directions, decided by which subunit and which chronic signal.
Then anchor the Bohr effect to bedside physiology: exercising muscle produces carbon dioxide and lactate, dropping local pH to about 7.2; the resulting right shift can release roughly twice as much oxygen at a given capillary tension. Blood stored for transfusion exhausts 2,3-BPG over two weeks, so massively transfused patients transiently hold oxygen without releasing it — a viva point connecting biochemistry to anaesthesia practice.
Where students slip
Writing "Bohr effect helps oxygen bind in lungs" earns a correction — the effect concerns unloading in tissues, while the lung, rid of carbon dioxide and at high pH, shifts the curve left passively. Second, students attribute the left shift of HbF to "stronger haem-oxygen bonds per se"; the mechanism is failure of 2,3-BPG binding to gamma chains. Third, do not confuse the T-to-R transition triggered by oxygen with the allosteric inhibition by 2,3-BPG — BPG stabilises whatever T state exists, it does not create it. Finally, remember myoglobin has no quaternary structure and no BPG site; if a question shows a hyperbolic curve, the answer is myoglobin.
Frequently asked questions
Which bonds stabilise haemoglobin's quaternary structure?
Ionic and hydrogen-bond salt bridges between unlike chains stabilise the T state; oxygen binding breaks them, rotating the alpha-beta interface in the R transition.
What is the molecular basis of the Bohr effect?
Protons protonate specific histidines, forming salt bridges that stabilise the deoxy T conformation, so lower pH reduces oxygen affinity and enhances tissue unloading.
Why does fetal haemoglobin have higher oxygen affinity?
Its gamma chains bind 2,3-BPG poorly, so the T state is less stabilised and the dissociation curve shifts left, allowing placental oxygen uptake at maternal tissue tensions.
How does 2,3-BPG shift the oxygen dissociation curve?
It binds 1:1 in the central cavity between beta chains of deoxyhaemoglobin, stabilising the T state and shifting the curve to the right.
Why does carbon monoxide poisoning cause left-shift curve hypoxia?
Carbon monoxide binds haem iron with over 200 times the affinity of oxygen and raises the affinity of remaining sites for oxygen, so total carriage and tissue release both fail despite a normal partial pressure.