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Haemoglobin


Haemoglobin
Haemoglobin Synthesis
The main function of red cells is to carry O2 to the tissues and to return carbon dioxide (CO2) from the tissues to the lungs. In order to achieve this gaseous exchange they contain the specialized protein haemoglobin. Each molecule of normal adult haemoglobin A (Hb A) (the dominant haemoglobin in blood after the age of 3–6 months) consists of four polypeptide chains, α2β2, each with its own haem group. Normal adult blood also contains small quantities of two other haemoglobins: Hb F and Hb A2. These also contain α chains, but with γ and δ chains, respectively, instead of β (Table 2.3). The synthesis of the various globin chains in the fetus and adult is discussed in more detail in Chapter 7.

Haem synthesis occurs largely in the mitochondria by a series of biochemical reactions commencing with the condensation of glycine and succinyl coenzyme A under the action of the key rate‐limiting enzyme δ‐aminolaevulinic acid (ALA) synthase (Fig. 2.7). Pyridoxal phosphate (vitamin B6) is a coenzyme for this reaction. Ultimately, protoporphyrin combines with iron in the ferrous (Fe2+) state to form haem (Fig. 2.8).
Haemoglobin synthesis in the developing red cell. The mitochondria are the main sites of protoporphyrin synthesis, iron (Fe) is supplied from circulating transferrin; globin chains are synthesized on ribosomes. δ‐ALA, δ‐ aminolaevulinic acid; CoA, coenzyme A.

Haemoglobin function
The red cells in systemic arterial blood carry O2 from the lungs to the tissues and return in venous blood with CO2 to the lungs. As the haemoglobin molecule loads and unloads O2 the individual globin chains move on each other (Fig. 2.9). The α1β1 and α2β2 contacts stabilize the molecule. When O2 is unloaded the β chains are pulled apart, per- mitting entry of the metabolite 2,3‐diphosphoglycerate (2,3‐DPG) resulting in a lower affinity of the molecule for O2. This movement is responsible for the sigmoid form of the haemoglobin O2 dissociation curve (Fig. 2.10). The P50 (i.e. the partial pressure of O2 at which haemoglobin is half saturated with O2) of normal blood is 26.6 mmHg. With increased affinity for O2, the curve shifts to the left (i.e. the P50 falls) while with decreased affinity for O2, the curve shifts to the right (i.e. the P50 rises).
Normally, in vivo, O2 exchange operates between 95% saturation (arterial blood) with a mean arterial O2 tension of 95 mmHg and 70% saturation (venous blood) with a mean venous O2 tension of 40 mmHg (Fig. 2.10).
The normal position of the curve depends on the concentration of 2,3‐DPG, H+ ions and CO2 in the red cell and on the structure of the haemoglobin molecule. High concentrations of 2,3‐DPG, H+ or CO2, and the presence of sickle haemoglobin (Hb S), shift the curve to the right (oxygen is given up more easily) whereas fetal haemoglobin (Hb F) – which is unable to bind 2,3‐DPG – and certain rare abnormal haemoglobins associated with polycythaemia shift the curve to the left because they give up O2 less readily than normal.
The oxygenated and deoxygenated haemoglobin molecule. α, β, globin chains of normal adult haemoglobin (Hb A). 2,3‐DPG, 2,3‐diphosphoglycerate.

Methaemoglobinaemia
This is a clinical state in which circulating haemoglobin is present with iron in the oxidized (Fe3+) instead of the usual Fe2+ state. It may arise because of a hereditary deficiency of methaemoglobin reductase deficiency or inheritance of a structurally abnormal haemoglobin (Hb M). Hb Ms contain an amino acid substitution affecting the haem pocket of the globin chain. Toxic methaemoglobinaemia (and/or sulphaemoglobinaemia) occurs when a drug or other toxic substance oxidizes haemoglobin. In all these states, the patient is likely to show cyanosis.