Structure and function

Different haemoglobins are synthesized in the embryo, fetus and adult, each adapted to their particular oxygen requirements. They all have a tetrameric structure made up of two different pairs of globin chains, each attached to one haem molecule (Figure 6.1). Adult and fetal haemoglobins have a-chains combined with P-chains (HbA, a2P2), S-chains (HbA2, a2S2) and

1 kilobase

Chromosome 16

1 kilobase

Chromosome 16

Chromosome 11

Hb Gower 1 Hb Portland Hb Gower 2 HbF

a2ß2 a2S2

HbA HbA2

Adult

Chromosome 11

Hb Gower 1 Hb Portland Hb Gower 2 HbF

Embryo

Fetus a2ß2 a2S2

HbA HbA2

Adult

Figure 6. 1 The genetic control of haemoglobin.

y-chains (HbF, a2y2). In embryos, a-like chains called Ç-chains combine with y-chains to produce Hb Portland (Ç2y2), or with e-chains to make Hb Gower 1 (Z2e2), and a- and e-chains combine to form Hb Gower 2 (a2e2). Fetal haemoglobin is itself heterogeneous. There are two kinds of y-chains that differ in their amino acid composition at position 136, where they have either glycine or alanine; those with glycine are called Gy-chains and those with alanine Ay-chains. The Gy- and Ay-chains are the products of separate (Gy and ^y) loci.

The sigmoid shape of the oxygen dissociation curve, which reflects the allosteric properties of haemoglobin, ensures that oxygen is rapidly taken up at the high oxygen tensions found in the lungs and is released readily at the low tensions encountered in the tissues. It is quite different to myoglobin, a molecule that consists of a single globin chain with haem attached to it and which has a hyperbolic dissociation curve. The transition from a hyperbolic to a sigmoid curve reflects cooperativity between the four haem molecules. When one haem takes on oxygen, the affinity for oxygen of the remaining haems of the tetramer increases markedly. This is because haemoglobin can exist in two configurations, deoxy(T) and oxy(R) (T and R stand for tight and relaxed states respectively). The T form has a lower affinity than the R form for ligands such as oxygen. At some point during the sequential addition of oxygen to the four haems, transition from the T to R configuration occurs and the oxygen affinity of the partially liganded molecule increases dramatically. The oxygen dissociation curve, which reflects these changes, can be modified in several ways. First, oxygen affinity is decreased with increasing CO2 tensions - the Bohr effect. This facilitates oxygen loading to the tissues, where a drop in pH due to CO2 influx lowers oxygen affinity. In contrast, in the lungs, efflux of CO2 and an increase in intracellular pH increases oxygen affinity and hence uptake. Oxygen affinity is also modified by the level of 2,3-biphosphoglycerate (2,3-BPG) in the red cell. Increasing concentrations shift the oxygen dissociation curve to the right, i.e. reduce oxygen affinity, whereas diminishing concentrations have the opposite effect. The clinical relevance of the allosteric properties of haemoglobin and the factors that modify its oxygen dissociation curve are considered together with the pathological haemoglobins in later sections and in Chapter 7.

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