Synthesis Of Hemoglobin

Anemias Due to Disorders of Hemoglobin Synthesis

Erythrocytes (RBCs) serve to transport O2 and CO2 and also as a buffer. Hemoglobin (Hb) is essential for all three functions. It is composed of four subunits (2a, 2p in HbA; see below), each of which is formed from three components: protoporphyrin, iron (Fe2+) and globin (a or p). When Fe2+ is built into protoporphyrin, heme is formed. If there is a deficiency or defect in one of the components, Hb synthesis is impaired. In this case the RBCs are usually small (MCV i) and their Hb content decreased (MCH i) (microcytic hypochromic anemia).

Disorders of protoporphyrin synthesis are due to inherited enzyme defects (^ p. 254), as for example, in hereditary sideroblastic anemia, in which the formation of 8-aminolevulinic acid (8-ALA) from glycine and succinyl-CoA is ^ reduced, and thus also heme synthesis g (^ A1). Heme inhibits 8-ALA synthase in a 2 negative feedback loop. If heme concentration rn is now reduced, inhibition of the enzyme is reversed and, despite the defect, sufficient amounts of heme are formed. Defects in subsequent enzymes lead to an increase in the concentration of intermediary products. While the rate of heme production is thus increased, these metabolites cause other disorders, namely porphyrias (^ p. 254).

Disorders of globin synthesis. Normally Hb is made up of 2 a chains of 141 amino acids each and 2 p chains of 146 amino acids (HbA, = HbAa2p2). Only 2-3% of Hb contains so-called 8-chains (HbA2 = Hba282) instead of the p-chains. Before birth a form of Hb is formed that has a higher O2 affinity (adaptation to a lower Po2 in the placenta). This fetal Hb (HbF) contains so-called y-chains (Hba2y2) instead of the p-chains.

The properties of Hb (solubility, O2 affinity, oxidizability, etc.) are dependent upon the particular amino acid sequence. However, most of the over 300 genetically-determined Hb variants which have been indentified so far do not signficantly impair function. On the other hand, even a single "false" amino acid (valine instead of glutamate in position 6 in the p-chain = HbS; ^ A2) can lead to extensive functional disorders, as seen in sickle cell anemia, 36 which is caused by a homozygous gene defect. In the deoxygenated form, HbS aggregates in a way that results in sickle-shaped erythrocytes (^ A). These sickle cells cannot be further deformed and get stuck inside the capillaries, causing occlusion of smaller blood vessels. Aggregation of HbS takes a few minutes so that it is especially those capillaries through which the blood flows slowly which are affected (spleen; vasa recta of the renal medulla; ^ p. 106). If blood flow is slowed in general (shock) or if hypoxia occurs (at high altitude, during a flight, anesthesia), the abnormalities can spread to other organs (e.g., to the heart). Occlusion of the blood vessels further slows down blood supply in the affected regions and the Po2 is further reduced, so that a vicious circle results (crisis). Sickle cell anemia occurs nearly exclusively in blacks who themselves, or whose forbears, come from regions of Central Africa with a high prevalence of malaria. "Survival" of the defective gene in 40% of the population in Central Africa, despite the fact that until recently the disease was fatal in homozygous children, can be explained by the fact that heterozygous gene carriers are protected against the dangerous forms of malaria (selective advantage).

In p-thalassemia the production of p-chains is restricted, thus leading to a deficiency of HbA. It can be only partly compensated by an increased production of HbA2 and HbF. The incorporation of Fe2+ is diminished so that it remains in the erythrocytes (sideroachresia) and may accumulate excessively in the body (secondary hemochromatosis; ^ p. 252). Although the RBCs' osmotic resistance (^ p. 40) is actually increased, their mechanical vulnerability is increased (rapid breakdown in the spleen, early hemolysis). While the heterozygous form (T. minor) causes few symptoms, the homozygous form (T. major) may be fatal even before puberty. The rare a-thalassemia usually causes death of the fetus, because without a-chains no HbF can be formed either. Hby,, produced in the fetus, and Hbp4, occurring postna-tally, are apparently inadequate substitutes for the normal Hb forms.

r A. Defects of Hemoglobin Synthesis -

Glycine Succinyl-CoA \ / a-ALA synthase ^

8-Aminolevulinic acid (5-ALA) *

Protoporphyrine

Glycine Succinyl-CoA \ / a-ALA synthase ^

8-Aminolevulinic acid (5-ALA) *

Protoporphyrine

Hemoglobin Synthesis

5 Glu 7

a-Thalassemia

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