Heme Biosynthesis in Erythroid Cells

The heme biosynthetic pathway occurs in practically all cell types. Heme is used to form different hemoproteins in a variety of organelles. Within hepatic and erythroid cells, for example, considerable quantities of heme are used as prosthetic groups for cytochrome P450 and hemoglobin, respectively. The regulation of heme biosynthesis has been under investigation for many years. In non-erythroid cells, the rate of heme biosynthesis depends on 5-aminolevulinate synthase (ALAS). This enzyme is largely controlled by the concentration of heme itself. In contrast, heme biosynthesis in erythroid cells is regulated by iron availability. Erythroid cells possess a 5-aminolevulinate synthase isozyme (e-ALAS) containing an iron responsive element (IRE).

Only mature erythrocytes lack the heme biosynthetic pathway. This is because certain pathway steps occur in the mitochondria, and mature erythrocytes lack this organelle (see figure 1) (7:4). Nucleated animal cells generally synthesize heme for incorporation into respiratory cytochromes. Liver and erythroid cells have the highest rates of heme synthesis. Erythroid cells synthesize about 90 percent of the total heme in the body (7:1-5). Most of this heme is used as the prosthetic group of hemoglobin (6:332).

The heme biosynthetic pathway requires 8 nuclear encoded enzymes. These enzymes are synthesized in the cytosol. Four of the proteins are then transported i

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contrast to non-erythroid cells, Ponka & Neuwirt (1974), Ponka & Schulman (1985a, b), and Laskey et al. (1986) have demonstrated that the regulation of heme synthesis in erythroid cells is primarily determined by rates of iron acquisition (1:683-692). The hypothesis that "the supply of iron to the critical sites of haem synthesis may be a limiting factor controlling the rate of haem synthesis" was first proposed by Ponka & Neuwirt in 1970 (9:173-187). Iron is essential to all living things. In animals, iron is transported between sites of absorption, storage, and utilization by the iron-binding protein, transferrin. Transferrin delivers iron to cells by binding to specific cell surface receptors, the transferrin receptors. These complexes are then internalized into endocytic vesicles. Within erythroid cells, there is evidence that iron is specifically targeted towards the mitochondria (9:173-187). The central iron atom of the heme molecule is crucial for hemoprotein functioning. The atom's ferrous state can be reversibly oxidized to the ferric state by the transfer of an electron. In addition, the ferrous state has a high affinity for oxygen. Thus, these attributes enable the prosthetic group to function as "a single-el
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