Erythroid cells, heme synthesis

All aerobic cells contain heme and closely related iron porphyrins these serve as the prosthetic groups of hemoproteins such as cytochromes and catalase. The amount of heme made by a stem cell or proerythroblast is minute compared with that which is required for hemoglobinization to form an erythroid cell. In the differentiation of the proerythroblast to erythroid cell the synthesis of heme as well as of globin must be turned on fully. 

Regulation of heme synthesis in erythroid cells occurs at enzymes catalyzing... 

A well studied example for control at the level of eIF-2 is the regulation of protein biosynthesis in erythroid cells (review Chen and London, 1995). A decrease in the heme concentration in reticulocytes leads to inhibition of globin synthesis at the level... 

However, during the most active phase of heme synthesis in maturing erythroid cells, there is a marked shift in the localization of cellular iron from a membrane bound pool to the cytosol (78). Moreover, as shown by Yoda and Israel (79), mitochondria incubated in cell sap or sucrose synthesize equivalent amounts of heme, but those in sucrose release only a small amount of heme to the surrounding medium. In other words, the release of heme from the mitochondria seems to depend on protein(s) in the suspending medium. Thus, the cytosol appears to facilitate the uptake of iron by the mitochondria as well as the release of heme from the mitochondria. 

Heme synthesis is controlled by a regulatory negative feedback loop in which heme inhibits the activity of fer-rochelatase and acquisition of iron fi om the transport protein transferrin. The decrease in iron acquisition leads to a decrease in iron uptake into the cell with subsequent decrease in 8-aminolevulinic acid and heme production. Iron deficiency and increased erythropoietin synthesis lead to the combination of the iron regulatory proteins with the iron-responsive elements in the transferrin receptor protein messenger ribonucleic acid (mRNA). This combination in turn leads to protection of the mRNA from degradation with subsequent increased uptake of iron into erythroid cells because of the increased expression of transferrin receptors on the cell membrane. 

Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis distant contact mechanisms in erythroid cells. Blood 1997 89 1-25. 

The bulk of transferrin iron is delivered to immature erythroid cells for utilization in heme synthesis. Iron in excess of this requirement is stored as ferritin and hemosiderin. Unloading of iron to immature erythroid cells is by receptor-mediated endocytosis. The process begins in the clathrin-coated pits with the binding of diferric transferrin to specific plasma membrane transferrin receptors that are associated with the HFE protein complex. The next step is the internalization of the transferrin-transferrin receptor-HFE protein complex with formation of endosomes. The iron transporter DMTl present in the cell membrane is also internalized into the endosomes. In the endosomes, a proton pump acidifies the complex to pH 5.4, and by altering conformation of proteins, iron is released from transferrin bound to transferrin receptor... 

In the erythroid cells, most of the iron released from the endosomes is transported into mitochondria for heme synthesis (discussed later) in nonerythroid cells, the iron is stored predominantly as ferritin and to some extent as hemosiderin. 

The protein kinase H RI (heme regulated eIF-2 kinase) was first identified in studies on the regulation of protein biosynthesis in erythroid cells. A decrease in the heme concentration in reticulocytes leads to inhibition of globin synthesis at the level of translation. This regulation mechanism ensures that only so much globin is produced as is heme available. If the level of heme drops, then HRI becomes activated. The activated HRI phosphorylates the eIF-2a subunit, which in turn shuts off protein biosynthesis (Fig. 1.48). The mechanism of regulation of HRI kinase by heme is not well understood. Heme binding sites have been identified on the N-terminus and the kinase domain of HRI. 

An additional emerging possibility of regulation of heme biosynthesis in differentiating erythroid cells resides at the ALAS2 mRNA translational level. ALAS2 synthesis is intimately related to the availability of iron. An iron-responsive ele-... 

A. Hradilek, J. Neuwirt (1990). The relationship between heme synthesis and iron uptake in erythroid cells. Biomed. Biochim. Acta, 49, S94-99. 

L.H. Conder, S. I. Woodard, H. A. Dailey (1991). Multiple mechanisms for the regulation of heme synthesis during erythroid cell differentiation. Possible role for coproporphyrinogen oxidase. Biochem. J., 275, 321-326. 

Porphyrias clinical conditions resulting from genetic defects in heme biosynthesis. For the pathway of heme biosynthesis, see Porphyrins. Inborn errors have been described for 7 of the 8 enzymes in this pathway. Although no major genetic defect has been described for the first enzyme of the pathway, S-aminolevulinate synthase (EC 2.3.1.37), low activity has been reported in a case of congenital sideroblastic anemia [G. R. Buchanan et al. Blood 55 (1980) 109-115]. Heme is an essential constituent of many important enzymes and hemoproteins. Absence of heme synthesis is therefore incompatible with life, and homozygotes of inherited autosomal dominant disorders of heme synthesis are not viable, unless there is residual activity of the enzyme concerned. P. are classified as erythropoietic or hepatic, depending on whether the defect is located mainly in the erythroid cells or the liver. 

We have discussed the effect of heme in the liver to decrease the induction of ALA-synthetase, and to decrease the induction of microsomal oxygenase enzymes. Heme also has a positive metabolic action in erythroid cells it stimulates globin synthesis. 

Erythroid cells afford a system for the study of cell differentiation and of control mechanisms in protein synthesis. In this discussion we are concerned with the differentiation of erythroid cells, the induction of hemoglobin synthesis, the regulation of the synthesis of heme and of globin, and the role of heme in the synthesis and assembly of hemoglobin. 

The difiFerentiation of erythroid cells, the induction of hemoglobin synthesis, and the switch from embryonic and fetal to adult hemoglobin synthesis, may be explicable in terms of control at the level of transcription of genes. Processes such as the coordination of synthesis of heme and globin and of assembly of a and j8 chains, which are operative during stages of erythroid cell development in which no RNA is synthesized, are more likely to be explicable in terms of translation. 

A role for heme in the repression of ALA synthetase has been proposed by Burnham and Lascelles (1963) and by Graniek and Kappas (1967). Heme has been shown to repress the synthesis of ALA synthetase in Khodopseudomonas spheroides (Bmnham and Lascelles, 1963). In liver cells and erythroid cells of the chick embryo, Gio and C21 j8-H steroids induce heme synthesis. This induction can be blocked by actinomycin D, by puromycin, and by added hemin (Graniek and Kappas, 1967). Graniek and his associates have proposed that heme... 

Granick, S., and Levere, R. D. (1964). Heme synthesis in erythroid cells. Progr. Hematol. 4, 1-47. 

Absorption, transport, and storage of iron. Intestinal epithelial cells actively absorb inorganic iron and heme iron (H). Ferrous iron that is absorbed or released from absorbed heme iron in the intestine (1) is actively transported into the blood or complexed with apoferritin (AF) and stored as ferritin (F). In the blood, iron is transported by transferrin (Tf) to erythroid precursors in the bone marrow for synthesis of hemoglobin (Hgb) (2) or to hepatocytes for storage as ferritin (3). The transferrin-iron complexes bind to transferrin receptors (TfR) in erythroid precursors and hepatocytes and are internalized. After release of the iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released. Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC hemoglobin and either export it or store it as ferritin (4). Hepatocytes use several mechanisms to... 

Heme, the most abundant iron cofactor, can play diversified roles in the cell. These roles include not only the already-mentioned regulatory and signal transduction processes, but also electron transfer, oxygen binding and transport, and direct involvement in the oxygen metabolism. The first step of the heme biosynthetic pathway in mammalian cells is catalyzed by 5-aminolevulinic acid synthase (ALAS), which is considered a rate-limiting step in the production of heme. The rate of synthesis of erythroid ALAS is directly dependent on the cellular iron concentration. Ferreira reviews recent structural and site-directed mutagenesis studies on ALAS (Chapter 2), which, for example, have revealed that the homodimeric enzyme s active site is located at the subunit interface and contains catalytically essential residues from both subunits. 

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