Hemoglobin synthesis control

Waxman HS, Rabinowitz M. 1966. Control of reticulocyte polyribosome content and hemoglobin synthesis by heme. Biochim Biophys Acta 129 369-379. 

Hemoglobin synthesis is controlled at the translational level by the availability of heme. It declines when heme concentration falls and increases when heme concentration rises. Heme deficiency activates an inhibitor. 

Heme synthesis is controlled primarily by 8-aminolevulinate synthase (ALA synthase). There are two mechanisms of control, and each involves a process that affects the concentration of the enzyme. First, the half-life of ALA synthase, as shown by experiments in rat liver, is very short (60-70 min). Like many mitochondrial proteins, ALA synthase is encoded by nuclear genes, synthesized on cytoplasmic ribosomes, and the enzyme is translocated into the mitochondria. The second and main regulating factor is the inhibition of ALA synthase by hemin. Hemin differs from heme in that the Fe atom is in the Fe3+ oxidation state. Heme spontaneously oxidizes to hemin when there is no globin to form hemoglobin. Hemin serves a second function in the regulation of hemoglobin synthesis in reticulocytes. It controls the synthesis of globin. 

Genetic Control of Hemoglobin Synthesis 2.3.1. Structural Loci... 

B8. Baglioni, C., and Colombo, B., Control of hemoglobin synthesis. Cold Spring Harbor Symp. Quant. Biol. 29, 347-356 (1964). 

H65. Hunter, A. R., Control of hemoglobin synthesis mRNA for alpha and beta chains. Proc. Int. Symp. Regul. Hemoglobin Syn. Bio-mol. Clin. Aspects, Bad Nauheim, Germany, 1971. 

W14. Weatherall, D. J., and Clegg, J. B., The control of human hemoglobin synthesis and function in health and disease. Progr. Hematol. 6, 261-304 (1969). 

TRANSLATIONAL CONTROL Eukaryotic cells can respond to various stimuli (e.g., heat shock, viral infections, and cell cycle phase changes) by selectively altering protein synthesis. The covalent modification of several translation factors (nonribosomal proteins that assist in the translation process) has been observed to alter the overall protein synthesis rate and/or enhance the translation of specific mRNAs. For example, the phosphorylation of the protein eIF-2 affects the rate of hemoglobin synthesis in rabbit reticulocytes (immature red blood cells). 

In this chapter we examine the synthesis and degradation of purines, pyrimidines, and hemes. These have complex structures, but are formed from simple precursors. All three can be synthesized in the body and have roles ranging from nucleic acids to hemoglobin. In addition to synthesis control of all three classes of compounds, a number of metabolic diseases associated particularly with purine and heme metabolism are discussed. The use of antimetabolites, as in chemotherapy, and the rationale for their use is presented. 

Itano, H. A. 1953. Qualitative and quantitative control of adult hemoglobin synthesis—a multiple allele hypothesis. Am. J. Human Genet. 5, 34. 

In animals the control of heme biosynthesis appears to be primarily a control on the rate of biosynthesis of the enzyme ALA-synthetase. Recent experiments [Sassa and Granick, 21] suggest that control of this enzyme occurs at both the transcription and the translation levels. Because these controls have been studied mainly in the liver, we shall discuss the evidence for the control mechanisms in this tissue, particularly the more recent work using chick embyro liver cells grown in primary culture. In later sections we shall discuss the ALA-synthetase control mechanism in the red cells for heme and hemoglobin synthesis, and the control mechanisms for chlorophyll synthesis in plants. 

Fig. 9. Hypothesis on the control of hemoglobin synthesis in chick embryo blastoderm by control of the synthesis of ALA-synthetase. In the nucleus a repressor protein (I) blocks transcription, and a 5jS-H steroid acts as a derepressor, permitting the structural gene (II) to code for the mRNA of ALA-synthetase. In the cytoplasm the information in the mRNA is translated into the enzyme ALA-synthetase (E,) which migrates into the mitochondrion where ALA (III) is made and finally converted by other enzymes (E2-E7) to heme (IV). Heme controls the synthesis of globin either by acting at the initiating site or by permitting proper folding of the globin.

It was found by Levere et ah [137] that the same 5)6-H steroids that actively stimulated the synthesis of ALA-synthetase in chick embryo liver cells in culture also stimulated hemoglobin synthesis in chick embryo blastoderm cells (Fig. 9). It is inferred that the stimulation by the steroids is brought about by the same mechanism as for the liver cells that is, the steroids induce the synthesis of ALA-synthetase at the transcriptional level. ALA-synthetase is the rate-limiting enzyme in early red cell precursors, and its increase causes an earlier increase in the formation of ALA the ALA, once made, is rapidly converted to heme, and once heme is made globin is synthesized. Thus the controlling step in hemoglobin synthesis appears to be one that is turned on by a 5y -H steroid. Stimulation of hemoglobin synthesis by Sfi-H steroids has recently also been demonstrated in mice and in humans [140,142],... 

A multiple-step mechanism could also control iron absorption through the intestine. For example, it has been proposed that the bone marrow controls the secretion of a specific humoral factor responsible for regulating the intestinal absorption of iron. If such a hormone exists, it is unlikely to be erythropoietin. Erythropoietin administration to animals has no effect on iron absorption. Conversely, intestinal absorption and the iron stores influence the rate of erythropoiesis. Iron loading of anemic dogs considerably stimulates hemoglobin synthesis. 

The answer is 3 [It C/. Plasma iron and erythropoietin levels are increased in aplastic anemia because the reduced bone marrow mass is unable to fully use these components in normal synthesis. Aplastic anemia usually is a result of r uced deoxyribonucleic acid (DNA)-controlled synthesis of pluripolent bone marrow precursors of erythrocytes, leukocytes, and thrombcxtytes. Fetal hemoglobin synthesis may increase in adults with aplastic anemia. Aplastic anemia is characterized by macrocytes and increased numbers of reticulocytes. 

Kaempfer, R., and Kaufman, J., 1972, Translational control of hemoglobin synthesis by an initiation factor required for recycling of ribosomes and for their binding to messenger RNA, Proc. Natl. Acad. Sci. USA 69 3317. 

The differential expression of Ctj and Ct2, which controls the synthesis of catalase in corn, is mainly dependent upon the ratio between synthesis and degradation rates (Quail and Scandalios, 1971). It is characteristic that the differential rate of translation is an important regulatory mechanism in hemoglobin synthesis in mammals, wherein the a-chain is translated faster than the j8-chain. Therefore, two different types of mRNA are translated at a different rate inside the same cell (Hunt et al., 1969). 

Differentiation of cells of the erythroid series is controlled by the hormone erythropoietin. Anemia stimulates erythropoietin formation, and this stimulates erythropoiesis. Erythropoietin also increases hemoglobin synthesis by stimulating synthesis of the corresponding messenger RNA (Krantz and Goldwasser, 1965). However, the possible link between erythropoietin and activation of adult hemoglobin (HbA and not HbF) has not yet been studied. 

It appears that a protein inhibitor termed "hemin controlled repressor" (HCR) forms in hemin-deficient cells from a latent "prorepressor." This inhibitor appears to function as a protein kinase, adding one to two phosphorus atoms to the small subunit of eIF-2. Whether this activity is cAMP dependent (Datta et al., 1978) or not (Gross, 1978 Safer and Anderson, 1978) has not been resolved. The effect of the HCR appears to be to decrease the amount of initiator Met-tRNAf which binds to the 40 S subunit. The ability of eIF-2 to counteract the effect of HCR, in conjunction with the data on phosphorylation, strongly supports a role for HCR as inhibitor of the action of eIF-2. However, the actual means by which phosphorylation of the initiator factor leads to inhibition, or how hemin works, is not clear. Clarification of this phenomenon should prove illuminating not only for hemoglobin synthesis but also for nonerythroid cells, since the effect of hemin is seen with extracts from other cells as well. 

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. 

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