Hemoglobins chain synthesis

Fig. 86. Model of the regulation of hemoglobin chain synthesis, o, operator RG regulator-gene i , repressor molecule synthesized under the control of RG /, inducer p, y, S, structural hemoglobin chain genes X, unknown structural gene region of impact of mu-...

During development, the synthesis of embryonic hemoglobin polypeptide chain (s) is succeeded by that of the y chains and at a later stage by that of the p and 8 (Fig. 9). The ontogeny of these hemoglobin chains is thoroughly reviewed by Kleihauer (K15), and Fig. 9 is based on information taken from that reference. Hb-Gower-1, or u, is the major... 

What is the mechanism controlling the rate of synthesis of each of these hemoglobin chains during development It has been suggested that the site of red cell production is a major factor however, (and 8) and 7 chains can be synthesized by red cell precursors in the bone marrow as well as in the liver (Fll, T4) whereas the presence of small amounts of Hb-Gower 2 (or 2 2) and of Hb-Portland-1 (or 72 2) in (some) cord blood samples (C2, H22) show that red cell precursors in sites other than in the metamorphosing embryo are able to synthesize these polypeptide chains. 

Tables II, III, IV, and V list abnormal hemoglobins which differ from the normal by the replacement of one amino acid residue by another at a specific position in either the a or the p chain. The total number is 132. Each of these hemoglobin types is produced because of a variation, by mutation, of the hemoglobin chain structural locus governing the synthesis of the specific polypeptide. The amino acid substitutions found in all these variants can be explained by the change of one nucleotide of the triplet which codes for the original residue.

Data from measurements of the rate of incorporation of leucine- C into a and j3 chains of hemoglobin in peripheral blood samples have shown that the rate of a chain synthesis is indeed depressed in various a-thalas-semia disorders while that of the chain remains normal (C19, K4). Kan et al. (K4) reported these a j8 specific activity ratios normals 1.02 0.07 a-Tha heterozygosity 0.82-0.95 a-Thj heterozygosity 0.77 0.05 hemoglobin H disease 0.41 0.11. These data illustrate conclusively the significant difference in expression between the two a-thalas-semia genes. 

Hemoglobin H. has been observed in association with some forms of leukemia, mostly erythroleukemia or Di Guglielmo s syndrome (B22, B30, R32, W22). In these cases, as in Hb-H disease, the excess chains form the tetrameric Hb-H molecule. The suppression of a chain synthesis might well be due to a yet undetectable chromosomal abnormality affecting the Hbo locus or loci (R32). 

H56. Huisman, T. H. J., and Schroeder, W. A., Genetic aspects of gamma chain synthesis. Proc. Int. Symp. Regul. Hemoglobin Syn. Bio mol. Clin. Aspects, Bad Nauheim, Qermany, 1971. 

Synthesis of the different hemoglobin chains is directed by different genes, at least one for each chain type. The chromosomal arrangement of these genes (Figure 28-12)... 

Beta-Thalassemia A disorder characterized by reduced synthesis of the beta chains of hemoglobin. There is retardation of hemoglobin A synthesis in the heterozygous form (thalassemia minor), which is asymptomatic, while in the homozygous form (thalassemia major, Cooley s anemia, Mediterranean anemia, erythroblastic anemia), which can result in severe compHcations and even death, hemoglobin A synthesis is absent. [NIH]... 

Hemoglobin synthesis may be interfered with by various mechanisms. One of the most obvious is the absence of red-cell production. This apparently occurs as a normal feature in a family of antarctic bony fish, the Chaenichthydae (Ruud, 1954). When red cells are present a decrease in the output per cell of individual hemoglobin chains is known as a heritable character in many human families. Most of the known abnormal human hemoglobins, while not unfit as oxygen carriers, are present in the red cells in subnormal amounts. 

The decrease in the rate of synthesis of hemoglobin chains is often more considerable in thalassemias than in the case of abnormal... 

Fig. 75, Model of genetic regulation of synthesis of different hemoglobin chains (Zuckerkandl, 1964). Two variants a and b. Explanation in text. Legend Oj and O2 represent operators RGi and RG2 regulator genes R repressor molecule synthesized under the control of RG and inducers 6 7, structural genes of hemoglobin chains X) unknown stractural gene FFH zone responsible for mutation of familial fetal hemoglobinemia Th zone possibly responsible for B halassemia mutation.

Figure 6. Major steps in initiation of polypeptide chain synthesis. Reproduced, by kind permission of the authors and Grune and Stratton, from "The biosynthesis of hemoglobin" by Benz and Forget (1974), Semin. Hematol. 11 463-523.

In the heme-repleted cell, the synthesis of a and of yS chains is stimulated approximately to the same degree. Excess a chain synthesis and the a pool are maintained, but heme appears to facilitate the combination of newly synthesized a and /8 chains immediately prior to or after their release from the polyribosomes (pathway 1). This effect of heme serves to bypass the a pool. In this manner, heme may be said to coordinate the synthesis of a and y8 chains. The ayS pool disappears by combination with heme pathway 4 is accelerated and hemoglobin formation is enhanced. 

The genetic defects known as thalassemias result from the partial or total absence of one or more a or P chains of hemoglobin. Over 750 different mutations have been identified, but only three are common. Either the a chain (alpha thalassemias) or P chain (beta thalassemias) can be affected. A superscript indicates whether a subunit is completely absent (a or p ) or whether its synthesis is reduced (a or P ). Apart from marrow transplantation, treatment is symptomatic. 

Changes in the quantities of the various normal hemoglobin components during developmental stages can be explained in terms of ill-defined regulatory mechanisms which control the rate of synthesis of the polypeptide chains. Such mechanisms have to... 

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