Globin synthesis

During p-globin synthesis in normal reticulocytes the sequoice his-atg-pro occurs at position 165-167. How many high-energy phosphate bonds are required to insert these 3 amino acids into the p-globin polypeptide during translation ... 

Accumulation of heme in reticulocytes can regulate globin synthesis by indirectly inacti-vati ng eIF-2. Which of the following steps is most directly affected by this mechanism ... 

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... 

High concentrations of hemin inhibit the transport of ALA synthase into the mitochondria, where one of the substrates, succinyl-CoA, is formed. Thus, heme synthesis is inhibited until enough globin is made to react with any heme already formed. Low concentrations, or the absence, of hemin is the signal that globin is not needed this protein (and, therefore, globin) synthesis is inhibited. In the absence of hemin, a protein kinase is activated this phosphorylates an initiation factor of (eukaryotic) protein synthesis, eIF-2, which then inhibits polypeptide chain initiation (Chap. 17) and hence inhibits globin synthesis. 

Eukaryotes potentially have many more opportunities for control of gene expression than do bacteria. For example, the cell could take advantage of control at the level of the processing of primary transcripts. It is known that RNA is not transported across the nuclear membrane until all introns are excised. A more subtle form of control could involve alternative modes of splicing a particular transcript. There are now examples known where this occurs to yield different mRNA molecules. Perhaps one of the best-known examples of yet another level of control in eukaryotes is that of translational control of globin synthesis. 

Globin is synthesized in reticulocytes (see Chap. 1, Prob. 1.1). which have no nucleus and therefore cannot utilize transcriptional and other potential modes of control. Control of globin synthesis from the pool of globin-enriched mRNA is geared to the concentration of hemin (Fe(III)-protoporphyrin]. which has the ability to inactivate a translational inhibitor of protein synthesis. The inhibitor is a protein kinase that phosphorylates and inactivates one of the initiation factors involved in initiation of translation. When the concentration of hemin is high, it binds to a regulatory subunit of the kinase and. as a result, initiation of globin synthesis can proceed. 

Transcriptional control of globin synthesis in reticulocytes is not possible because transcription does not occur in these cells. Does this mean that the overall control of globin synthesis is completely lacking an aspect of transcriptional control ... 

Globin synthesis defect, for example a- or /3-thalassaemia, HbE syndrome, HbC syndrome and various other unstable haemoglobin diseases. 

Macrocytic anaemia can be further divided into megaloblastic anaemia and non-megaloblastic macrocytic anaemia . Megaloblastic anaemia is primarily a failure of DNA synthesis with preserved RNA synthesis, which results in restricted cell division of the progenitor cells. Non-megaloblastic macrocytic anaemias have different aetiologies (i.e. an unimpaired DNA globin synthesis). 

B17. Bargellesi, A., Pontremoli, S., and Conconi, F., Absence of jS-globin synthesis and excess of a-globin synthesis in homozygous -thalassemia. Eur. J. Biochem. 1, 73-79 (1967). 

Schwartz, E., Heterozygous beta thalassemia balanced globin synthesis in bone marrow cells. Science 167, 1512-1514 (1970). 

The first three are a -thalassemias, and the last is an a°-thalassemia. Since non-a-globin synthesis is not affected in a-thalassemia, the relative proportions of hemoglobins A, A2, and F are unchanged, although all three are reduced in concentration. 

In thalassemias of the jS-globin gene family, there is reduced synthesis of chains, with or without reduced synthesis of y or 5 chains. An isolated decrease in y- or 5-globin synthesis would probably be benign and likely to be detected only by chance. Hemoglobin Lepore is usually included with the jS-thalassemias, since synthesis of normal chains is reduced or absent. 

Characteristics of the more common /3-thalassemia syndromes are summarized in Table 28-4. Not included are two different abnormal heterozygotes. Anemia results from precipitation of excess a-globin chains, premature red cell destruction in bone marrow and the circulation, and deficiency of functional hemoglobin tetramer. /S-Thalassemia major, or Cooley s anemia, occurs when /3-globin synthesis is markedly depressed or absent. The ineffective erythropoiesis causes massive erythroid proliferation, skeletal deformities, and extramedullary erythropoiesis. The usual treatment is frequent blood transfusion. 

Thalassemias, Lepore hemoglobin thalassemia, and HPFH are characterized by lack of /6-globin synthesis and are caused by deletions in the /3-gene family on chromosome 11 (Figure 28-14). 

Two boys with mental disability are found to have mutations in a gene on the X chromosome that has no homology with globin genes. Both are also noted to have deficiency ol a-globin synthesis with a thalassemia. Which of the following is the best explanation for their phenotype ... 

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. 

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