Globin biosynthesis

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... 

Specific inhibition of templated biosynthesis by electroneutral polynucleotide analogs can be achieved even with complex templates Messenger RNA coding for globin, similarly to other messenger RNA molecules, contains a polyadenylate sequence located... 

The biosynthesis of Hb requires the biosynthesis of both heme and the globin polypeptide chains. 

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. 

The evidence that ceruloplasmin (Cp) (E.C. 1.12.3,1) is a direct molecular link between copper and iron metabolism is summarized. Copper deficiency results in low plasma Cp and iron, reduced iron mobilization, and eventually anemia, even with high iron storage in the liver. Cp controls the rate of iron uptake by transferrin. Transferrin plays a key role in the availability of iron for the biosynthesis of hemo-globin in the reticulocytes. The ferroxidase activity of Cp results in the reduction of free iron ion generating a conr centration gradient from the iron stores to the capillary system, thus promoting a rapid iron efflux in the reticuloendothelial system. It has been confirmed both in vivo and in the perfused liver that lOr M Cp specifically induces a rapid rise in plasma iron. 

Equation (1) indicates that a low heme content may be due to a lack of the two vitamins, pyridoxal phosphate and CoA, which are required for the limiting step in porphyrin biosynthesis. The smallness of the red cells in pyridoxal phosphate deficiency is probably due not only to the necessity of this coenzyme for amino acid and heme synthesis, but also to the fact that, without heme, globin is not synthesized. 

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