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Cell Mol Biol (Noisy-le-grand). 1997 Feb;43(1):103-14.

Translational control of erythroid delta-aminolevulinate synthase in immature human erythroid cells by heme.

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Department of Medicine, University of Cambridge, Addenbrooke's Hospital, U.K.


Heme formation in immature erythroid cells is subject to end-product negative feedback control. Although studies with immature erythroid cells obtained from animals have shown that increased intracellular hemin inhibits the acquisition of iron from transferrin, our experiments with human reticulocytes indicate that feedback inhibition of heme biosynthesis is primarily regulated at one or more steps that lead to formation of the first committed precursor, delta-aminolevulinate (ALA). To identify the site of control of heme biosynthesis in the human erythron further, region-specific antibodies to human erythroid delta-ALA synthase (e-ALA synthase) were used to immunoprecipitate newly-synthesised enzyme from human reticulocytes after biosynthetic labelling. Low concentrations of exogenous hemin (30-35 microM) inhibited the biosynthetic labelling of mature erythroid ALA synthase that was detected by exon 4 peptide-specific antibodies and antibodies raised against the entire recombinant human erythroid ALA synthase molecule. Pulse-chase experiments after biosynthetic labelling indicated no differences in the effect of hemin on the turnover of the radiolabelled enzyme and hemin did not influence the distribution of precursor froms of the ALA synthase molecule. Parallel experiments using antibodies directed against human H-chain ferritin confirmed the specificity of the effects of hemin on translation of the e-ALA synthase mRNA. At the concentrations of hemin used to inhibit heme formation from 14C-glycine, no significant effects on the rate of overall protein synthesis were observed. We conclude that heme regulates synthesis of the first committed precursor of the porphyrin biosynthetic pathway in immature human erythroid cells by effects on the synthesis of the e-ALA synthase molecule. Although the mechanism of hemin action is unknown, it is apparently independent of 5'-iron-response elements and influences the translational activity of erythroid ALA synthase mRNA.

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