REGULATION OF HEME-SYNTHESIS IN ERYTHROID-CELLS - HEMIN INHIBITS TRANSFERRIN IRON UTILIZATION BUT NOT PROTOPORPHYRIN SYNTHESIS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 65  (4) , 850-857
Abstract
The inhibition of .delta.-aminolevulinic acid (ALA) synthase activity by heme is commonly thought to regulate the overall rate of heme synthesis in erythroid cells. Since heme inhibits erythroid cell uptake of Fe from transferrin, the hypothesis that in reticulocytes heme regulates its own synthesis by controlling the cellular acquisition of iron from transferrin rather than by controlling the synthesis of ALA was tested. Hemin added to reticulocytes in vitro inhibits not only the total cell incorporation of 59Fe from transferrin but also the incorporation of [2-14C]-glycine and transferrin-bound 59Fe into heme. Hemin did not inhibit [2-14C]-glycine incorporation into protoporphyrin. Cycloheximide, which increases the level of non-Hb heme in [rabbit] reticulocytes, also inhibited [2-14C]-glycine into heme but not into protoporphyrin. With high concentrations of ferric pyridoxal benzoylhydrazone (Fe-PBH), which, independent of tranferrin and transferrin receptors, can be used as a source of Fe for heme synthesis in reticulocytes, significantly more Fe is incorporated into heme than from saturating concentrations of Fe-transferrin. Some step (or steps) in the pathway of Fe from extracellular transferrin to protoporphyrin apparently limits the overall rate of heme synthesis in reticulocytes. Hemin in concentrations that inhibit the utilization of transferrin-bound Fe for heme synthesis has no effect on the incorporation of Fe from Fe-PBH into heme. In reticulocytes heme inhibits and controls the utilization of Fe from transferrin but has no effect on the enzymes of porphyrin biosynthesis and ferrochelatase. This mode of regulation of heme synthesis may be a specific characteristic of the Hb biosynthetic pathway.

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