Molecular regulation--biological role of heme in hematopoiesis.

Heme synthesis and degradation play pivotal roles in the regulation of growth and differentiation of erythroid and non-erythroid cells. Heme synthesis in mammalian cells involves eight enzymes which are localized in mitochondrial and cytoplasmic compartments. These enzymes have been well-characterized and cDNAs for six of the enzymes has been cloned. Two enzymes in the enzymes of the heme biosynthetic pathway, delta-aminolevulinic acid synthase (ALAS) and porphobilinogen deaminase (PBG-D) have special features and may have regulatory functions in heme synthesis by hematopoietic cells. ALAS exists as two isozymes which are encoded by non-erythroid and erythroid-specific genes, respectively. By contrast, PBG-D, which also exists as two isozymes, arises from a single gene comprised of two overlapping transcriptional units, each with its own promoter. Transcription from one or the other of these promoters gives rise through differential splicing to two distinct mRNA species which encode the distinct nonerythroid and erythroid isoforms. On the other hand, heme catabolism is determined by the levels of the heme oxygenase system. The enzyme has been purified and the cDNA for heme oxygenase has been cloned. Repression of heme oxygenase in erythroid progenitor cells may initiate differentiation. In addition, recent evidence has suggested that heme may have a broader role in hematopoiesis and in the network of cytokine production by adherent stromal cells.