Regulation of Mammalian Heme Biosynthesis
Regulation of the heme biosynthetic pathway in mammals occurs via two distinct mechanisms. These mechanisms reflect the fact that while most cells need to closely regulate relatively low levels of intracellular heme, differentiating erythroid cells must produce massive amounts of heme during a short period to satisfy the needs of hemoglobinization. In erythroid precursor cells all pathway enzymes are induced via erythroid-specific promoter elements and the first enzyme, erythroid-specific 5-aminolevulinate synthase (ALAS-2) encoded by a gene on the X chromosome, is also subject to translational regulation due to the presence of an iron-responsive element located in the 5′ end of the mRNA. In nonerythroid cells a house-keeping regulatory scheme exists where most regulation appears to be via transcriptional regulation of a housekeeping 5-aminolevulinate synthase (ALAS-1) that is encoded on human chromosome 3. While the proteins of the mature forms of ALAS-1 and ALAS-2 are highly similar, the regulatory elements that control their expression are distinctly different and only ALAS-2 mRNA possesses an iron-regulatory element. Additional regulatory features exist throughout the pathway, but the major regulation appears to occur at the level of ALAS.
KeywordsErythroid Differentiation Heme Biosynthesis Iron Responsive Element Erythroid Precursor Cell Variegate Porphyria
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