Albertine Donker

General Introduction 23 1 Most heme synthesis takes place in developing RBC’s in the bone marrow in order to be incorporated in hemoglobin; about 15% of the daily production takes place in the liver for the formation of other heme-containing proteins. 54 the regulatory mechanisms controlling heme synthesis in these two organ systems differ. In the next paragraphs we focus on heme synthesis in the erythropoietin precursors in the bone marrow. The heme biosynthetic pathway consists of eight enzymatic steps; two reactions take place inside the mitochondria and six inside the cytosol or the intermembrane space of the mitochondria ( Figure 4 ). 54,55 The first and rate-limiting step of heme synthesis occurs in the mitochondrial matrix with the condensation of succinyl-CoA and glycine by ALAS2 to generate aminolevulinic acid (ALA). Pyridoxal 5-Phosphate (vitamin B6) is required as a cofactor in this enzymatic reaction. Both transcriptional and translational mechanisms regulate the synthesis of ALAS2. Transcriptional regulation of ALAS2 is mediated by erythroid-specific factors (including GATA1), which interact with sequences in the promoter region. Translational regulation involves the IRE/IRP system since the ALAS2 transcript contains a 5′ IRE that interacts with an IRP. This IRE/IRP complex prevents translation of the ALAS2 mRNA. Addition of a Fe/S abolishes the ability of the IRP to bind to this IRE and permits translation to occur. Fe/S clusters are generated and exported by mitochondria, linking regulation of heme biosynthesis in the red cell to iron availability and mitochondrial function. 56 For further details concerning heme synthesis, see Figure 4 . 46,54,55