Heme biosynthesis regulation

Figure 9-7. Pathway for heme biosynthesis. Regulation by hemin at the key aminolevulinic acid (ALA) synthase-catalyzed step and by lead at two steps is indicated.

Several other iron metabolism proteins contain IREs, including ferroportin, an iron exporter, the erythrocyte form of aminolevulinic acid synthase, an enzyme important in heme biosynthesis, an alternatively spliced transcript of the iron transporter DMTl, and mammalian mitochondrial aconitase. The importance of these IREs in regulation of these transcripts is the subject of ongoing research. 

Woods, J.S., Fowler, B.A. (1978). Altered regulation of mammalian hepatic heme biosynthesis and urinary porphyrin excretion during prolonged exposure to sodium arsenate. Toxicol. Appl. Pharmacol. 43(2) 361-71. 

C) 5-aminolevulinate synthetase catalyzes the regulated and rate-limiting step in heme biosynthesis... 

May BK, Dogra SC, Sadlon TJ, Bhasker CR, Cox TC, Bottomley SS. Molecular regulation of heme biosynthesis in higher vertebrates. Prog Nucleic Acid Res Mol Biol 1995 51 1-51. 

ALA synthase has a turnover rate of 70 minutes in adult rat liver and is inducible. Its induction is suppressed by hemin and increased by a variety of xenobiotics (e.g., environmental pollutants) and natural steroids. In erythropoietic tissues, where the largest amount of heme is synthesized, regulation of heme biosynthesis may also involve the process of cell differentiation and proliferation of the erythron, which occurs to meet change in requirements for the synthesis of heme. The differentiation and proliferation are initiated by erythropoietin. 

Iron-dependent regulation of bacterial heme biosynthesis... 

We devised a screen for isolating mutants defective in iron-dependent regulation of heme biosynthesis that did not require prior knowledge of the mechanism or of the rate-limiting steps [83]. We speculated that if the pathway as a whole were regulated by iron, a mutant defective in that control would accumulate protoporphyrin under iron limitation. Mutants defective in the heme synthesis enzymes ferrochelatase [75] or protoporphyrinogen oxidase would likely have a similar phenotype, but porphyrin accumulation would likely be independent of iron in the structural gene mutants, and those strains would also be expected to be heme auxotrophs. 

An additional emerging possibility of regulation of heme biosynthesis in differentiating erythroid cells resides at the ALAS2 mRNA translational level. ALAS2 synthesis is intimately related to the availability of iron. An iron-responsive ele-... 

Despite the critical importance of heme A to aerobic metabolism, many gaps remain in our understanding of heme A biosynthesis, regulation, and transport. This chapter summarizes recent progress in the field and our current understanding of the heme A biosynthetic pathway. 

---