REGULATION OF 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. 

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-... 

A well studied example for control at the level of eIF-2 is the regulation of protein biosynthesis in erythroid cells (review Chen and London, 1995). A decrease in the heme concentration in reticulocytes leads to inhibition of globin synthesis at the level... 

Ingi, T., Chiang, G., Ronnett, G.V. (1996). The regulation of heme turnover and carbon monoxide biosynthesis in cultured primary rat olfactory receptor neurons. J. Neurosci. 16 5621-8. 

The protein kinase H RI (heme regulated eIF-2 kinase) was first identified in studies on the regulation of protein biosynthesis in erythroid cells. A decrease in the heme concentration in reticulocytes leads to inhibition of globin synthesis at the level of translation. This regulation mechanism ensures that only so much globin is produced as is heme available. If the level of heme drops, then HRI becomes activated. The activated HRI phosphorylates the eIF-2a subunit, which in turn shuts off protein biosynthesis (Fig. 1.48). The mechanism of regulation of HRI kinase by heme is not well understood. Heme binding sites have been identified on the N-terminus and the kinase domain of HRI. 

In the solution containing 0.5% Tween 20, the oxidase occurs as the dimer of the minimal structural unit. One of two heme A molecules in the dimer reacts with CO the dimer seems to be cytochrome aa3. The dimer reacts with CO even in air like other cytochromes aa3, while the CO complex of the monomer dissociates easily to CO and the oxidized form of the monomeric oxidase in air. The dimeric oxidase shows proton pumping activity, while the monomeric enzyme does not show proton pumping activity (Shoji, 1992). The dimeric oxidase dissociates to the monomeric enzyme on addition of ATP (more than 700 pM) (Shoji et al., 1999). As the proton pumping activity of cytochrome c oxidase is related to the biosynthesis of ATP, the dissociation of the dimeric oxidase by ATP seems to be related with the regulation of ATP biosynthesis in the bacterium. In Table 4.2, some properties of monomeric and dimeric species of S. novella cytochrome c oxidase are compared. 

Heme A is an obligatory cofactor in all eukaryotic and most bacterial cytochrome c oxidase enzymes (CcO). Because of its importance to CcO and aerobic metabolism, considerable effort has recently been invested in understanding the mechanism and regulation of heme A biosynthesis. The activity of heme A synthase is strictly dependent on O2, and yet there is no incorporation of O2 into the products. Heme A synthase is now known to utilize a unique electron-transfer mechanism when oxidizing heme O to heme A. Interestingly, the heme A biosynthetic pathway is regulated at least partly via a heme-dependent process in which heme A synthase is positively regulated by intracellular heme levels via Hapl. 

Regulation of Heme A Biosynthesis via Intracellular Heme Levels... 

Fig. 1.56. Control of eIF-2 by phosphorylation. Phosphorylated eIF-2 GDP binds strongly to eIF-2B without nucleotide exchange occurring. Initiation of protein biosynthesis is not possible in this case.In reticulocytes, eIF-2 is subject to phosphorylation by the heme-regulated eIF-2-kinase (HRI). The activity of the dimeric HRI is regulated via the heme concentration. Another protein kinase that can phosphorylate and regulate eIF-2 is the RNA-dependent eIF2a-kinase (PKR). The latter is induced by interferons and activated by double stranded RNA.

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. 

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