Molecular Regulation of Heme Biosynthesis in Higher Vertebrates

May, Brian K.; Dogra, Satish C.; Sadlon, Tim; Bhasker, C. Ramana; Cox, Timothy C.; Bottomley, Sylvia S.

doi:10.1016/s0079-6603(08)60875-2

Cited by 135 publications

(124 citation statements)

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“…Although heme is also produced in non-erythroid cells, its biosynthesis is specifically regulated during erythroid differentiation. [1][2][3] Thus, mutations in some specific genes involved in heme production have been shown to cause several human blood disorders, such as sideroblastic anemias. 4 This type of anemia is characterized by abnormal erythroid differentiation with a reduction in the total number of erythrocytes.…”

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confidence: 99%

“…Finely tuned compartmentalization and proper mitochondrial function are not only relevant for the rates of heme production but also are essential for cell viability, as accumulation of heme intermediates or regulators of their production in cytosol and/or mitochondria can lead to oxidative stress and toxicity. 1,2,4,11 In this regard, ABC-me overexpression in erythroid derived cells (murine erythroleukemia cells) increases both the total levels and production rates of hemoglobin, without affecting the shape or the number of mitochondria. 6 Furthermore, ABC-me and its yeast ortholog multidrug resistance-like 1 were shown to protect from increased mitochondrial oxidative stress caused by ischemiareperfusion in the heart or by atm deletion in yeast, respectively.…”

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The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

et al. 2012

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The mitochondrial transporter ATP binding cassette mitochondrial erythroid (ABC-me/ABCB10) is highly induced during erythroid differentiation by GATA-1 and its overexpression increases hemoglobin production rates in vitro. However, the role of ABC-me in erythropoiesis in vivo is unknown. Here we report for the first time that erythrocyte development in mice requires ABC-me. ABC-meÀ/À mice die at day 12.5 of gestation, showing nearly complete eradication of primitive erythropoiesis and lack of hemoglobinized cells at day 10.5. ABC-meÀ/À erythroid cells fail to differentiate because they exhibit a marked increase in apoptosis, both in vivo and ex vivo. Erythroid precursors are particularly sensitive to oxidative stress and ABC-me in the heart and its yeast ortholog multidrug resistance-like 1 have been shown to protect against oxidative stress. Thus, we hypothesized that increased apoptosis in ABC-meÀ/À erythroid precursors was caused by oxidative stress. Within this context, ABC-me deletion causes an increase in mitochondrial superoxide production and protein carbonylation in erythroid precursors. Furthermore, treatment of ABC-meÀ/À erythroid progenitors with the mitochondrial antioxidant MnTBAP (superoxide dismutase 2 mimetic) supports survival, ex vivo differentiation and increased hemoglobin production. Altogether, our findings demonstrate that ABC-me is essential for erythropoiesis in vivo. Cell Death and Differentiation (2012) 19, 1117-1126 doi:10.1038/cdd.2011; published online 13 January 2012A central event during erythroid development is the induction of the components responsible for heme biosynthesis. Although heme is also produced in non-erythroid cells, its biosynthesis is specifically regulated during erythroid differentiation. 1-3 Thus, mutations in some specific genes involved in heme production have been shown to cause several human blood disorders, such as sideroblastic anemias. 4 This type of anemia is characterized by abnormal erythroid differentiation with a reduction in the total number of erythrocytes. 4 In addition, there are idiopathic anemias (either genetic or druginduced) in which the primary molecular defect is unknown. Recently, a novel bioinformatic approach identified new genes involved in heme biosynthesis that could be potential therapeutic targets for these disorders. 5 Furthermore, this large-scale computational screen identified again the ATP Binding Cassette mitochondrial erythroid transporter (ABCme/ABCB10) as an important protein for heme biosynthesis. 5 We previously identified ABC-me as a downstream target of an essential transcription factor for terminal erythroid differentiation, namely GATA-1. 6 ABC-me is a homodimeric transporter located in the inner mitochondrial membrane, which shows the highest expression levels in erythroid tissues. 6,7 Importantly, during early stages of mouse development (day 10 post coitus, pc), ABC-me expression is detected exclusively at the primitive sites of hematopoiesis, namely the yolk sac blood islands. 6 Furthermore, at day 9.5-10.5 pc,...

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The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

et al. 2012

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“…AIP is an autosomal hereditary metabolic aberration resulting from a partial defect in the activity of the third-step enzyme (porphobilinogen deaminase) during the course of heme synthesis (12). Any factor leading to an increased enzyme requirement, using heme as a prosthetic group, or to increased degradation of heme will reduce the heme pool (55) and consequently stimulate ALAS synthesis. This in turn leads to an accumulation of porphyrin precursors prior to porphobilinogen deaminase.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Nuclear Factor 3 and Nuclear Factor 1 Regulate 5-Aminolevulinate Synthase Gene Expression and Are Involved in Insulin Repression

Scassa

Guberman

Ceruti

et al. 2004

Journal of Biological Chemistry

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Although the negative regulation of gene expression by insulin has been widely studied, the transcription factors responsible for the insulin effect are still unknown. The purpose of this work was to explore the molecular mechanisms involved in the insulin repression of the 5-aminolevulinate synthase (ALAS) gene. Deletion analysis of the 5 -regulatory region allowed us to identify an insulin-responsive region located at ؊459 to ؊354 bp. This fragment contains a highly homologous insulin-responsive (IRE) sequence. By transient transfection assays, we determined that hepatic nuclear factor 3 (HNF3) and nuclear factor 1 (NF1) are necessary for an appropriate expression of the ALAS gene. Insulin overrides the HNF3␤ or HNF3␤ plus NF1-mediated stimulation of ALAS transcriptional activity. Electrophoretic mobility shift assay and Southwestern blotting indicate that HNF3 binds to the ALAS promoter. Mutational analysis of this region revealed that IRE disruption abrogates insulin action, whereas mutation of the HNF3 element maintains hormone responsiveness. This dissociation between HNF3 binding and insulin action suggests that HNF3␤ is not the sole physiologic mediator of insulin-induced transcriptional repression. Furthermore, Southwestern blotting assay shows that at least two polypeptides other than HNF3␤ can bind to ALAS promoter and that this binding is dependent on the integrity of the IRE. We propose a model in which insulin exerts its negative effect through the disturbance of HNF3␤ binding or transactivation potential, probably due to specific phosphorylation of this transcription factor by Akt. In this regard, results obtained from transfection experiments using kinase inhibitors support this hypothesis. Due to this event, NF1 would lose accessibility to the promoter. The posttranslational modification of HNF3 would allow the binding of a protein complex that recognizes the core IRE. These results provide a potential mechanism for the insulin-mediated repression of IRE-containing promoters.

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“…It is an essential component of numerous heme proteins, with functions including oxygen transport, energy metabolism, and drug biotransformation. The two major sites of heme synthesis are the bone marrow, where hemoglobin is produced, and the liver, where various hemoproteins [in particular, microsomal cytochromes P450 (CYP)] rely on prosthetic heme to catalyze the oxidation of endogenous and exogenous compounds (1,2). The rate of heme synthesis in the liver is controlled at the first committed step: the condensation of glycine and succinyl-CoA to 5-aminolevulinate, which is catalyzed by 5-aminolevulinic acid synthase (ALAS).…”

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confidence: 99%

“…The rate of heme synthesis in the liver is controlled at the first committed step: the condensation of glycine and succinyl-CoA to 5-aminolevulinate, which is catalyzed by 5-aminolevulinic acid synthase (ALAS). The regulatory role of ALAS is underlined by the fact that ALAS mRNA is markedly increased under physiological conditions demanding more heme, whereas expression levels of the other enzymes in the pathway do not change significantly (1).…”

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Identification of the xenosensors regulating human 5-aminolevulinate synthase

Podvinec

Handschin

Looser

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Heme is an essential component of numerous hemoproteins with functions including oxygen transport, energy metabolism, and drug biotransformation. In nonerythropoietic cells, 5-aminolevulinate synthase (ALAS1) is the rate-limiting enzyme in heme biosynthesis. Upon exposure to drugs that induce cytochromes P450 and other drug-metabolizing enzymes, ALAS1 is transcriptionally upregulated, increasing the rate of heme biosynthesis to provide heme for cytochrome P450 hemoproteins. We used a combined in silico-in vitro approach to identify sequences in the ALAS1 gene that mediate direct transcriptional response to xenobiotic challenge. We have characterized two enhancer elements, located 20 and 16 kb upstream of the transcriptional start site. Both elements respond to prototypic inducer drugs and interact with the human pregnane X receptor NR1I2 and the human constitutive androstane receptor NR1I3. Our results suggest that the fundamental mechanism of drug induction is the same for cytochromes P450 and ALAS1. Transcriptional activation of the ALAS1 gene is the first step in the coordinated up-regulation of apoprotein and heme synthesis in response to exogenous and endogenous signals controlling heme levels. Understanding the direct effects of drugs on heme synthesis is of clinical interest, particularly in patients with hepatic porphyrias.

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Molecular Regulation of Heme Biosynthesis in Higher Vertebrates

Cited by 135 publications

References 123 publications

The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

The mitochondrial transporter ABC-me (ABCB10), a downstream target of GATA-1, is essential for erythropoiesis in vivo

Hepatic Nuclear Factor 3 and Nuclear Factor 1 Regulate 5-Aminolevulinate Synthase Gene Expression and Are Involved in Insulin Repression

Identification of the xenosensors regulating human 5-aminolevulinate synthase

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