Regulation of erythroid 5-aminolevulinate synthase expression during erythropoiesis

• Published in: International Journal of Biochemistry and Cell Biology Vol. 31; no. 10; pp. 1153 - 1167
• Main Authors: Sadlon, Tim J, Dell’Oso, Tania, Surinya, Kathy H, May, Brian K
• Format: Book Review Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.10.1999
• Subjects: 5-Aminolevulinate Synthetase - genetics; ALAS2 expression; Anemia, Sideroblastic - enzymology; Animals; Cell Differentiation; Enhancer Elements, Genetic; Erythroid Precursor Cells - enzymology; Erythropoiesis; Erythropoiesis - physiology; Gene Expression Regulation, Enzymologic; Heme - biosynthesis; Heme - physiology; Humans; Introns; Iron - metabolism; Protein Biosynthesis; Role of heme; Transcription Factors - metabolism; Transcriptional and post-transcriptional control; X-linked sideroblastic anemia; Erythropoiesis; X-linked sideroblastic anemia; EKLF, erythroid Krüppel-like factor; TBP, TATA binding protein; FC, ferrochelatase; ALA, 5-aminolevulinate; CBP, CREB binding protein; ALAS, 5-aminolevulinate; PBGD, porphobilinogen deaminase; EpoR, erythropoietin receptor; XLSA, X-linked sideroblastic anemia; Transcriptional and post-transcriptional control; Role of heme; Epo erythropoietin; LCR, locus control region; DMSO, dimethyl sulfoxide; IRP, iron regulatory protein; ALAD, 5-aminolevulinate dehydratase; ALAS2 expression; IRE, iron responsive element
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/S1357-2725(99)00073-4

Erythroid tissue is the major site of heme production in the body. The synthesis of heme and globin chains is coordinated at both the transcriptional and post-transcriptional levels to ensure that virtually no free heme or globin protein accumulates. The key rate-controlling enzyme of the heme biosynthetic pathway is 5-aminolevulinate synthase (ALAS) and an erythroid-specific isoform (ALAS2) is up-regulated during erythropoiesis. Differentiation of embryonic stem cells with a disrupted ALAS2 gene has established that expression of this gene is critical for erythropoiesis and cannot be compensated by expression of the ubiquitous isoform of the enzyme (ALAS1). Interestingly, heme appears to be important for expression of globin and other late erythroid genes and for erythroid cell differentiation although the mechanism of this effect is not clear. Transcriptional control elements that regulate the human gene for ALAS2 have been identified both in the promoter and in intronic enhancer regions. Subsequent translation of the ALAS2 mRNA is dependent on an adequate iron supply. The mechanism by which transcription of the gene for ALAS2 is increased by erythropoietin late in erythropoiesis remains an interesting issue. Erythropoietin action may result in altered levels of critical erythroid transcription factors or modulate the phosphorylation/acetylation status of these factors. Defects in the coding region of the gene for ALAS2 underlie the disease state X-linked sideroblastic anemia. In this review, we focus on the regulation and function of erythroid-specific 5-aminolevulinate synthase during erythropoiesis and its role in the X-linked sideroblastic anemia.