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• W2102807244 abstract "The structure of the single copy gene encoding the putative housekeeping isoform of Drosophila melanogaster δ-aminolevulinate synthase (ALAS) has been determined. Southern and immunoblot analyses suggest that only the housekeeping isoform of the enzyme exists in Drosophila. We have localized a critical region for promoter activity to a sequence of 121 base pairs that contains a motif that is potentially recognized by factors of the nuclear respiratory factor-1 (NRF-1)/P3A2 family, flanked by two AP4 sites. Heme inhibits the expression of the gene by blocking the interaction of putative regulatory proteins to its 5′ proximal region, a mechanism different from those proposed for other hemin-regulated promoters. Northern and in situ RNA hybridization experiments show that maternal alas mRNA is stored in the egg; its steady-state level decreases rapidly during the first hours of development and increases again after gastrulation in a period where the synthesis of several mRNAs encoding metabolic enzymes is activated. In the syncytial blastoderm, the alasmRNA is ubiquitously distributed and decreases in abundance substantially through cellular blastoderm. Late in embryonic development alas shows a specific pattern of expression, with an elevated mRNA level in oenocytes, suggesting an important role of these cells in the biosynthesis of hemoproteins inDrosophila. The structure of the single copy gene encoding the putative housekeeping isoform of Drosophila melanogaster δ-aminolevulinate synthase (ALAS) has been determined. Southern and immunoblot analyses suggest that only the housekeeping isoform of the enzyme exists in Drosophila. We have localized a critical region for promoter activity to a sequence of 121 base pairs that contains a motif that is potentially recognized by factors of the nuclear respiratory factor-1 (NRF-1)/P3A2 family, flanked by two AP4 sites. Heme inhibits the expression of the gene by blocking the interaction of putative regulatory proteins to its 5′ proximal region, a mechanism different from those proposed for other hemin-regulated promoters. Northern and in situ RNA hybridization experiments show that maternal alas mRNA is stored in the egg; its steady-state level decreases rapidly during the first hours of development and increases again after gastrulation in a period where the synthesis of several mRNAs encoding metabolic enzymes is activated. In the syncytial blastoderm, the alasmRNA is ubiquitously distributed and decreases in abundance substantially through cellular blastoderm. Late in embryonic development alas shows a specific pattern of expression, with an elevated mRNA level in oenocytes, suggesting an important role of these cells in the biosynthesis of hemoproteins inDrosophila. δ-aminolevulinate synthase nuclear respiratory factor glutathione S-transferase luciferase base pair(s) kilobase pair(s) polymerase chain reaction untranslated region downstream promoter element Heme serves as the redox prosthetic group of respiratory cytochromes and other hemoproteins including oxygen carrier proteins. It also plays an important role in cellular homeostasis, participating in the regulation of many biological processes, such as transcription, translation, and protein translocation (1Ponka P. Blood. 1997; 89: 1-25Crossref PubMed Google Scholar, 2Padmanaban G. Venkateswar V. Rangarajan P.N. Trends Biochem. Sci. 1989; 14: 492-496Abstract Full Text PDF PubMed Scopus (153) Google Scholar, 3Zhang L. Guarente L. EMBO J. 1995; 14: 313-320Crossref PubMed Scopus (249) Google Scholar, 4Lathrop J.T. Timko M.P. Science. 1993; 259: 522-525Crossref PubMed Scopus (243) Google Scholar). In particular, heme may regulate the expression of a number of nuclear genes encoding mitochondrial proteins that participate in regulatory mechanisms involving the orchestration of changes in mitochondrial biogenesis in response to different metabolic conditions (5Grivell L.A. Eur. J. Biochem. 1989; 182: 477-493Crossref PubMed Scopus (164) Google Scholar, 6Lenka N. Vijayasarathy C. Mullick J. Avadhani N.G. Prog. Nucleic Acid Res. Mol. Biol. 1998; 61: 309-344Crossref PubMed Google Scholar).δ-Aminolevulinate synthase (ALAS1; succinyl-CoA:glycineC-succinyltransferase, EC 2.3.1.37) is the first enzyme in the heme biosynthetic pathway in animals (1Ponka P. Blood. 1997; 89: 1-25Crossref PubMed Google Scholar, 7May B.K. Borthwick I.A. Srivastava G. Pirola B.A. Elliott W.H. Curr. Top. Cell Regul. 1986; 28: 233-262Crossref PubMed Scopus (54) Google Scholar, 8Ferreira G.C. J. Bioenerg. Biomembr. 1995; 27: 147-150Crossref PubMed Scopus (25) Google Scholar). ALAS is a pyridoxal phosphate-dependent enzyme that exists as homodimer in the mitochondrial matrix, where it catalyzes the formation of δ-aminolevulinic acid by condensation of glycine and succinyl-CoA (9Kappas A. Sassa S. Galbraith R.A. Nordmann Y. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. 2. McGraw-Hill, New York1995: 2.103-2.160Google Scholar). In vertebrates, ALAS is encoded by two different genes (10Riddle R.D. Yamamoto M. Engel J.D. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 792-796Crossref PubMed Scopus (145) Google Scholar) that have been isolated and characterized in several organisms, including humans (11May B.K. Dogra S.C. Sadlon T.J. Bhasker C.R. Cox T.C. Bottomley S.S. Prog. Nucleic Acids Res. Mol. Biol. 1995; 51: 1-51Crossref PubMed Scopus (119) Google Scholar). One gene (alas2 or alas-E) encodes two isoforms generated by alternative splicing that are expressed exclusively in erythroid cells, where they are required for the synthesis of hemoglobin (12Conboy J.G. Cox T.C. Bottomley S.S. Bawden M.J. May B.K. J. Biol. Chem. 1992; 267: 18753-18758Abstract Full Text PDF PubMed Google Scholar, 13Schoenhaut D.S. Curtis P.J. Nucleic Acids Res. 1989; 17: 7013-7028Crossref PubMed Scopus (37) Google Scholar). The second gene (alas1 oralas-N) encodes the nonspecific or housekeeping isoform and is expressed in all cell types (including erythroid) with the highest level found in liver (7May B.K. Borthwick I.A. Srivastava G. Pirola B.A. Elliott W.H. Curr. Top. Cell Regul. 1986; 28: 233-262Crossref PubMed Scopus (54) Google Scholar, 14Ferreira G.C. Gong J. J. Bioenerg. Biomembr. 1995; 27: 151-159Crossref PubMed Scopus (79) Google Scholar), where it is required for the synthesis of cytochromes P450.The expression of ALAS is regulated in vertebrates by a variety of transcriptional and post-transcriptional mechanisms that are different for each gene (1Ponka P. Blood. 1997; 89: 1-25Crossref PubMed Google Scholar). Expression of alas1 is elevated in liver after treatment with porphyrogenic drugs (7May B.K. Borthwick I.A. Srivastava G. Pirola B.A. Elliott W.H. Curr. Top. Cell Regul. 1986; 28: 233-262Crossref PubMed Scopus (54) Google Scholar, 15May B.K. Bhasker C.R. Bawden M.J. Cox T.C. Mol. Biol. Med. 1990; 7: 405-421PubMed Google Scholar) and is repressed by heme (16Yamamoto M. Kure S. Engel J.D. Hiraga K. J. Biol. Chem. 1988; 263: 15973-15979Abstract Full Text PDF PubMed Google Scholar, 17Srivastava G. Borthwick I.A. Maguire D.J. Elferink C.J. Bawden M.J. Mercer J.F. May B.K. J. Biol. Chem. 1988; 263: 5202-5209Abstract Full Text PDF PubMed Google Scholar, 18Srivastava G. Hansen A.J. Bawden M.J. May B.K. Mol. Pharmacol. 1990; 38: 486-493PubMed Google Scholar). Heme also inhibits the transport of ALAS1 to mitochondria (19Hayashi N. Watanabe N. Kikuchi G. Biochem. Biophys. Res. Commun. 1983; 115: 700-706Crossref PubMed Scopus (55) Google Scholar), probably through the heme response motif located in the amino-terminal region of the protein (4Lathrop J.T. Timko M.P. Science. 1993; 259: 522-525Crossref PubMed Scopus (243) Google Scholar). Transcription of thealas2 gene does not respond to changes in heme concentration, but it is developmentally regulated (both isoforms in parallel) during erythroid differentiation, probably by erythroid-specific transcription factors such as GATA-1 or NFE-2 (20Cox T.C. Bawden M.J. Martin A. May B.K. EMBO J. 1991; 10: 1891-1902Crossref PubMed Scopus (304) Google Scholar). At the post-transcriptional level, the translation of thealas2 mRNA is controlled by the iron content of the cell through the iron response element located in the 5′-untranslated region of the mRNA (21Gray N.K. Pantopoulous K. Dandekar T. Ackrell B.A. Hentze M.W. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4925-4930Crossref PubMed Scopus (164) Google Scholar, 22Hentze M.W. Kuhn L.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 8175-8182Crossref PubMed Scopus (1126) Google Scholar, 23Casey J.L. Hentze M.W. Koeller D.M. Caughman S.W. Rouault T.A. Klausner R.D. Harford J.B. Science. 1988; 240: 924-928Crossref PubMed Scopus (506) Google Scholar), a regulatory mechanism that is not present in the housekeeping gene. Similar to ALAS1, heme also regulates the transport to mitochondria of the ALAS2 isoforms via the heme response motif.Because the majority of the studies on the alas genes have been carried out in liver and erythroid cells of vertebrates, very little is known about the mechanisms controlling the expression of the housekeeping gene in order to supply the necessary heme for the respiratory complexes (1Ponka P. Blood. 1997; 89: 1-25Crossref PubMed Google Scholar) and coordinate the synthesis of hemocytochromes with the respiratory demand of the different tissues (24Moyes C.D. Battersby B.J. Leary S.C. J. Exp. Biol. 1998; : 299-307Google Scholar, 25Wallace D.C. Sci. Am. 1997; 277: 40-47Crossref PubMed Scopus (157) Google Scholar). This coordination is central for understanding both the physiology and pathology of mitochondrial function (26Wallace D.C. Trends Genet. 1993; 9: 128-133Abstract Full Text PDF PubMed Scopus (105) Google Scholar, 27Zeviani M. Petruzzella V. Carrozzo R. J. Bioenerg. Biomembr. 1997; 29: 121-130Crossref PubMed Scopus (16) Google Scholar). Interestingly, the promoter of the alas1 gene (28Braidotti G. Borthwick I.A. May B.K. J. Biol. Chem. 1993; 268: 1109-1117Abstract Full Text PDF PubMed Google Scholar) contains DNA binding sites recognized by NRF-1, a transcription factor involved in nucleo-mitochondrial interaction (29Virbasius C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (275) Google Scholar), reinforcing the important role of the enzyme in organelle biogenesis.Heme biosynthesis has been studied in Saccharomyces cerevisiae by a combination of molecular and genetic strategies (5Grivell L.A. Eur. J. Biochem. 1989; 182: 477-493Crossref PubMed Scopus (164) Google Scholar, 30Grivell L.A. Crit. Rev. Biochem. Mol. Biol. 1995; 30: 121-164Crossref PubMed Scopus (142) Google Scholar, 31Costanzo M.C. Fox T.D. Annu. Rev. Genet. 1990; 24: 91-113Crossref PubMed Google Scholar). In yeast, heme functions as a sensor of oxygen tension, and its level regulates the expression of genes involved in mitochondrial function, modulating the activity of the transcription factor HAP1, the only regulatory protein responding to heme that is well characterized in eukaryotic cells (32Zhang L. Guarente L. J. Biol. Chem. 1994; 269: 14643-14647Abstract Full Text PDF PubMed Google Scholar, 33Zhang L. Guarente L. EMBO J. 1996; 15: 4676-4681Crossref PubMed Scopus (42) Google Scholar, 34Zhang L. Hach A. Wang C. Mol. Cell. Biol. 1998; 18: 3819-3828Crossref PubMed Scopus (90) Google Scholar). Among animals,Drosophila also offers an excellent opportunity to study complex biological processes in vivo using molecular and genetic tools (35Bate M. Martinez-Arias A. The Development of Drosophila Melanogaster. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1993Google Scholar), including mitochondrial gene expression under differing physiological conditions such as embryogenesis or aging (36Calleja M. Pena P. Ugalde C. Ferreiro C. Marco R. Garesse R. J. Biol. Chem. 1993; 268: 18891-18897Abstract Full Text PDF PubMed Google Scholar, 37Pena P. Ugalde C. Calleja M. Garesse R. Biochem. J. 1995; : 887-897Crossref PubMed Scopus (12) Google Scholar, 38Talamillo A. Chisholm A.A. Garesse R. Jacobs H.T. Mol. Biol. Rep. 1998; 25: 87-94Crossref PubMed Scopus (11) Google Scholar). As a first step to study the mechanisms controlling heme synthesis and its coordination with mitochondrial biogenesis, we have cloned a Drosophila melanogaster alas gene. In this paper, we describe the structure of this single copy gene, its spatio-temporal pattern of expression during development and the characterization of its proximal promoter region.DISCUSSIONWe have cloned and studied a Drosophila gene encoding the mitochondrial matrix enzyme δ-aminolevulinate synthase, which catalyzes the major regulatory step in the heme biosynthetic pathway. In animals, the enzyme has been characterized in vertebrates, mainly in mammals, which contain three ALAS isoforms encoded by two distinct genes. alas1 is expressed ubiquitously, and alas2is expressed exclusively in erythroid cells. This is the first report of an invertebrate alas gene.The D. melanogaster alas gene is located on the right arm of the second chromosome, spans a region of approximately 3 kb, and contains two exons interrupted by a single intron of 144 bp that is located at a position 375 bp from the 3′-end. In contrast to the situation in vertebrates, several experiments suggest thatDrosophila ALAS is encoded by a single gene: repetitive screenings of several cDNA and genomic libraries recovered phages harboring DNAs corresponding to the same genomic region; Southern analyses under low stringency conditions detected only fragments from this DNA region; and Northern analyses revealed the presence of a single mRNA in embryos and adults. More importantly, immunoblot analysis using a polyclonal antibody raised against the complete ALAS protein detected a single band corresponding to the predicted mature protein. The logical interpretation of these results is that theDrosophila alas gene encodes the constitutive form of the enzyme. Accordingly, the 5′-UTR of the mRNA does not contain the iron response element, a characteristic feature of the erythroid ALAS isoform in vertebrates, that is absent in the housekeeping isoform. Moreover, this interpretation is consistent with the respiratory mechanism of the fly, since oxygen reaches the cells directly through the tracheolar network without the need of respiratory pigments (53Wigglesworth V.B. The Principles of Insect Physiology. Chapman and Hall, London1970: 411-475Google Scholar). In this regard, it would be interesting to determine if other invertebrates that transport oxygen by hemoproteins contain one or twoalas genes.The D. melanogaster alas gene has a TATA-less promoter with two major transcriptional start sites located at positions −60 and −84. During embryogenesis, the −84 initiation site is used preferentially, while adult mRNAs start predominantly at the −60-position. This raises the interesting possibility that the expression of the gene is regulated differentially in embryos and adults. In addition, the Drosophila alas promoter contains a DPE located in the 5′-UTR. DPEs substitute for the TATA-box to provide a binding site for TFIID and have been found recently to interact with TAFII60 (54Burke T.W. Kadonaga J.T. Genes Dev. 1996; 10: 711-724Crossref PubMed Scopus (324) Google Scholar). They are conserved betweenDrosophila and humans and are critical for the function of a subset of TATA-less promoters (55Burke T.W. Kadonaga J.T. Genes Dev. 1997; 11: 3020-3031Crossref PubMed Scopus (396) Google Scholar, 56Arkhipova I.R. Genetics. 1995; 139: 1359-1369Crossref PubMed Google Scholar).Using transient transfection analysis in Schneider cells, we have characterized the 5′ upstream region of the Drosophila alasgene. We have delimited the region responsible to direct maximal activity in Schneider cells to the proximal 238 nucleotides. In particular, the nucleotides encompassing the −238 to −117 region are necessary to recover full promoter activity. Within this region, we have identified several putative transcription factor binding sites and in particular one located at position −140 potentially recognized by P3A2. Notably, P3A2 is a regulatory protein identified in sea urchin that is itself developmentally regulated (51Calzone F.J. Hoog C. Teplow D.B. Cutting A.E. Zeller R.W. Britten R.J. Davidson E.H. Development. 1991; 112: 335-350Crossref PubMed Google Scholar, 52Hoog C. Calzone F.J. Cutting A.E. Britten R.J. Davidson E.H. Development. 1991; 112: 351-364PubMed Google Scholar) and contains a DNA-binding domain that shares high identity with theDrosophila ERECT WING and the mammalian NRF-1 factors (29Virbasius C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (275) Google Scholar). NRF1 is probably involved in a coordinated response of genes encoding key components of energy metabolism (29Virbasius C.A. Virbasius J.V. Scarpulla R.C. Genes Dev. 1993; 7: 2431-2445Crossref PubMed Scopus (275) Google Scholar, 57Scarpulla R.C. J. Bioenerg. Biomembr. 1997; 29: 109-119Crossref PubMed Scopus (229) Google Scholar), including ALAS (28Braidotti G. Borthwick I.A. May B.K. J. Biol. Chem. 1993; 268: 1109-1117Abstract Full Text PDF PubMed Google Scholar). Genetic and molecular analyses in Drosophila have demonstrated that erect wing plays an important role in the development of muscle and the nervous system (58DeSimone S.M. White K. Mol. Cell. Biol. 1993; 13: 3641-3649Crossref PubMed Scopus (83) Google Scholar, 59DeSimone S. Coelho C. Roy S. VijayRaghavan K. White K. Development. 1996; 122: 31-39PubMed Google Scholar), two tissues with a very high energetic requirement that demand high mitochondrial activity and therefore require elevated synthesis of respiratory pigments.ALAS activity is subject to a variety of heme-mediated negative control mechanisms including the inhibition of mRNA synthesis (11May B.K. Dogra S.C. Sadlon T.J. Bhasker C.R. Cox T.C. Bottomley S.S. Prog. Nucleic Acids Res. Mol. Biol. 1995; 51: 1-51Crossref PubMed Scopus (119) Google Scholar), which is one of the few examples of a feedback mechanism by end product at the level of transcription (2Padmanaban G. Venkateswar V. Rangarajan P.N. Trends Biochem. Sci. 1989; 14: 492-496Abstract Full Text PDF PubMed Scopus (153) Google Scholar). In vertebrates, this mechanism has been detected only in the gene encoding the alas housekeeping isoform, although these data are controversial (1Ponka P. Blood. 1997; 89: 1-25Crossref PubMed Google Scholar). We have detected a substantial decrease in the activity of the Drosophila alaspromoter in Schneider cells treated with 30 μm hemin. Furthermore, we have delimited the sequence elements responsible for the heme-mediated inhibitory effect to a DNA fragment of 117 bp that includes 60 bp of the proximal core promoter and the 5′-UTR. Although we cannot rule out formally the possibility that the 5′-UTR mediates a decrease in mRNA stability of the luciferase transcript, the most likely interpretation is that the heme effect is exerted at the level of transcription and is mediated by the proximal 5′ upstream sequences and/or the UTR. Remarkably, the 117-bp fragment confers a heme response on heterologous promoters. Moreover, heme exerts a negative effect on the interaction of regulatory proteins and/or factors of the basal transcriptional machinery with the alas gene, blocking the binding of these proteins to the proximal 5′ upstream region of the gene.This inhibitory mechanism is different from that described for other genes that are transcriptionally regulated by heme. For example, in yeast, heme also acts as an important regulator of gene expression (60Forsburg S.L. Guarente L. Annu. Rev. Cell Biol. 1989; 5: 153-180Crossref PubMed Scopus (129) Google Scholar). This effect is mediated, at least in some genes, by the zinc finger transcription factor HAP-1, which binds DNA in the presence of heme (61Haldi M.L. Guarente L. Mol. Gen. Genet. 1995; 248: 229-235Crossref PubMed Scopus (20) Google Scholar, 62Zhang L. Guarente L. Genetics. 1994; 136: 813-817Crossref PubMed Google Scholar). The presence of DNA regulatory proteins that bind the promoter of the mammalian ferritin gene in a heme-dependent manner has also been described recently, and in this case the effect is mediated by the ubiquitous transcription factor NF-Y (47Marziali G. Perrotti E. Ilari R. Testa U. Coccia E.M. Battistini A. Mol. Cell. Biol. 1997; 17: 1387-1395Crossref PubMed Scopus (83) Google Scholar, 63Coccia E.M. Profita V. Fiorucci G. Romeo G. Affabris E. Testa U. Hentze M.W. Battistini A. Mol. Cell. Biol. 1992; 12: 3015-3022Crossref PubMed Scopus (48) Google Scholar, 64Coccia E.M. Stellacci E. Orsatti R. Testa U. Battistini A. Blood. 1995; 86: 1570-1579Crossref PubMed Google Scholar). Another example of a gene regulated at the transcriptional level by heme is the tartrate-resistant acid phosphatase. This effect is mediated by the interaction of a heterogeneous complex composed of Ku antigen, the redox factor protein Ref1 and a 133-kDa protein with a GAGGC tandem repeated motif (65Reddy S.V. Alcantara O. Roodman G.D. Boldt D.H. Blood. 1996; 88: 2288-2297Crossref PubMed Google Scholar, 66Reddy S.V. Alcantara O. Boldt D.H. Blood. 1998; 91: 1793-1801Crossref PubMed Google Scholar). Finally, the heat shock factor 1 mediates the transcription of the gene hsp70 mediated by heme; in this case, the mechanism could be indirect, involving the inhibition by heme of intracellular proteolysis (67Yoshima T. Yura T. Yanagi H. J. Biol. Chem. 1998; 273: 25466-25471Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar).Vertebrate alas genes have been studied mainly in liver and cell culture. The characterization of the Drosophila alasgene has allowed us to study the spatio-temporal pattern of expression of an alas gene during development. alas mRNA of maternal origin is homogeneously distributed in the syncytial blastoderm at relatively high levels, and, consistent with Northern analyses, its concentration decreases rapidly and it is almost absent in cellular blastoderm. Interestingly, in later stages of embryogenesis after retraction of the germ band, the mRNA is expressed highly in oenocytes and in two symmetrical groups of cells located in the anterior part of the embryo. Oenocytes are a small group of cells of ectodermal origin, located in each of the abdominal segments that contain histoblasts (68Martinez-Arias A. Bate M. Martinez Arias A. The Development of Drosophila melanogaster. 1. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1993: 517-608Google Scholar). Their development is associated with the differentiation of fat cells, and some of the oenocytes invade the larval fat body and are found in its inner surface. Adult oenocytes are smaller than the larval ones and are clearly recognizable and distinct from the fat body cells (69Demerec M. Biology of Drosophila. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1994Google Scholar). Some observations have suggested a potential role in secretion, although their function remains largely unknown. The specific pattern of expression of alas in oenocytes suggests that these cells are highly active in the synthesis of hemoproteins, perhaps cytochrome P450, and may be involved in detoxification mechanisms in Drosophila. Heme serves as the redox prosthetic group of respiratory cytochromes and other hemoproteins including oxygen carrier proteins. It also plays an important role in cellular homeostasis, participating in the regulation of many biological processes, such as transcription, translation, and protein translocation (1Ponka P. Blood. 1997; 89: 1-25Crossref PubMed Google Scholar, 2Padmanaban G. Venkateswar V. Rangarajan P.N. Trends Biochem. Sci. 1989; 14: 492-496Abstract Full Text PDF PubMed Scopus (153) Google Scholar, 3Zhang L. Guarente L. EMBO J. 1995; 14: 313-320Crossref PubMed Scopus (249) Google Scholar, 4Lathrop J.T. Timko M.P. Science. 1993; 259: 522-525Crossref PubMed Scopus (243) Google Scholar). In particular, heme may regulate the expression of a number of nuclear genes encoding mitochondrial proteins that participate in regulatory mechanisms involving the orchestration of changes in mitochondrial biogenesis in response to different metabolic conditions (5Grivell L.A. Eur. J. Biochem. 1989; 182: 477-493Crossref PubMed Scopus (164) Google Scholar, 6Lenka N. Vijayasarathy C. Mullick J. Avadhani N.G. Prog. Nucleic Acid Res. Mol. Biol. 1998; 61: 309-344Crossref PubMed Google Scholar). δ-Aminolevulinate synthase (ALAS1; succinyl-CoA:glycineC-succinyltransferase, EC 2.3.1.37) is the first enzyme in the heme biosynthetic pathway in animals (1Ponka P. Blood. 1997; 89: 1-25Crossref PubMed Google Scholar, 7May B.K. Borthwick I.A. Srivastava G. Pirola B.A. Elliott W.H. Curr. Top. Cell Regul. 1986; 28: 233-262Crossref PubMed Scopus (54) Google Scholar, 8Ferreira G.C. J. Bioenerg. Biomembr. 1995; 27: 147-150Crossref PubMed Scopus (25) Google Scholar). ALAS is a pyridoxal phosphate-dependent enzyme that exists as homodimer in the mitochondrial matrix, where it catalyzes the formation of δ-aminolevulinic acid by condensation of glycine and succinyl-CoA (9Kappas A. Sassa S. Galbraith R.A. Nordmann Y. Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. 2. McGraw-Hill, New York1995: 2.103-2.160Google Scholar). In vertebrates, ALAS is encoded by two different genes (10Riddle R.D. Yamamoto M. Engel J.D. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 792-796Crossref PubMed Scopus (145) Google Scholar) that have been isolated and characterized in several organisms, including humans (11May B.K. Dogra S.C. Sadlon T.J. Bhasker C.R. Cox T.C. Bottomley S.S. Prog. Nucleic Acids Res. Mol. Biol. 1995; 51: 1-51Crossref PubMed Scopus (119) Google Scholar). One gene (alas2 or alas-E) encodes two isoforms generated by alternative splicing that are expressed exclusively in erythroid cells, where they are required for the synthesis of hemoglobin (12Conboy J.G. Cox T.C. Bottomley S.S. Bawden M.J. May B.K. J. Biol. Chem. 1992; 267: 18753-18758Abstract Full Text PDF PubMed Google Scholar, 13Schoenhaut D.S. Curtis P.J. Nucleic Acids Res. 1989; 17: 7013-7028Crossref PubMed Scopus (37) Google Scholar). The second gene (alas1 oralas-N) encodes the nonspecific or housekeeping isoform and is expressed in all cell types (including erythroid) with the highest level found in liver (7May B.K. Borthwick I.A. Srivastava G. Pirola B.A. Elliott W.H. Curr. Top. Cell Regul. 1986; 28: 233-262Crossref PubMed Scopus (54) Google Scholar, 14Ferreira G.C. Gong J. J. Bioenerg. Biomembr. 1995; 27: 151-159Crossref PubMed Scopus (79) Google Scholar), where it is required for the synthesis of cytochromes P450. The expression of ALAS is regulated in vertebrates by a variety of transcriptional and post-transcriptional mechanisms that are different for each gene (1Ponka P. Blood. 1997; 89: 1-25Crossref PubMed Google Scholar). Expression of alas1 is elevated in liver after treatment with porphyrogenic drugs (7May B.K. Borthwick I.A. Srivastava G. Pirola B.A. Elliott W.H. Curr. Top. Cell Regul. 1986; 28: 233-262Crossref PubMed Scopus (54) Google Scholar, 15May B.K. Bhasker C.R. Bawden M.J. Cox T.C. Mol. Biol. Med. 1990; 7: 405-421PubMed Google Scholar) and is repressed by heme (16Yamamoto M. Kure S. Engel J.D. Hiraga K. J. Biol. Chem. 1988; 263: 15973-15979Abstract Full Text PDF PubMed Google Scholar, 17Srivastava G. Borthwick I.A. Maguire D.J. Elferink C.J. Bawden M.J. Mercer J.F. May B.K. J. Biol. Chem. 1988; 263: 5202-5209Abstract Full Text PDF PubMed Google Scholar, 18Srivastava G. Hansen A.J. Bawden M.J. May B.K. Mol. Pharmacol. 1990; 38: 486-493PubMed Google Scholar). Heme also inhibits the transport of ALAS1 to mitochondria (19Hayashi N. Watanabe N. Kikuchi G. Biochem. Biophys. Res. Commun. 1983; 115: 700-706Crossref PubMed Scopus (55) Google Scholar), probably through the heme response motif located in the amino-terminal region of the protein (4Lathrop J.T. Timko M.P. Science. 1993; 259: 522-525Crossref PubMed Scopus (243) Google Scholar). Transcription of thealas2 gene does not respond to changes in heme concentration, but it is developmentally regulated (both isoforms in parallel) during erythroid differentiation, probably by erythroid-specific transcription factors such as GATA-1 or NFE-2 (20Cox T.C. Bawden M.J. Martin A. May B.K. EMBO J. 1991; 10: 1891-1902Crossref PubMed Scopus (304) Google Scholar). At the post-transcriptional level, the translation of thealas2 mRNA is controlled by the iron content of the cell through the iron response element located in the 5′-untranslated region of the mRNA (21Gray N.K. Pantopoulous K. Dandekar T. Ackrell B.A. Hentze M.W. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4925-4930Crossref PubMed Scopus (164) Google Scholar, 22Hentze M.W. Kuhn L.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 8175-8182Crossref PubMed Scopus (1126) Google Scholar, 23Casey J.L. Hentze M.W. Koeller D.M. Caughman S.W. Rouault T.A. Klausner R.D. Harford J.B. Science. 1988; 240: 924-928Crossref PubMed Scopus (506) Google Scholar), a regulatory mechanism that is not present in the housekeeping gene. Similar to ALAS1, heme also regulates the transport to mitochondria of the ALAS2 isoforms via the heme response motif. Because the majority of the studies on the alas genes have been carried out in liver and erythroid cells of vertebrates, very little is known about the mechanisms controlling the expression of the housekeeping gene in order to supply the necessary heme for the respiratory complexes (1Ponka P. Blood. 1997; 89: 1-25Crossref PubMed Google Scholar) and coordinate the synthesis of hemocytochromes with the respiratory demand of the different tissues (24Moyes C.D. Battersby B.J. Leary S.C. J. Exp. Biol. 1998; : 299-307Google Scholar, 25Wallace D.C. S" @default.
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• W2102807244 date "1999-12-01" @default.
• W2102807244 modified "2023-09-29" @default.
• W2102807244 title "Structure and Regulated Expression of the δ-Aminolevulinate Synthase Gene from Drosophila melanogaster" @default.
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• W2102807244 doi "https://doi.org/10.1074/jbc.274.52.37321" @default.
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