Different responses of the hepatic and erythropoietic σ-aminolevulinic acid synthetase of mice

Wada, Osamu; Sassa, Shigeru; Takaku, Fumimaro; Yano, Yuzo; Urata, Gumpei; Nakao, Kazuwa

doi:10.1016/0304-4165(67)90165-1

Cited by 39 publications

(12 citation statements)

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“…In contrast to these observations in hepatic tissue, the erythroid form of the enzyme is unresponsive to chemicals that normally induce porphyria, and this isozyme does not appear to accumulate in the cytoplasm of erythrocytes on treatment of animals with the same porphyrogenic agents (14)(15)(16)(17)(18). Instead, the biosynthesis of ALA synthase in erythroid cells appears to be strongly stimulated by chemical agents normally used for induction of anemia [e.g., phenylhydrazine (G. Kikuchi and M. Hasegawa, personal communication)].…”

mentioning

confidence: 47%

Isolation of recombinant cDNAs encoding chicken erythroid delta-aminolevulinate synthase.

Yamamoto¹,

Yew²,

Federspiel³

et al. 1985

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

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We report the isolation of cDNA clones encoding 6-aminolevulinate synthase (ALA synthase; EC 2.3.1.37), the first enzyme in the heme biosynthetic pathway in animal cells. The gene was isolated from a chicken erythroid cDNA library prepared in the bacteriophage X fusion/ expression vector gtll, using rabbit antibody raised against the relatively abundant chicken liver enzyme. The chicken liver and red cell ALA synthase isozymes share substantial crossreactivity to the antibody, thereby allowing isolation of the erythroid-specific gene by using the heterologous antibody in immune screening of the red cell cDNA library. Preliminary analysis documenting the tissue specificity of transcription indicates that the enzyme is encoded by a highly homologous set of messages, which appear to differ in size in various avian tissues. From analysis using strand-specific RNA probes, it appears that the different ALA synthase mRNAs detected may be transcribed from a family of genes that are closely related in nucleotide sequence and are each regulated in a developmentally specific manner.8-Aminolevulinate synthase (ALA synthase; EC 2.3.1.37), the first enzyme in the biosynthetic pathway leading to heme production, catalyzes the condensation of glycine and succinyl-CoA to form 8-aminolevulinic acid (1). The mRNA for the enzyme is encoded in the nucleus, from which it is transported to the cytoplasm, where it is translated into an enzymatically active precursor form. The ALA synthase preenzyme is processed into the mature mitochondrial enzyme (a proteolytic cleavage product of the preenzyme) as it traverses the mitochondrial membrane, where it finally occupies its normal cellular compartment (2).Various studies have previously shown that both the ALA synthase gene and the enzyme are subject to a complex array of regulatory interactions. Thus, the enzyme form found in the liver is responsive to feedback regulation by the end product (heme) and can be induced by a variety of chemical effectors of hepatic porphyria, notably 3,5-dicarbethoxy-1,4-dihydrocollidine and allylisopropylacetamide. Furthermore, this induction appears to be regulated at both the transcriptional and translational levels (3-11). In the liver, heme also appears to directly interfere with the translocation of the preenzyme from the cytoplasmic to the mitochondrial compartments, causing abnormal increases in the cytoplasmic levels of the preenzyme (12, 13).In contrast to these observations in hepatic tissue, the erythroid form of the enzyme is unresponsive to chemicals that normally induce porphyria, and this isozyme does not appear to accumulate in the cytoplasm of erythrocytes on treatment of animals with the same porphyrogenic agents (14-18). Instead, the biosynthesis of ALA synthase in erythroid cells appears to be strongly stimulated by chemical agents normally used for induction of anemia [e.g., phenylhydrazine (G. Kikuchi and M. Hasegawa, personal communication)]. Thus the enzyme activity appears to be regulated in a cell-specific manner. In keeping ...

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mentioning

confidence: 47%

Isolation of recombinant cDNAs encoding chicken erythroid delta-aminolevulinate synthase.

Yamamoto¹,

Yew²,

Federspiel³

et al. 1985

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

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“…Previous studies of mammalian ALAS, the first enzyme of the heme biosynthetic pathway, revealed that hepatic, but not erythroid ALAS, was induced in response to exogenously delivered porphyrinogenic drugs such as allylisopropylacetamide or 3,5-dicarbethoxy-1,4-dihydrocollidine (35,38). In addition, hemin administration blocked transport of ALAS to the mitochondria in adult rat liver, but hemin had no effect on ALAS activity or transport in erythroid tissue (39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Enzymatic defect in "X-linked" sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency.

Cotter

Baumann

Bishop

1992

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

140

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Recently, the human gene encoding erythroid-specific -aminolevulinate synthase was localized to the chromosomal region Xp2l-Xq2l, identifying this gene as the logical candidate for the enzymatic defect causing "X -linked" sideroblastic anemia. To investigate this hypothesis, the 11 exonic coding regions of the -aminolevulinate synthase gene were amplified and sequenced from a 30-year-old Chinese male with a pyridoxine-responsive form of X-linked sideroblastic anemia. A single T --A transition was found in codon 471 in a highly conserved region of exon 9, resulting in an ile -+ Asn substitution. This mutation interrupted contiguous hydrophobic residues and was predicted to transform a region of (3-sheet structure to a random-coil structure. Prokaryotic expression of the normal and mutant cDNAs revealed that the mutant construct expressed low levels of enzymatic activity that required higher concentrations of pyridoxal 5'-phosphate to achieve maximal activation than did the normal enzyme. The amino acid substitution occurred in the exon containing the putative pyridoxal 5'-phosphate binding site and may account for the reduced ability of the cofactor to catalyze the formation of 6aminolevulinic acid.The sideroblastic anemias are a clinically heterogeneous group of disorders resulting from inherited or acquired causes (1, 2). The inherited types are X chromosome-linked or autosomal, and the acquired forms are secondary to chemical induction or to inflammatory disease or are idiopathic. Patients in these classifications can be further subdivided into those who are responsive to pyridoxine and those who are refractory. Sideroblastic anemia is classified as a disorder of heme synthesis since the activities of certain heme biosynthetic enzymes were reported to be deficient (3), whereas globin synthesis was normal. Since many patients had reduced 8-aminolevulinate synthase [ALAS; succinylCoA:glycine C-succinyltransferase (decarboxylating); EC 2.3.1.37] enzymatic activity in bone marrow (4, 5) and because pyridoxal 5'-phosphate (PLP), the pyridoxine metabolite, is a required cofactor, ALAS has been suggested as a candidate gene for mutations leading to some types of sideroblastic anemia (6).The human genes encoding the housekeeping and erythroid forms of ALAS were isolated and characterized (7-9). Although the two genes predicted proteins with 59% amino acid identity, they were mapped to different chromosomes by somatic cell hybrid and in situ hybridization methods. The housekeeping gene mapped to chromosome 3p2l, and the erythroid gene was localized to the X chromosomal region Xp2l-Xq2l (9-13). The X-chromosomal assignment suggested that the erythroid form of ALAS (designated ALAS2) might be the enzymatic defect in "X-linked" sideroblastic anemia (XLSA).To investigate this hypothesis, the erythroid ALAS2 coding regions were amplified and sequenced from a male affected with pyridoxine-responsive XLSA. In this communication, an exonic point mutation in the ALAS2 gene that predicted the substitution of asparagine f...

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“…Low AP decreased liver ALA-S activity in intact mice while high AP had an opposite effect. Wada et al [3] have found that hepatic ALA-S activity of mice living in an atmo sphere of 10% 02 p.v. and normal AP did not actually differ from that of the controls.…”

Section: Preliminary Phasementioning

confidence: 99%

“…to be effective on the homologous enzyme of the erythroblasts which is markedly induced by erythropoietin [2] or hypoxia [3], Several other differences between the erythropoietic and the hepatic ALA-S have been described…”

Section: Introductionmentioning

confidence: 99%

Effect of Abnormal Atmospheric Pressure Conditions upon Mouse Liver δ-Aminolevulinic Acid Synthetase Activity

Ag¹,

Lyberatos²,

Argyropoulos³

et al. 1985

Enzyme

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Liver δ-aminolevulinic acid synthetase activity was measured in mice living under abnormal atmospheric pressure conditions for 15 h. In the group living under low atmospheric pressure (51 kPa) the enzymic activity, either basal or induced by starvation and/or allylisopropylacetamide, was significantly (p< 0.001) lower than that of the control group. In the group living under high atmospheric pressure (153 kPa) the enzymic activity was significantly (p< 0.001) higher than the one of the controls. Our results might possibly be explained by changes in the cellular redox state, the heme oxygenase activity or the serum erythropoietin levels.

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Different responses of the hepatic and erythropoietic σ-aminolevulinic acid synthetase of mice

Cited by 39 publications

References 10 publications

Isolation of recombinant cDNAs encoding chicken erythroid delta-aminolevulinate synthase.

Isolation of recombinant cDNAs encoding chicken erythroid delta-aminolevulinate synthase.

Enzymatic defect in "X-linked" sideroblastic anemia: molecular evidence for erythroid delta-aminolevulinate synthase deficiency.

Effect of Abnormal Atmospheric Pressure Conditions upon Mouse Liver δ-Aminolevulinic Acid Synthetase Activity

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