Inhibition of δ-aminolevulinate dehydratase in trichloroethylene-exposed rats, and the effects on heme regulation

Fujita, Hideaki; Yamamoto, Masayuki; Kumai, Miho; Sadamoto, Tetsuo; Ikeda, Masayuki

doi:10.1016/0304-4165(84)90087-4

Cited by 27 publications

(10 citation statements)

References 34 publications

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“…On the other hand, the prevalence of low erythrocyte ALAD activity <50% of normal has been estimated to be about 2% in the Swedish population ( Thunell et al , 1987 ), and it is highly likely that more mutations of the ALAD gene may be found in asymptomatic low ALAD carriers by screening. The implication of low ALAD carriers and its identification by molecular analysis is obvious, since these subjects may be more vulnerable to toxic effects of compounds which may inhibit enzyme activity, such as lead ( Sassa et al , 1975 ), succinylacetone ( Lindblad et al , 1977 ; Sassa & Kappas, 1983), styrene oxide ( Fujita et al , 1986 ) or trichloroethylene ( Fujita et al , 1984 ).…”

Section: Discussionmentioning

confidence: 99%

A novel mutation of δ‐aminolaevulinate dehydratase in a healthy child with 12% erythrocyte enzyme activity

Akagi

Yasui

Harper³

et al. 1999

Br J Haematol

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Summary. Cloning, expression and phenotype studies of the defective gene for d-aminolaevulinate dehydratase (ALAD) in a family with an asymptomatic girl who had ALAD de®ciency were carried out. The proband was identi®ed by neonatal ALAD screening, and had erythrocyte ALAD activity at 12% of the normal control. She was heterozygous for ALAD de®ciency, which was inherited from her father. Nucleotide sequence analysis of the cloned ALAD cDNA revealed C 36 to G and T 168 to C mutations on the same allele. The former mutation resulted in F12L substitution, whereas the latter was a silent mutation. All family members who had decreased ALAD activity had the same mutation. Expression of the mutant ALAD cDNA in Chinese hamster ovary cells produced an ALAD protein without signi®cant enzyme activity. Additionally, the mutant ALAD cDNA which encodes F12L substitution produced an aberrant migration pattern in polyacrylamide gel electrophoresis under denaturing conditions. This ®nding probably re¯ects an abnormal folding of the F12L protein, since the mutation occurred in the a1 helix of the N-terminal arm of the enzyme, which is involved in the extensive quaternary interactions among the subunits. This is also the ®rst report of ALAD gene mutation in an asymptomatic subject.

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Section: Discussionmentioning

confidence: 99%

A novel mutation of δ‐aminolaevulinate dehydratase in a healthy child with 12% erythrocyte enzyme activity

Akagi

Yasui

Harper³

et al. 1999

Br J Haematol

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“…Because ALAD is exceptionally sensitive to the toxic effects of certain chemicals such as lead, trichloroethylene, styrene oxide, and succinylacetone, the enzyme holds a unique place in toxicology as the sensitive target of environmental insults. 17,19,[39][40][41] It is thus important to examine the enzymologic and toxicologic characteristics of mutant ALAD phenotypes, and purified GST-fusion ALAD offers a useful model for these studies.The structural analysis of the yeast ALAD has permitted For personal use only. on May 9, 2018. by guest www.bloodjournal.org From insights into the basis for the malfunction of 5 mutant ALA enzymes.…”

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confidence: 99%

Highly heterogeneous nature of δ-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria

Maruno

Furuyama

Akagi

et al. 2001

Blood

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The properties of 9 ␦-aminolevulinate dehydratase (ALAD) mutants from patients with ALAD porphyria (ADP) were examined by bacterial expression of their complementary DNAs and by enzymologic and immunologic assays. ALADs were expressed as glutathione-S-transferase (GST) fusion proteins in Escherichia coli and purified by glutathioneaffinity column chromatography. The GST-ALAD fusion proteins were recognized by anti-ALAD antibodies and were enzymatically active as ALAD. The enzymatic activities of 3 ALAD mutants, K59N, A274T, and V153M, were 69.9%, 19.3%, and 41.0% of that of the wild-type ALAD, respectively, whereas 6 mutants, G133R, K59N/G133R, F12L, R240W, V275M, and delTC, showed little activity (< 8%). These variations generally reflect the phenotype of ALAD in vivo in patients with ADP and indicate that GST-ALAD fusion protein is indeed useful for predicting of the phenotype of ALAD mutants. The location of F12L mutation in the enzyme's molecular structure indicates that its disturbance of the quaternary contact of the ALAD dimer appears to have a significant influence on the enzymatic activity. Mouse monoclonal antibodies to human ALAD were developed that specifically recognized a carboxy terminal portion of ALAD, or other regions in the enzyme. This study represents the first complete analysis of 9 mutants of ALAD identified in ADP and indicates the highly heterogeneous nature of mutations in this disorder. IntroductionDelta-aminolevulinate dehydratase (ALAD) deficiency porphyria (ADP) is an autosomal recessive disorder caused by a homozygous ALAD deficiency. Patients with this condition have clinical symptoms of acute hepatic porphyria such as abdominal pain, vomiting, pain in the arms and legs, and neuropathy. ALAD is the second enzyme in the heme biosynthetic pathway. It catalyzes the Knorr-type condensation of 2 molecules of aminolevulinate acid (ALA) to form a monopyrrole, porphobilinogen (PBG). 1 This enzyme activity is present in large excess compared to other enzymes in the heme biosynthetic pathway, and its partial deficiency does not usually result in any clinical consequences. Seven patients with ADP have been reported to date, 2-6 though only 4 of them have been confirmed by immunochemical or molecular analysis. [2][3][4] Of these 4 cases, the first 2 were German patients reported by Doss and coworkers, 7 the third was a Swedish baby boy studied by Thunell and colleagues, 8 and the fourth was an elderly Belgian man reported by Hassoun and associates. 9 Recently, an asymptomatic Swedish baby girl has been identified to have a markedly decreased ALAD activity. 10 Thus far, a total of 9 point mutations of the alad gene have been identified in these 5 subjects, which resulted in different amino acid changes. However, the enzymatic activity of ALAD expressed by mutant ALAD was investigated only for 4 mutants, A274T and R240W, in German patient B, 3 and V153M and delTC in German patient H 11 (singleletter amino acid codes). This previous study with German patient B demonstrated that ALAD activity co...

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“…No. 1 The next question will be identification of physiological target genes for Bach1. Bach1 targets will be found among genes that possess MARE(s) in their regulatory regions and are induced by heme.…”

Section: Discussionmentioning

confidence: 99%

“…In the field of environmental sciences, the heme metabolism is known to be disturbed by many chemical hazards, for example, lead, dioxin, and trichloroethylene inhibit enzyme(s) in the heme biosynthetic pathway, while cadmium, dioxin and arsenate induce heme oxygenase (HO)-1, the key enzyme for heme catabolism. Thus, these chemicals tend to decrease the so-called "free (or regulatory) heme pool" as was observed in trichloroethylene intoxication 1) and halothane exposure. 2) Preceding studies suggest that the free heme regulates genes encoding the rate-limiting enzyme of heme biosynthesis as well as catabolism, i.e., δ-aminolevulinate synthase (ALAS) [3][4][5] and HO-1, 6,7) respectively.…”

Section: Introductionmentioning

confidence: 91%

Heme-Regulated Transcription Factor Bach1.

Ogawa

Igarashi

Nishitani

et al. 2002

JOURNAL OF HEALTH SCIENCE

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Heme is believed to control expression of genes involved in the synthesis of globins and heme itself. However, heme-regulated transcription factor had not been identified in vertebrates. The mammalian transcription factor Bach1 functions as a repressor of the Maf recognition element (MARE) by forming antagonizing hetero-oligomers with the small Maf family proteins. Recently, we found that heme binds specifically to Bach1 and regulates its DNA binding activity. Deletion studies demonstrated that the heme binding region of Bach1 is confined within its C-terminal region that possesses four di-peptide cysteine-proline (CP) motifs. Mutations in all of the CP motifs of Bach1 abolished its interaction with heme. The DNA binding activity of Bach1 as a MafK hetero-oligomer was markedly inhibited by heme in gel mobility shift assays. The repressor activity of Bach1 was lost upon addition of hemin in transfected cells. These results suggest that increased level of intracellular heme inactivates the repressor Bach1, resulting in induction of a host of genes with MAREs.

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Inhibition of δ-aminolevulinate dehydratase in trichloroethylene-exposed rats, and the effects on heme regulation

Cited by 27 publications

References 34 publications

A novel mutation of δ‐aminolaevulinate dehydratase in a healthy child with 12% erythrocyte enzyme activity

A novel mutation of δ‐aminolaevulinate dehydratase in a healthy child with 12% erythrocyte enzyme activity

Highly heterogeneous nature of δ-aminolevulinate dehydratase (ALAD) deficiencies in ALAD porphyria

Heme-Regulated Transcription Factor Bach1.

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