The effects of succinylacetone (4,6-dioxoheptanoic acid) on δ-aminolevulinate synthase activity and the content of heme in monolayers of chick embryo liver cells

Schoenfeld, Nili; Greenblat, Yehudit; Epstein, O; Atsmon, A

doi:10.1016/0167-4889(82)90096-9

Cited by 26 publications

(9 citation statements)

References 26 publications

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“…In patients with HT, increased excretions of SA are usually found along with increased excretion of ALA (Berger et al 1983;Sassa and Kappas 1983). Based on competitive inhibition of PBG synthase (Schoenfeld et al 1982;Beru et al 1983;Kvittingen et al 1983), a linear correlation between high urinary SA and ALA concentrations was expected. Until now no clinical studies on SA and ALA in urine of patients with HT have been performed to investigate the long-term interrelationship between these compounds.…”

Section: Resultsmentioning

confidence: 99%

Hereditary tyrosinaemia type I: A long‐term study of the relationship between the urinary excretions of succinylacetone and δ‐aminolevulinic acid

Schierbeek

Beukeveld

Faassen

et al. 1993

J of Inher Metab Disea

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Patients with hereditary tyrosinaemia type I (HT) excrete large amounts of succinylacetone (SA) in urine. Owing to structural resemblance of SA to delta-aminolevulinic acid (ALA), SA inhibits the second enzyme in the pathway for haeme biosynthesis, porphobilinogen synthase, resulting in increased urinary ALA excretion. We investigated the relationship between urinary SA and ALA excretions of two patients with different forms of HT (late-infantile and juvenile). In both patients the urinary SA and ALA excretions showed a more or less inverse correlation. The patient with the early-infantile form of HT had a relatively greater increase in urinary SA and ALA excretions in comparison to the patient with the juvenile form of HT. A possible explanation for this unexpected inverse correlation between the urinary excretion of SA and ALA might be a lack of intramitochondrial glycine, a substrate for delta-aminolevulinic acid synthesis. It has been reported previously that high concentrations of SA reversibly and competitively inhibit the transport of glycine through membranes.

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Section: Resultsmentioning

confidence: 99%

Hereditary tyrosinaemia type I: A long‐term study of the relationship between the urinary excretions of succinylacetone and δ‐aminolevulinic acid

Schierbeek

Beukeveld

Faassen

et al. 1993

J of Inher Metab Disea

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“…9). Such levels of SA are known to inhibit heme formation in chick embryo hepatocytes or other systems as well as to decrease total cel lular heme [51,52] and cytochrome P450 [53] levels. SA had a significant stimulatory effect on synthesis of ALA synthase [52,53], the rate-limiting enzyme of heme synthesis, an effect which has been interpreted to indi cate that the regulatory pool of intracellular heme was depleted by the action of SA.…”

Section: Role Of Iron Source In Regulation Of Ferritin Mrna Translationmentioning

confidence: 99%

Translational Regulation of Ferritin Synthesis by Iron

Eisenstein

Munro²

1990

Enzyme

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This review starts with a description of certain features of mammalian ferritins and their DNA and RNA structures relevant to translational control of ferritin synthesis. Although the amino acid sequences of the two ferritin subunits (H and L) diverge in about 50% of the coding region, their five a-helices and the exon sizes of their genes are compatible with the proposition that they diverged from a single ancestral gene. Of particular note is their long 5'-untranslated regions (5'UTRs) which include a 28-nucleotide sequence almost completely identical in the H- and L-subunits of a range of species. This motif near the cap region of the 5'-UTR, which forms a specific stem-loop structure, provides for regulation of the translation of H- and L-ferritin mRNAs. When intracellular levels of chelatable iron are not in excess, a large reserve of H- and L-mRNAs is present in the cell sap, restrained from translation by a protein with an M(r) of about 90-100,000 which binds to the stem-loop structure. When excess iron floods the cytosol, this protein/RNA complex appears to dissociate and the 40S ribosome subunit is now able to initiate ferritin protein synthesis so that the dormant mRNAs become active and are transferred to the polyribosomes. The mechanism whereby the binding protein is regulated in response to iron is currently under investigation. The regulatory protein occurs in the cell sap and is present in several interchangeable forms which appear to differ in the redox state of specific sulphydryls within the protein. Under some circumstances, the abundance of these forms appears to be altered by intracellular iron status. It is unclear how iron influences binding of the regulatory protein to ferritin mRNA. Some investigators consider that iron binds in the form of heme to the regulatory protein, for which they offer in vitro evidence. We have examined the role of heme versus inorganic chelatable iron in the regulation of ferritin and heme oxygenase synthesis in rat fibroblasts and hepatoma cells. By manipulating the flow of iron between the intracellular chelatable iron and heme iron pools we have concluded that chelatable iron can act as a regulator of ferritin synthesis in a manner which is independent of heme formation. This conclusion does not exclude a role for heme in some specialized cell types.

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“…2.3.1.37) is the first and rate-controlling enzyme of heme biosynthesis in liver. ALA synthase can be induced in high levels by a variety of compounds (1)(2)(3)(4)(5)(6)(7). Activity of this enzyme is elevated in human subjects with acute porphyria , in whom occurrence of clinical illness is associated with increased excretion of porphyrins and porphyrin precursors, the biochemical hallmarks of the acute porphyrias.…”

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confidence: 99%

Repression of hepatic δ-aminolevulinate synthase by heme and metalloporphyrins: Relationship to inhibition of heme oxygenase

Cable

Bonkovsky

1993

Hepatology

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Heme- and tin-chelated metalloporphyrins are known to decrease the activity of hepatic delta-amino-levulinate synthase, the rate-controlling enzyme of heme synthesis. We performed experiments in primary chick embryo liver cells with tin-, zinc- and copper-chelated porphyrins to assess their effects on activities of delta-aminolevulinate synthase induced by prior treatment of cells with glutethimide and ferric nitrilotriacetate. These different metalloporphyrins were tested to form the experimental foundation for eventual studies in patients with acute porphyrias, in which uncontrolled induction of hepatic delta-amino-levulinate synthase, which plays a key role in pathogenesis of disease. Zinc and tin porphyrins reduced delta-aminolevulinate synthase activities, whereas copper-chelated porphyrins did not. When heme (iron protoporphyrin) was added with zinc or tin porphyrins, delta-aminolevulinate synthase activity was further reduced. Effects of the nonheme metalloporphyrins on delta-aminolevulinate synthase were closely correlated with their abilities to inhibit heme oxygenase (r = 0.78). The largest decrease of delta-aminolevulinate synthase (67%) was obtained with zinc mesoporphyrin and heme. Dose-response data indicated that only nanomolar concentrations of zinc mesoporphyrin and heme are required to obtain this effect. We found no effect of exposure to heme (10 mumol/L) or heme (200 nmol/L) plus zinc mesoporphyrin (50 nmol/L) on the half-life of activity of delta-aminolevulinate synthase (1.9 to 2.1 hr, regardless of treatment). This result suggests that the repressive effect of heme is directed toward decreasing synthesis, increasing breakdown or decreasing the translation of the messenger RNA of delta-aminolevulinate synthase.(ABSTRACT TRUNCATED AT 250 WORDS)

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The effects of succinylacetone (4,6-dioxoheptanoic acid) on δ-aminolevulinate synthase activity and the content of heme in monolayers of chick embryo liver cells

Cited by 26 publications

References 26 publications

Hereditary tyrosinaemia type I: A long‐term study of the relationship between the urinary excretions of succinylacetone and δ‐aminolevulinic acid

Hereditary tyrosinaemia type I: A long‐term study of the relationship between the urinary excretions of succinylacetone and δ‐aminolevulinic acid

Translational Regulation of Ferritin Synthesis by Iron

Repression of hepatic δ-aminolevulinate synthase by heme and metalloporphyrins: Relationship to inhibition of heme oxygenase

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