Control of Porphyrin Biosynthesis through a Negative-Feedback Mechanism. STUDIES WITH PREPARATIONS OF δ-AMINOLAEVULATE SYNTHETASE AND δ-AMINOLAEVULATE DEHYDRATASE FROM <i>RHODOPSEUDOMONAS SPHEROIDES</i>

Burnham, Bruce F.; Pierce, Wayne S.; Williams, Katherine; Boyer, Markley H.; Kirby, C K

doi:10.1042/bj0870462

Cited by 289 publications

(42 citation statements)

References 25 publications

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“…Heme functions as an allosteric inhibitor and repressor of ALA synthase in photosynthetic bacteria (7,15,17), and it appears to act as a central regulator of bacteriochlorophyll synthesis in Rhodopseudomonas spheroides (17) by controlling the part of the pathway that is common to both heme and Chl formation. Because certain iron chelators have been found to induce accumulation of porphyrin and Mg-porphyrin Chl precursors while blocking heme synthesis in etiolated plant tissues (10,12,13), it has been proposed that heme may act to repress ALA formation in plants, thus regulating Chl precursor synthesis in a manner similar to the case in photosynthetic bacteria (8,10).…”

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confidence: 99%

Induction of δ-Aminolevulinic Acid Synthase Activity and Inhibition of Heme Synthesis in Euglena gracilis by N-Methyl Mesoporphyrin IX

Beale

Foley²

1982

Plant Physiol.

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N-Methyl mesoporphyrin IX, an inhibitor of heme synthesis, increases extractable 8-aminolevulinic acid (ALA) synthase activity when administered to growing cultures of Euglena gracilis Klebs strain Z Pringsheim in micromolar concentrations. Wild-type light-grown green cells and white aplastidic cells exhibited 2.8-fold and 1.8-fold increases, respectively, in ALA synthase activity within five to six hours after incubation with 4 x 106 molar N-methyl mesoporphyrin IX. Protoheme levels were decreased and 59Fe incorporation into heme was inhibited by N-methyl mesoporphyrin IX, indicating that, as in animal cells, N-methyl mesoporphyrin IX acts specifically to block iron insertion into protoporphyrin IX. Chlorophyll synthesis in wild-type cells was not affected within the first 6 hours after administration of N-methyl mesoporphyrin IX. In animals, fungi, and bacteria, the first identified step hepatic ALA synthase within 4 h after injection into mice. We now report that N-methyl mesoporphyrin IX increases extractable ALA synthase activity, inhibits incorporation of exogenous 59Feinto heme in vivo, and diminishes heme levels in Euglena, but has no effect on Chl formation within the first 6 h after administration.MATERIALS AND METHODS Cultures of Euglena gracilis Klebs strain Z Pringsheim and an aplastidic mutant derived from this strain, W14ZNa 1 L (23), were kindly provided by H. Lyman (State University of New York, Stony Brook, NY). Cells were grown at 23°C and 32 ltE m-2s-' of cool white and red fluorescent light in a glucose-based heterotrophic medium as previously described (6). Cell population densities were determined with a Coulter Counter (Model ZBI, Coulter Electronics). Chl was extracted into methanol and quantitated by spectrophotometry, using the absorption coefficients of MacKinney (19). ALA synthase was extracted and assayed by the methods previously reported (6), except that cells were disrupted by sonication for four periods using a Sonifier (Model W 185, Heat Systems-Ultrasonics), and ALA was measured by condensation with ethyl acetoacetate at pH 6.8 (18) followed by color development with Ehrlich Hg reagent (26). Spectrophotometry was performed on a Cary Model 219 instrument (Varian).Protoheme was extracted by slight modification of the method of Stillman and Gassman (25). All operations were carried out at ice temperature. Cells were extracted with three 5-ml portions of 90% acetone containing 10-2 M NH40H. These extracts were discarded. The cells were then extracted with 2 ml acetone containing 2% HCI. A second l-ml acetone-HCl extraction supernatant was added to the first, and then 2 ml peroxide-free diethyl ether were added to the combined acetone extracts. After mixing, 6 ml H20 were added, the solution was thoroughly mixed, and briefly centrifuged to separate the phases. The upper ether phase was removed and the lower phase was extracted with I ml ether. The combined heme-containing ether phases were backwashed once with 1 ml H20. After evaporation of the ether, protoheme was de...

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confidence: 99%

Induction of δ-Aminolevulinic Acid Synthase Activity and Inhibition of Heme Synthesis in Euglena gracilis by N-Methyl Mesoporphyrin IX

Beale

Foley²

1982

Plant Physiol.

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“…In photosynthetic bacteria and in some heme-forming systems, ALA synthetase is a site of regulation of the pathway, being subject to feedback inhibition and induction (5,12).…”

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The Biosynthesis of δ-Aminolevulinic Acid in Higher Plants

Beale¹,

Castelfranco²

1974

Plant Physiol.

119

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8-Aminolevulinic acid dehydrase activity in cucumber (Cucumis sativus L. var. Alpha green) cotyledons did not change as the tissue was allowed to green for 24 hours. 5-Aminolevulinic acid accumulated in greening cucumber cotyledons, and barley (Hordeum sativum L. var. Numar) and bean (Phaseolus vulgaris L. var. Red Kidney) leaves incubated in the presence of levulinic acid, a specific competitive inhibitor of 5-aminolevulinic acid dehydrase. The rate of 5-aminolevulinic acid accumulation in levulinic acid-treated cucumber cotyledons paralleled the rate of chlorophyll accumulation in the controls, and the quantitv of 5-aminolevulinic acid accumulated compensated for the decrease in chlorophyll accumulation. When levulinic acid-treated cucumber cotyledons were returned to darkness, 5-aminolevulinic acid accumulation ceased.8-Aminolevulinic acid accumulation showed an absolute requirement for oxygen and was inhibited drastically by cyanide and azide, and to a lesser extent by arsenite and malonate.2,4-Dinitrophenol, 3-(3,4.dichlorophenyl)-1, 1-dimethyl urea, sodium fluoroacetate, and hydroxylamine hydrochloride showed no effect under the conditions tested. Freezing and thawing of the tissue completely prevented the accumulation of 5-aminolevulinic acid.The findings of this investigation are consistent with the hypothesis that 5-aminolevulinic acid is a chlorophyll precursor in higher plants, and that chlorophyll biosynthesis is regulated at the level of the formation of 5-aminolevulinic acid.

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“…8-Aminolevulinic acid synthetase (ALAS) is the first and rate-limiting enzyme in the heme biosynthetic pathway (1), and Burnham and Lascelles have shown an inhibitory effect of hemin on this enzyme in the microorganism Rhodopseudomonas spheroides (2). Heady, Jacobs, and Deibel have demonstrated that the addition of hemin to cultures of Staphylococcus epidermidis inhibits the accumulation of coproporphyrin un-der conditions of impaired heme synthesis (3).…”

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confidence: 99%

The Inhibitory Effect of Heme on Heme Formation In Vivo: Possible Mechanism for the Regulation of Hemoglobin Synthesis*

Gallo¹

1967

J. Clin. Invest.

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Summary. 1) The effect of hemin on heme synthesis was studied in vivo. Heme synthesis was measured by determining red cell 59Fe uptake and glycine-2-14C incorporation into red cell hemin in normal CF1 female mice.2) Both bovine and human hemin significantly decreased red cell 59Fe uptake 48, 72, and 96 hours after hemin injection.3) Glycine-2-14C incorporation into red cell hemin was decreased to 50% of control values after the administration of hemin (90 Jumoles per kg).4) There was no significant difference between the plasma iron of mice injected with hemin and the values in control groups.5) Protoporphyrin decreased the inhibitory effect of hemin on red cell 59Fe uptake by 64%.6) There was no measurable effect of 8-aminolevulinic acid on hemin inhibition of red cell 59Fe uptake. 7) Data are presented to show that the effect of hemin is not by a dilution mechanism nor by a decrease in red cell maturation and subsequent release of reticulocytes into the peripheral blood. The findings are discussed in regard to the possible site of a negative feedback control of heme synthesis by heme.

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Control of Porphyrin Biosynthesis through a Negative-Feedback Mechanism. STUDIES WITH PREPARATIONS OF δ-AMINOLAEVULATE SYNTHETASE AND δ-AMINOLAEVULATE DEHYDRATASE FROM RHODOPSEUDOMONAS SPHEROIDES

Abstract: Succinyl-CoA was prepared by the method of Simon & Shemin (1953) and was used immediately. The values quoted for succinyl-CoA are based on the amount of CoA

Cited by 289 publications

References 25 publications

Induction of δ-Aminolevulinic Acid Synthase Activity and Inhibition of Heme Synthesis in Euglena gracilis by N-Methyl Mesoporphyrin IX

Induction of δ-Aminolevulinic Acid Synthase Activity and Inhibition of Heme Synthesis in Euglena gracilis by N-Methyl Mesoporphyrin IX

The Biosynthesis of δ-Aminolevulinic Acid in Higher Plants

The Inhibitory Effect of Heme on Heme Formation In Vivo: Possible Mechanism for the Regulation of Hemoglobin Synthesis*

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