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PubMed1972

The role of iron in the pathogenesis of porphyria cutanea tarda. An in vitro model.

Porphyria cutanea tarda (PCT) is characterized biochemically by excessive hepatic synthesis and urinary excretion of uroporphyrin I. Clinical evidence has implicated iron in the pathogenesis of PCT. The synthesis of the normally occurring isomer of uroporphyrin, namely uroporphyrin III, from porphobilinogen (PBG) requires two enzymes; uroporphyrinogen I synthetase and uroporphyrinogen III cosynthetase (COSYN). In the absence of COSYN only uroporphyrinogen I is formed. These experiments were designed to study the effect of iron on porphyrin biosynthesis in porcine and human crude liver extracts and to measure COSYN activity in the presence of iron.Mitochondria-free crude liver extracts were prepared in 0.25 m sucrose at pH 7.4 by centrifugation at 37,000 g. Preparations were incubated with either 0.2 mm amino-levulinic acid (ALA) or 0.1 mm PBG. The addition of ferrous ion (either from ferritin iron [4 mug/ml] and cysteine [6.7 mm] or ferrous ammonium sulfate [0.3 mm Fe] and cysteine) significantly increased the rate of uroporphyrin synthesis from either ALA or PBG. The predominant porphyrin synthesized in the presence of ferrous ion was uroporphyrin I whereas coproporphyrin III predominated in its absence. Orthophenanthroline blocked these effects of ferrous ion.To investigate the effect of ferrous ion on COSYN, crude liver extracts were incubated with ferrous ammonium sulfate (0.3 mm Fe) and cysteine (6.7 mm) and the COSYN activity of the incubates was assayed directly. In both porcine and human extracts ferrous ion caused marked inhibition of COSYN activity. Orthophenanthroline blocked the inhibitory effect.Inactivation of COSYN by heating resulted in marked enhancement of porphyrin synthesis from PBG. The sole product was uroporphyrin I.Thus, inactivation of COSYN results in accelerated synthesis of uroporphyrin I. This effect of ferrous ion provides a possible biochemical explanation for the excess production and excretion of uroporphyrin I in patients with PCT and the reversal of this defect by phlebotomy.

Ammonia-Lyases↗

PubMed1993

The Circadian Oscillator Coordinates the Synthesis of Apoproteins and Their Pigments during Chloroplast Development.

Greening has been studied at circadian times of maximal and minimal levels of mRNA for the light-harvesting chlorophyll a/b binding protein in photosystem II (Cab mRNA) after circadian synchronization of etiolated barley plantlets (Hordeum vulgare cv Apex) by heat-shock treatments. It was found that greening occurs faster and without a lag period when illumination was started at the time of maximal Cab mRNA accumulation. This holds true for the rate of accumulation of Cab and early light-inducible protein mRNAs, the levels of their correspondent proteins, and the levels of chlorophyll a and b. When illumination was started at the time of Cab mRNA minimum, a lag in the appearance of all components mentioned above was observed. Under these conditions, the lag in chlorophyll b accumulation was by far more pronounced than that found for chlorophyll a. The circadian oscillation in the capacity of chlorophyll synthesis appears to be controlled via [delta]-aminolevulinic acid ([delta]-ALA) synthesis. [delta]-ALA accumulation after levulinic acid treatment is itself under circadian control; the maxima in stationary concentrations coincide with those of Cab mRNA levels. The amounts of protochlorophyllide and photoconvertible protochlorophyllide showed only minor differences between circadian minima and maxima, the levels being slightly lower during the time of minimum.

Journal Article↗

PubMed2004

Photodynamic therapy for subungual Bowen's disease.

A 35-year-old police shooting instructor with a 4-year history of Bowen's disease of the nail bed on his right index finger confirmed histologically, was successfully treated with photodynamic therapy (PDT). Four cycles of PDT were used with two different photosensitizers: 20% 5-amino-levulinic acid oil in water emulsion and methyl amino-levulinate (Metvix) cream. The lesion was successfully treated with clinical and histological clearance. There was minimal loss of time from work, with neither functional nor cosmetic deficits.

Adult↗

PubMed1977

Induction of delta-Aminolevulinic Acid Formation in Etiolated Maize Leaves Controlled by Two Light Systems.

A short illumination of etiolated maize (Zea mays) leaves with red light causes a protochlorophyll(ide)-chlorophyll(ide) conversion and induces the synthesis of delta-aminolevulinic acid (ALA) during a subsequent dark period. In leaves treated with levulinic acid, more ALA is formed in the dark than in control leaves. Far red light does not cause a conversion of protochlorophyll(ide) into chlorophyll(ide) and does not induce accumulation of ALA in the dark. Both red and far red preilluminations cause a significant potentiation of ALA synthesis during a period of white light subsequent to the dark period. The results indicate a dual light control of ALA formation. The possible role of phytochrome and protochlorophyllide as photoreceptors in this control system is discussed.

Journal Article↗

PubMed1999

[Interaction of 3'-fluoro-3'-deoxyanalogs of a trimer of (2'-5')oligoadenylic acid with (2'-5')A3-antibodies: stereochemical aspect].

Mouse antibodies to (2'-5')oligoadenylates were obtained by the immunization of animals with the (2'-5')oligoadenylic acid trimer conjugated with bovine serum albumin through a 2',3'-levulinic acid residue. Using radioimmunoassay, the reactivity of mouse polyclonal antibodies to the (2'-5')oligoadenylic acid trimer was studied for the trimer analogues containing 9-(3-deoxy-3-fluro-beta-D- xylofuranosyl)adenine and 3'-deoxy-3'-fluoro-adenosine in various positions of the chain. It was found that (a) the three-dimensional structure of short oligonucleotides is an important factor in the antibody recognition; (b) antibodies are more sensitive to modifications of the 5'-terminal and central ribose fragments of the (2'-5')oligoadenylic acid trimer; (c) the 3'-hydroxyl group plays a secondary role in the formation of the antigen determinant.

Adenine Nucleotides↗

PubMedDate not supplied

Comparison of aminolevulinic-acid-induced fluorescence from normal and inflamed gingiva in the canine model.

Fluorescence spectroscopic detection using 5-amino levulinic acid (ALA) may provide an effective, noninvasive approach for early detection of oral cancer. In the present study, the use of ALA-induced fluorescence ratio (red/orange) to differentiate between normal and gingivitis-affected gingiva is investigated. Five dogs with varying degrees of gingivitis are studied. Based on previous studies, a dose of 25 mg/kg of ALA is administered intravenously to the dogs. Autofluorescence and ALA-induced fluorescence from three sites: normal gingiva, pigmented gingiva, and gingivitis, are detected with a fiber optic probe coupled to an optical multichannel analyzer. Four dogs show higher and earlier ALA-induced fluorescence from the gingivitis site as compared to the unpigmented gingiva. In two dogs, ALA-induced fluorescence peaks are seen 15 min after ALA administration. Statistical analysis using mean separation procedures reveal differences in the fluorescence from the various sites in each dog. Using a fluorescence (ratio) cutoff of 1.5, the sensitivity and specificity are found to be 92 and 80%, respectively, 1 h after administration of ALA. The indications from this study-that the characteristic protoporphyrin IX (PpIX) fluorescence is seen earlier and in higher magnitude in more vascular areas of the oral cavity-has implications for oral cancer diagnosis.

Algorithms↗

PubMed1984

In vivo study on lead and alcohol interaction and the inhibition of erythrocyte delta-aminolevulinic acid dehydratase in man.

The effect on alcohol (EtOH) consumption on the inhibition of erythrocyte delta-amino-levulinic acid dehydratase (ALAD) was investigated in 13 male lead workers and 7 "normal" male subjects. Lead and zinc protoporphyrin in blood and lead, delta-aminolevulinic acid, porphobilinogen and coproporphyrin in 24-h urine specimens were also determined. During 1 h the subjects drank 122.8 (SD 18.65) ml of an almost lead-free brandy, ie, a dose of 11.07 mmol/kg of body weight. This dose resulted in a trend toward a parallel decrease in ALAD activity and an increase in lead in blood (PbB), both of which approached the prealcohol value 24 h after the initial alcohol ingestion. A trend toward increased lead excretion in urine (PbU) was observed on the day of alcohol ingestion, as compared to the preceding and succeeding 24-h urine specimens. However, the observed increase in PbB and PbU cannot be attributed to the small amount of lead ingested through the brandy, ie, 7.09 (SD 1.06) nmol. The characteristic dose-effect relationship between PbB and ALAD (examined prior to and 1, 3, 5, and 24 h after the initial alcohol ingestion) reached the highest correlation coefficient 3 h after the initial alcohol ingestion (p less than 0.001). The data obtained appear to support the hypothesis of a possible role for the body lead pool and the lead-mediated influence of alcohol consumption on ALAD activity in man.

Dose-Response Relationship, Drug↗

PubMed1983

Control of the formation of bacteriochlorophyll, and B875- and B850-bacteriochlorophyll complexes in Rhodopseudomonas sphaeroides mutant strain H5.

Rhodopseudomonas sphaeroides mutant H5 lacking 5-aminolevulinic acid synthase was employed to study the control of the formation of total bacteriochlorophyll as well as of the B875- and B850-bacteriochlorophyll protein complexes. The organisms were grown phototrophically in a chemostat where cell protein formation was limited by iron ions and bacteriochlorophyll by 5-aminolevulinic acid. 0.07 mol of bacteriochlorophyll was formed per mol of 5-amino-levulinic acid consumed. This stoichiometric relationship was not influenced by a twelve-fold variation in light energy flux. However, cell protein levels increased and, consequently, cellular specific bacteriochlorophyll contents decreased with increases in light energy flux. The ratio of B875- to B850-pigment protein complexes was inversely proportional to the velocity of 5-aminolevulinic acid supply (mol per cell protein and time) which in this system equals the velocity of 5-aminolevulinic acid consumption and the velocity of bacteriochlorophyll formation. Light had no direct effect on the ratio of B875- per B850-pigment complexes but an indirect effect via its control of protein formation. Changes in the ratio of the two pigment complexes resulted from the fact that significantly lower amounts of 5-aminolevulinic acid supplied per protein and time were required to saturate the system assembling the B875-complexes than that assembling the B850-complexes. The data suggest lack of light-dependent control in the formation of bacteriochlorophyll and its complexes subsequent to the 5-aminolevulinic acid pool.

Aminolevulinic Acid↗

PubMed1994

Inhibition of porphobilinogenase by porphyrins in Saccharomyces cerevisiae.

The biosynthesis of uroporphyrinogen III, the precursor of hemes, chlorophylls, corrins and related structures, is catalyzed by the porphobilinogenase system (PBGase), a complex of two enzymes, PBG-Deaminase (PBG-D) and Isomerase. Although the separate enzymes have been studied in some detail less work has been performed on the properties of the complex. In this study the kinetic behaviour of the enzyme PBGase in a normal yeast strain, D273-10B, and its derivative B231 has been investigated. Uroporphyrinogen formation was linear with time up to 2 hr at 37 degrees C. The enzyme complex shows classical Michaelis-Menten kinetics. From the double reciprocal plots kinetic parameters were estimated for PBGase and PBG-D. Porphyrins were found to be competitive inhibitors with respect to porphobilinogen (PBG) and these compounds appeared to act as inhibitors by forming dead-end complexes with the free enzyme. 5-Aminolevulinic acid (ALA) also inhibited PBGase and this inhibition was overcome by addition of levulinic acid (2 microM). These results indicate that ALA, is not an inhibitor but acts through its conversion into porphyrins which are the true inhibitors.

Aminolevulinic Acid↗

PubMed2000

Rapid method for determining the rate of DNA synthesis and cellular proliferation.

A new method has been developed for determination of DNA synthesis during cell proliferation. The method is based on the metabolism of [U-(13)C(6)]glucose to deoxyribose (DR) and then incorporation of [U-(13)C(5)]DR into newly synthesized DNA. Extracted cellular DNA is subjected to HCl hydrolysis (2 h at 100 degrees C), which converts DR into levulinic acid. The (13)C enrichment in DR is determined in the trimethylsilyl derivative of levulinate using gas chromatography-mass spectrometry. The method is rapid and sensitive. It can precisely determine (13)C enrichment below 1 at.% excess in as little as 4 ng DNA. We have used this method to determine the rate of cell proliferation in vitro and the level of DR in a given amount of DNA. The current approach has significant advantages over previously described methods and overcomes several difficulties related to the determination of DNA synthesis both in vivo and in vitro.

Biological Assay↗

PubMed1984

[N-aryl pyrrol derivatives with analgesic and anti-inflammatory activity. 1. 1-Arylpyrroles substituted at positions 4 and 5].

The derivatives in question are prepared by reaction of substituted anilines with 1,4-ketones in an acidic medium. The diketones are themselves obtained either using Friedel and Crafts reaction with levulinic acid chloride, or by Stetter's method reacting Mannich bases with aryl aldehydes in the presence of sodium cyanide. The results of test of acute toxicity and of analgesic and anti-inflammatory activity are reported.

Analgesics↗

PubMed1990

An acute form of tyrosinemia type I with multiple intrahepatic mass lesions.

The acute form of tyrosinemia type I usually causes severe hepatocellular dysfunction. We report a 4-month-old infant with hepatosplenomegaly, ascites, and multiple intrahepatic mass lesions mimicking hepatoma. A marked increase of serum alpha-fetoprotein (97.6 micrograms/ml) and multiple small low-density lesions in the liver demonstrated by computed tomography suggested the presence of hepatoma. The liver specimens obtained at laparatomy showed mixed nodular cirrhosis with fatty metamorphosis. Serum levels of tyrosine (6.6 mg/100 ml) and methionine (5.9 mg/100 ml) were increased. Urinary organic acid analyses disclosed increased excretions of succinylacetone (1,330 mg/g creatinine) and delta-amino-levulinic acid (113.6 mg/g creatinine). Histological abnormalities and biochemical evidences led to the correct diagnosis. This case emphasizes the need for complete investigations of puzzling cases and warns against undue reliance on noninvasive imaging techniques.

Amino Acid Metabolism, Inborn Errors↗

PubMed1994

Cloning and characterization of the hemA gene for synthesis of delta-aminolevulinic acid in Xanthomonas campestris pv. phaseoli.

The gene from Xanthomonas campestris pv. phaseoli that is involved in the C5 pathway of delta-amino-levulinic acid (ALA) of Escherichia coli. Subcloning of deletion fragments from the initial 2.5-kilobase (kb) chromosomal fragment allowed the isolation of a 1.6-kb fragment that could complement the hemM mutation. Nucleotide sequence analysis of the 1.6-kb DNA fragment revealed an open reading frame that encodes a polypeptide of 426 amino acid residues, and the deduced molecular mass of this polypeptide is 46768 Da. The amino acid sequence shows a high degree of homology of the HemA protein, which is glutamyl-tRNA reductase, to other organisms. Thus, we examined the complementation test of the cloned gene from Xanthomonas with a hemA mutation of E. coli and found that the gene complemented the hemA mutation. These results suggest that the cloned gene is hemA and the gene from Xanthomonas also complements both hemA and hemM mutations, as in the case of the E. coli hemA.

Aldehyde Oxidoreductases↗

PubMed1978

Two Biosynthetic Pathways to delta-Aminolevulinic Acid in a Pigment Mutant of the Green Alga, Scenedesmus obliquus.

Pigment mutant C-2A' of the unicellular green alga Scenedesmus obliquus develops only traces of chlorophyll and has no detectable amount of delta-aminolevulinic acid (ALA) when grown in the dark. In light it develops ALA and in the presence of levulinic acid (LA), a competitive inhibitor of ALA dehydratase, it accumulates 0.18 mmoles of ALA per 10 microliters of packed cell volume per 12 hours. This amount could be increased up to 15 times by feeding precursors and cofactors.Incubation with [U-(14)C]glutamate, [1-(14)C]glutamate, and [2-(14)C]glycine yielded significantly labeled ALA, whereas [1-(14)C]glycine did not label the ALA specifically. Thus, two pathways using either glycine/succinyl-coenzyme A or incorporating the whole C-5-skeleton of glutamate into ALA are present in this alga. The efficiency of the glycine/succinyl-coenzyme A pathway seems to be three times higher than that of the glutamate pathway. Incubation with [5-(14)C]2-ketoglutarate, which can serve both pathways as a precursor, resulted in radioactivity of ALA as high as the sum of both labeling with [1-(14)C]glutamate and [2-(14)C]glycine.Since the newly synthesized chlorophyll was radioactive regardless of labeled substrate employed, both pathways culminate in chlorophyll formation.

Journal Article↗

PubMed1980

Biosynthesis of delta-Aminolevulinic Acid from Glutamate in Agmenellum quadruplicatum.

delta-Aminolevulinic acid accumulated in the culture medium when Agmenellum quadruplicatum strain PR-6 was incubated in the presence of levulinic acid, a competitive inhibitor of delta-aminolevulinic acid dehydratase, and specifically labeled glutamate and glycine. The delta-aminolevulinic acid was purified using Dowex 50W-X8 and cleaved by periodate to yield succinic acid and formaldehyde. The distribution of radioactivity in the two fragments suggested that in blue-green algae the carbon skeleton of delta-aminolevulinic acid is derived directly from glutamate. However the possibility of the pathway of delta-aminolevulinic acid synthesis, from glycine and succinyl-coenzyme A also functioning in blue-green algae was not eliminated as uptake of glycine was minimal.

Journal Article↗

PubMed2000

Effect of singlet oxygen generating substances on the ascorbic acid and glutathione content in pea leaves.

Ascorbate and glutathione levels were investigated in pea leaf discs exposed to various singlet oxygen generating compounds: eosin, rose bengal, monuron, acifluorfen and 5-amino-levulinic acid (ALA). The cellular level of the major antioxidant ascorbate was markedly decreased by the herbicides monuron, acifluorfen and ALA (in light-dependent reactions), as well as by the xanthene dyes eosin and rose bengal (independently of light). No significant accumulation of dehydroascorbate could be observed in any treatments. In contrast to ascorbate, the foliar glutathione levels were considerably increased by subtoxic or slightly toxic concentrations of eosin, rose bengal, acifluorfen and ALA in a light-dependent manner. Monuron treatments led to unchanged or decreasing glutathione contents. The activities of three antioxidative enzymes (ascorbate peroxidase, glutathione reductase and glutathione S-transferase) were also induced by eosin in light-dependent reactions.

Journal Article↗

PubMed1999

Retinoic acid in association with tin-metalloporphyrins influences heme metabolism in vivo in rats.

In the current study we report the perturbation of key enzymes of the heme metabolic pathway, i.e. delta-amino levulinic acid synthase, heme oxygenase and biliverdin reductase, in vivo by administration of retinoic acid (RA) and retinoic acid in association with tin-metalloporphyrins, viz., tin-protoporphyrin (SnPP) and tin-mesoporphyrin (SnMP) in the liver, spleen, heart and lung of rats. RA at a dosing regimen of 50,000 I.U. stimulated splenic ALA-S activity, whereas co-administration of tin-metalloporphyrins with RA antagonised the RA mediated induction of ALA-S. In the other tissues viz., liver, heart and lung our results showed a diminution of ALA-S activity on RA administration, the level of repression was further attenuated when tin-metalloporphyrins were co-administered with RA. This marked suppression of ALA-S brought forth by concurrent administration of RA and tin-metalloporphyrins is suggestive of the beneficial effect of this formulation in acute attacks of porphyria, similar to heme. Furthermore, our results emphasize that the combined dosing of RA with tin-metalloporphyrins leads to a substantial decline in bilirubin levels due to a profound inhibition of HMOX in the probed tissues. The features of the combined action of RA and tin-metalloporphyrins in vivo lead to a substantial suppression of formation of the potentially toxic metabolite bilirubin, and the enhancement of disposal of the untransformed substrate (heme) of the enzyme that is inhibited. These results define some of the characteristics of a therapeutically useful formulation and represent a new therapeutic approach for the amelioration and management of hyperbilirubinemia.

5-Aminolevulinate Synthetase↗

PubMed1974

Induction of porphyrin synthesis in etiolated bean leaves by chelators of iron.

Primary leaves of 7- to 9-day-old etiolated seedlings of Phaseolus vulgaris L. var. Red Kidney infiltrated in darkness with aqueous solutions of alpha, alpha'-dipyridyl, o-phenanthroline, pyridine-2-aldoxime, pyridine-2-aldehyde, 8-hydroxyquinoline, or picolinic acid synthesize large amounts of magnesium protoporphyrin monomethyl ester and lesser amounts of magnesium protoporphyrin, protoporphyrin, and protochlorophyllide. Pigment formation proceeds in a linear manner for up to 21 hours after vacuum infiltration with 10 mm alpha, alpha'-dipyridyl. Etiolated tissues of Zea mays L., Cucumis sativus L., and Pisum sativum L. respond in the same way to dipyridyl treatment. Compounds active in eliciting this response are aromatic heterocyclic nitrogenous bases which also act as bidentate chelators and form extremely stable complexes with iron; other metal ion chelators, such as ethylenediaminetetraacetic acid, salicylaldoxime, and sodium diethyldithiocarbamate, do not elicit any pigment synthesis. The ferrous, ferric, cobaltous, and zinc chelates of alpha, alpha'-dipyridyl are similarly ineffective. If levulinic acid is supplied to etiolated bean leaves together with alpha, alpha'-dipyridyl, porphyrin production is inhibited and delta-aminolevulinic acid accumulates in the tissue. Synthesis of porphyrins proceeds in the presence of 450 micrograms per milliliter chloramphenicol or 50 micrograms per milliliter cycloheximide with only partial diminution. We propose that heme or an iron-protein complex blocks the action of the enzyme(s) governing the synthesis of delta-aminolevulinic acid in etiolated leaves in the dark and that iron chelators antagonize this inhibition, leading to the biosynthesis of delta-aminolevulinic acid and porphyrins.

Journal Article↗