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At least 1,135 records · Page 63Linked to original sources
PubMed1972

Delta-aminolaevulinate dehydratase, the regulatory enzyme of the haem-biosynthetic pathway in Neurospora crassa.

The activity of delta-aminolaevulinate dehydratase is very low in the mould Neurospora crassa compared with the activities detected in bacterial and animal systems. The enzyme is inducible in iron-deficient cultures by addition of iron and is repressed by protoporphyrin. The properties of the purified enzyme indicate its allosteric nature and susceptibility to feedback inhibition by coproporphyrinogen III. Neurospora extracts also contain a protein inhibitor of the enzyme and a small-molecule activator, which appears to be associated with the enzyme. The regulatory function of this enzyme in vivo is correlated with the accumulation of delta-aminolaevulinic acid in normal cultures of N. crassa. The decay curve of the iron-induced enzyme in vivo shows a biphasic pattern, with one of the components showing a half-life of 4-5 min.

Adenosine Diphosphate↗
PubMed1974

Biochemical and toxicological response of infant baboons to lead driers in paint.

In an effort to define the toxicology and disposition of lead compounds that presently exist in paint (i.e., organic driers), a controlled dose feeding study was initiated early this year with the use of 28 infant baboons as experimental animals. The infant baboon, established as a metabolic model for a child ingesting lead, will be used to determine the adequacy of present as well as recently recommended limitations for lead in paint to assure protection from this potential source of lead exposure. To accomplish this goal, research has been designed to determine basic dose-response relationships in animals ingesting constant daily doses of a dried paint, a lead octoate drier, and lead acetate. Doses for these compounds have been chosen to cover a broad range of concentrations including that recommended by the American Academy of Pediatrics from the maximum daily permissible lead ingestion, and associated estimates of paint intake by children with pica. PARAMETERS OF METABOLIC RESPONSE FOR EACH LEAD COMPOUND, INCLUDE: general clinical surveillance, lead concentrations in blood, urine and feces, erythrocytic delta-aminolevulinic acid dehydratase and free erythrocytic porphyrin. The response of several of these measures of lead exposure as a function of time will be discussed for each compound at the several dose levels administered.

Administration, Oral↗
PubMed1980

The effect of delta-aminolevulinic acid on the synthesis and metabolism of GABA in rabbit brain homogenates.

The porphyrin precursor delta-aminolevulinic acid (delta-ALA) is a structural analogue of the putative amino acid neurotransmitter, gamma-aminobutyric acid (GABA). This study has demonstrated that delta-ALA has no effect on glutamate decarboxylase activity and only a small inhibitory effect of GABA aminotransferase activity. This would suggest that if accumulation of delta-ALA is related to development of the acute attack of porphyria, it is not via an effect on GABA synthesis and metabolism.

Animals↗
PubMed1969

The synthesis and turnover of rat liver peroxisomes. II. Turnover of peroxisome proteins.

After preliminary experiments had established that the injection of Triton WR-1339 necessary for the separation of lysosomes and peroxisomes did not affect the turnover rate of catalase, the decay of (3)H-leucine incorporated into peroxisomes was studied in whole particles and in protein subfractions. It was shown that peroxisomes are destroyed in a completely random way, probably as wholes since the apparent half-life was the same for all subfractions, about 3(1/2) days. In agreement with the results of Price et al. (11), the half-life of catalase derived from the rate of recovery from aminotriazole inhibition was about 11(1/2) days, as was the apparent half-life of the heme prosthetic groups measured with (14)C-alpha-aminolevulinic acid. Guanidino-labeled arginine gave an apparent half-life of 2(1/2) days with large statistical uncertainty. Either the leucine label was reutilized very extensively in our animals and the true half-life of peroxisomes is 1(1/2) days, or the prosthetic groups of catalase turn over more rapidly than the protein part of the molecule.

Animals↗
PubMed1971

Chemically induced porphyria: increased microsomal heme turnover after treatment with allylisopropylacetamide.

Excessive induction of delta-aminolevulinic acid synthetase in rats after treatment with porphyria-inducing chemicals, such as allylisopropylacetamide, is accompanied by a decrease in microsomal heme and cytochrome P450 concentrations. Measurement of the radioactive decay after labeling of the heme moiety of submicrosomal particles shows increased breakdown of heme in rats treated with allylisopropylacetamide. The effects of allylisopropylacetamide on heme synthesis and heme turnover may be interrelated

Acetates↗
PubMed1974

Topology and growth of the intracytoplasmic membrane system of Rhodopseudomonas spheroides: protein, chlorophyll, and phospholipid insertion into steady-state anaerobic cells.

An equilibrium density gradient centrifugation study involving the separation of "old" and "new" membranes has been developed to determine the manner in which protein, lipid, and chlorophyll are incorporated into growing intracytoplasmic membranes (chromatophores) of Rhodopseudomonas spheroides. Chromatophores derived from cells grown in an H(2)O-medium had a density of 1.175 to 1.180 g/cm(3) and were readily separable from chromatophores having a density of 1.220 to 1.230 isolated from cells grown in a 70% D(2)O-medium. After a shift from "D(2)O-" to "H(2)O"-based media, only hybrid chromatophores derived from a combination of "heavy" (old) and "light" (new) chromatophore material could be detected. The experimentally determined, median density values for the growing intracytoplasmic membrane system followed a theoretically determined profile which was calculated from the density of full "heavy" and full "light" material assuming random, homogeneous incorporation of new material into old membrane. The distribution of the radioactive labels for protein (leucine) and chlorophyll (delta-aminolevulinic acid) were identical and showed a reproducible displacement of the "old" material to the heavy side of the optical density at 365 nm (OD(365)) absorbance and a displacement of the "new" material to the light side of the OD(365) absorbance profile. Specific phospholipid growth showed no displacement for either the "old" or "new" material from the median absorbance profile.

Acetates↗
PubMed1993

Lead exposure among nursery children in Chorzów.

The main goal of this study was to determine the level of exposure to lead of selected representatives of the child population attending nursery school, aged 2 to 4 years, residing in three districts of Chorzów with different traffic intensities. The numbers of tested samples of children were 41, 43, 40. The tests were made in summer. Lead (Pb-B), zinc protoporphyrin level (ZPP), hemoglobin (Hb), erythrocyte count in blood (E), and delta-aminolevulinic acid (ALA) and creatinine concentration in urine were determined. The highest Pb-B level observed was 300 micrograms/l; the geometric means of the blood lead concentrations were 131, 132 and 119 micrograms/l and were not statistically different. Median ranges were 118, 133 and 114 micrograms/l. Ranges above the 200 micrograms/l level were found in 19.5%, 11.8% and 15% of the children. The obtained data suggest higher lead absorption in the examined child population.

Child, Preschool↗
PubMed1973

The reconstitution of oxidase activity in membranes derived from a 5-aminolaevulinic acid-requiring mutant of Escherichia coli.

1. The reconstitution of oxidase activity in cell-free extracts of a mutant of Escherichia coli K12Ymel, that require 5-aminolaevulinic acid for growth on non-fermentable carbon sources, is described. 2. The reconstitution is dependent on haematin or a haem extract from a prototrophic strain of E. coli, and the product of the reaction has been identified as NADH-reducible cytochrome b. 3. The requirement for haematin cannot be replaced by four other porphyrins. Coproporphyrin III does not inhibit the haematin-dependent reconstitution, mesoporphyrin IX and protoporphyrin IX apparently compete with haematin for a binding site on the cytochrome apoprotein(s) and deuteroporphyrin IX binds to cytochrome apoprotein(s) and cannot be subsequently replaced by haematin. 4. The properties of electron-transport particles from cell-free extracts of the mutant strain, grown aerobically in the presence or absence of 5-aminolaevulinic acid, are described. In the absence of 5-aminolaevulinic acid no detectable cytochromes are produced, and oxidase activities are lowered but there is no apparent effect on the activities of the NADH dehydrogenase and d-lactate dehydrogenase. 5. The reconstitution of oxidase activity by electron-transport particles from cells grown in the absence of 5-aminolaevulinic acid requires ATP and haematin, and the product of the reaction was identified as NADH-reducible cytochrome b. 6. It is concluded that the cytochrome apoproteins are synthesized and incorporated into the cytoplasmic membrane of E. coli in the absence of haem synthesis. The subsequent reconstitution of functional cytochrome(s) requires protohaem, but the nature of the side chain on the 2 and 4 positions of the porphyrin appears to be important.

Adenosine Triphosphate↗
PubMed1988

Possible control of transcript levels by chlorophyll precursors in Chlamydomonas.

Steady-state mRNA levels of the three nuclear genes cab1, rbcS1 and rbcS2 (coding for the light-harvesting chlorophyll-binding protein (LHCP) and the small subunit of ribulose 1,5-bisphosphate carboxylase, respectively) and of the two plastid-encoded genes rbcL and psaA2 (coding for the large subunit of the carboxylase and a member of the P700 chlorophyll a protein, respectively) have been investigated in synchronized Chlamydomonas cells in response to light and inhibitors interfering with chlorophyll synthesis. The accumulation of cab1, rbcS1 and psaA2 transcripts is light-dependent, whereas transcripts from rbcS2 and rbcL genes are present in high amounts in the light and in the dark. Dioxoheptanoic acid, an inhibitor blocking chlorophyll synthesis prior to porphyrin formation, does not affect the accumulation of all five mRNAs. However, inhibition of chlorophyll synthesis by incubating cells with dipyridyl, cycloheximide or nitrogen promotes the accumulation of porphyrin compounds, but specifically prevents the accumulation of light-dependent transcripts. Although functionally unrelated, these inhibitors are known to block an Fe-dependent oxygenase, which is involved in the formation of the isocyclic ring in the chlorophyll molecule. The data are explained as a control by chlorophyll precursors over the accumulation of light-dependent transcripts.

2,2'-Dipyridyl↗
PubMed1981

An alternative pathway for the biosynthesis of isoprenoid compounds in bacteria.

The pattern of incorporation of radioactivity from [1-14C]acetate and [2-14C]acetate into the polyprenyl side-chain of ubiquinones in bacteria (Azotobacter vinelandii, Pseudomonas sesami, Escherichia coli and Rhodopseudomonas capsulata) was studied. For this purpose, a new degradation method involving a modified Barbier-Wieland reaction of laevulinic acid was developed, and used along with the iodoform reaction. Both C-1 and C-2 of acetate were incorporated exclusively into C-2 of laevulinic acid suggesting that the well-known pathway through acetoacetyl-CoA ('acetoacetate pathway') was not operative in these bacteria. An alternative pathway ('acetolactate pathway'), starting with pyruvate and acetaldehyde as the distal precursors, and utilizing the reactions of leucine and valine metabolism, was postulated. It was also postulated that C-1 of acetate is incorporated not directly, but after oxidation to CO2. The pattern of incorporation of radioactivity from [U-14C]valine, [U-14C]alanine and NaH14CO3 into the side-chain of ubiquinone of R. capsulata was in agreement with the operation of the 'acetolactate pathway'.

Acetates↗
PubMed2000

[Prototype of light source for photodynamic therapy in Centre of Electron Microscopy].

The Photodynamic Therapy (PDT) is a cancer treatment based on specific accumulation of a photosensitizer in the malignant tissue and its subsequent irradiation at appropriate wave lengths induce the production of oxygen singlets responsible for peroxidation of cell organelles and cell death. A prototype of a 630 nm non coherent light source designed and constructed at the Centre of Electron Microscopy of The Cordoba National University allowed a successful application of PDT, in nonmelanoma skin tumors, for the first time in this Country. A topical treatment with 20% delta aminolevulinic acid (ALA) in aqueous solution was applied in 100 lesions of actinic keratosis of 27 patients. The results obtained in this study were the following: Complete Remission (RC) 84%, Partial Remission (RP) 10%, No Response (SR) 0% and No data (SD) 6%. In the latter group are included those patients who did not return for reevaluation. The high efficiency plus the excellent cosmetic response and low aggressiveness, make the PDT the method of choice treatment of this skin pathology. In addition to be no invasive and well tolerated, the prototype of light source used in this study, was remarkably effective.

Aged↗
PubMed2005

Isolevuglandins, oxidatively truncated phospholipids, and atherosclerosis.

Isolevuglandins (isoLGs) and oxidatively truncated phospholipids are products of lipid peroxidation. Some of these, especially isoLGs and gamma-hydroxyalkenal analogues (e.g., the 5-hydroxy-8-oxo-6-octenoic acid and 9-hydroxy-12-oxo-10-dodecenoic acid esters of 2-lysophosphatidylcholine, HOOA-PC or HODA-PC, respectively) of 4-hydroxy-2(E)-nonenal (HNE), damage proteins by covalent adduction, thereby interfering with their normal functions. These lipid-derived protein modifications may serve as dosimeters of oxidative injury. Elevated plasma levels of isoLG-protein epitopes are associated with atherosclerosis but are independent of total cholesterol, a classical risk factor. Both protein adducts and oxidatively truncated phospholipids (oxPL) can also elicit receptor-mediated cellular responses that include endocytosis of oxidized low-density lipoprotein (LDL) and expression of chemokines, which may foster infiltration of monocyte macrophages into the subendothelial space, where they become foam cells through unregulated endocytosis of oxidatively damaged LDL.

Arteriosclerosis↗
PubMed2004

The X-ray structure of the plant like 5-aminolaevulinic acid dehydratase from Chlorobium vibrioforme complexed with the inhibitor laevulinic acid at 2.6 A resolution.

5-Aminolaevulinic acid dehydratase (ALAD), an early enzyme of the tetrapyrrole biosynthesis pathway, catalyses the dimerisation of 5-aminolaevulinic acid to form the pyrrole, porphobilinogen. ALAD from Chlorobium vibrioforme is shown to form a homo-octameric structure with 422 symmetry in which each subunit adopts a TIM-barrel fold with a 30 residue N-terminal arm extension. Pairs of monomers associate with their arms wrapped around each other. Four of these dimers interact principally via their arm regions to form octamers in which each active site is located on the surface. The active site contains two invariant lysine residues (200 and 253), one of which (Lys253) forms a Schiff base link with the bound substrate analogue, laevulinic acid. The carboxyl group of the laevulinic acid forms hydrogen bonds with the side-chains of Ser279 and Tyr318. The structure was examined to determine the location of the putative active-site magnesium ion, however, no evidence for the metal ion was found in the electron density map. This is in agreement with previous kinetic studies that have shown that magnesium stimulates but is not required for activity. A different site close to the active site flap, in which a putative magnesium ion is coordinated by a glutamate carboxyl and five solvent molecules may account for the stimulatory properties of magnesium ions on the enzyme.

Allosteric Site↗
PubMed1969

Effect of oxygen on heme and porphyrin accumulation from delta-aminolevulinic acid by suspensions of anaerobically grown Staphylococcus epidermidis.

The effect of various conditions on the accumulation of porphyrins and heme by resting suspensions of anaerobically grown cells of Staphylococcus epidermidis was examined. Anaerobically grown cells contain 10 to 15% of the amount of protoheme found in cells grown aerobically. Resting suspensions of anaerobically grown cells, when incubated aerobically in buffer with delta-aminolevulinic acid and glucose for 60 min, exhibited a fourfold increase in protoheme content. At high levels of delta-aminolevulinic acid, there was also a significant accumulation of porphyrins with the solubility and chromatographic properties of coproporphyrin and uroporphyrin. Protoporphyrin was not accumulated. When oxygen was excluded from the incubation mixture, accumulation of protoheme was prevented, but accumulation of coproporphyrin and total porphyrin was enhanced. Nitrate served as an electon acceptor as indicated by its reduction to nitrite; however, nitrate did not substitute for oxygen in causing the accumulation of protoheme. These results suggested that oxygen is required for one of the late steps of heme synthesis in S. epidermidis, possibly for the conversion of coproporphyrinogen to protoporphyrin. The inability of nitrate to substitute for oxygen suggests a role for molecular oxygen as a substrate rather than as an electron acceptor for heme synthesis.

Chromatography, Thin Layer↗
PubMed1999

Ornithine and glutamate decarboxylases catalyse an oxidative deamination of their alpha-methyl substrates.

Ornithine decarboxylase (ODC) from Lactobacillus 30a catalyses the cleavage of alpha-methylornithine into ammonia and 2-methyl-1-pyrroline; glutamate decarboxylase (GAD) from Escherichia coli catalyses the cleavage of alpha-methylglutamate into ammonia and laevulinic acid. In our analyses, 2-methyl-1-pyrroline and laevulinic acid were identified by HPLC and mass spectroscopic analysis, and ammonia was identified by means of glutamate dehydrogenase. Molecular oxygen was consumed during these reactions in a 1:2 molar ratio with respect to the products. The catalytic efficiencies (k(cat)/K(m)) of the reactions catalysed by ODC and GAD were determined as 12500 and 9163 M(-1).min(-1) respectively. When the reactions were performed under anaerobic conditions, no ammonia, 2-methyl-1-pyrroline or laevulinic acid was produced to a significant extent. The formation of ammonia and O(2) consumption (in a 1:2 molar ratio with respect to ammonia) were also detected during the reaction of ODC and GAD with putrescine and gamma-aminobutyrate respectively. Taken together, these findings clearly indicate that ODC and GAD catalyse an oxidative deamination of their decarboxylation products, a reaction similar to that catalysed by dopa decarboxylase (DDC) with alpha-methyldopa [Bertoldi, Dominici, Moore, Maras and Borri Voltattorni (1998) Biochemistry 37, 6552-6561]. Furthermore, this reaction was accompanied by a decarboxylation-dependent transamination occurring for GAD, DDC and ODC with a frequency of approx. 0.24%, 1% and 9% respectively compared with that of oxidative deamination.

Ammonia↗
PubMed1979

[Methodological hints on the gas chromatographic determination of kelevan and kepone in potatoes, potato foliage and soil].

The gas chromatographic determination of Kelevan, an ethyllaevulinic acid derivative of Kepone, requires its conversion to Kepone. Thermal decomposition in the injection block of the gas chromatograph at 45 degrees C. has proved to be well suited for routine work. The sample is extracted with acetonitrile; the extract is purified and concentrated under reduced pressure. The separation of Kelevan from Kepone already metabolically produced is possible by column chromatography (silica gel; elution with benzene and 5% acetone in benzene). The determination of pre-existent Kepone and of Kelevan (after thermal conversion to Kepone) was achieved by means of a Pye-Unicam gas chromatograph. The limits of detection are 0.002 p.p.m. for Kepone, and 0.003 p.p.m. for Kelevan. The recovery of Kelevan and Kepone added to control samples (for every 10 determinations with different amounts added to potatoes, potato foliage and soil samples) ranges from 63 to 88%; the standard derivation, from +/- 1.7 to 7.3%.

Chlordecone↗
PubMed1999

The Schiff base complex of yeast 5-aminolaevulinic acid dehydratase with laevulinic acid.

The X-ray structure of the complex formed between yeast 5-aminolaevulinic acid dehydratase (ALAD) and the inhibitor laevulinic acid has been determined at 2.15 A resolution. The inhibitor binds by forming a Schiff base link with one of the two invariant lysines at the catalytic center: Lys263. It is known that this lysine forms a Schiff base link with substrate bound at the enzyme's so-called P-site. The carboxyl group of laevulinic acid makes hydrogen bonds with the side-chain-OH groups of Tyr329 and Ser290, as well as with the main-chain >NH group of Ser290. The aliphatic moiety of the inhibitor makes hydrophobic interactions with surrounding aromatic residues in the protein including Phe219, which resides in the flap covering the active site. Our analysis strongly suggests that the same interactions will be made by P-side substrate and also indicates that the substrate that binds at the enzyme's A-site will interact with the enzyme's zinc ion bound by three cysteines (133, 135, and 143). Inhibitor binding caused a substantial ordering of the active site flap (residues 217-235), which was largely invisible in the native electron density map and indicates that this highly conserved yet flexible region has a specific role in substrate binding during catalysis.

Binding Sites↗
PubMed1990

Design of an effective mechanism-based inactivator for a zinc protease.

(R)-2-Benzyl-5-cyano-4-oxopentanoic acid (compound 4) was studied as a mechanism-based inactivator (suicide substrate) for the zinc protease carboxypeptidase A (CPA; peptidyl-L-amino-acid hydrolase, EC 3.4.17.1). This compound was designed rationally based on the knowledge of the active site topology and the reported stereospecific proton exchange on ketonic substrate analogue (R)-3-(p-methoxybenzoyl)-2-benzylpropanoic acid [Sugimoto, T. & Kaiser, E. T. (1978) J. Am. Chem. Soc. 100, 7750-7751] by CPA. It is suggested that enzymic deprotonation on the C-5 methylene moiety may result in the transient formation of a ketenimine as the key intermediate that partitions between turnover and enzyme inactivation. The enzyme inactivation exhibited pseudo-first-order kinetics, was irreversible, and could be fully prevented in the presence of the reversible inhibitor benzyl-succinate. The inactivation rate constant, kintact, was evaluated to be 0.083 +/- 0.003 min-1 and kcat was measured at 1.78 +/- 0.06 min-1. In turn, a partition ratio of 28 +/- 3 was calculated. The reversible inhibitor constant (Ki) was measured at 1.8 +/- 0.5 microM, indicative of a high affinity for compound 4 shown by CPA; however, Km for the turnover process was determined at 4.93 +/- 0.43 mM. Kinetic analysis and labeling by the radioactive form of the inactivator suggested that the stoichiometry for protein modification by compound 4 approaches a 1:1 ratio.

Carboxypeptidases↗