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PubMed1994

A derivative of a rigid glutamate analog protects the retina from excitotoxicity.

In the retina, the activation of metabotropic glutamate receptors (mGluRs) reduces the toxic effect of N-methyl-D-aspartate (NMDA). We have induced NMDA-mediated excitotoxicity in the adult rat retina by a single intraocular injection of NMDA. The damage that resulted was estimated by assessing the NMDA-induced loss of retinal choline acetyltransferase (ChAT) activity. The new rigid glutamate analog, dimethyl ester of (+/-)-trans-azetidine-2,4-dicarboxylic acid (t-DMADA), with a putative mGluR-agonistic activity, protected the retina from NMDA-induced loss of ChAT activity. This study demonstrated that t-DMADA can be considered a prototype of new retino-protective agents.

Animals↗
PubMed1995

Open field behaviour in rats: role of metabotropic glutamate receptors.

Previous studies have shown that spatial memory retention is affected by the metabotropic glutamate receptor (mGluR) influencing agents (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) and trans-azetidine-2,4-dicarboxylic acid (tADA). In the present investigation we examined whether the mGluR antagonist MCPG (20 mM and 200 mM/5 microliters, respectively) and the agonist tADA (20 mM/5 microliters) have other behavioural effects using the open field test on two successive days. Only minor effects of MCPG (decrease of crossings during the 1st min on day 1) and tADA (increase of rearings on both days) were found. These results suggest that memory influencing doses of MCPG and tADA have no or only little behavioural effects in the open field situation.

Animals↗
PubMed1979

Phosphorylation of a ribosomal protein and of virus-specific proteins in cells infected with herpes simplex virus.

In cells infected with herpes simplex virus a protein associated with the small subunit of ribosomes became phosphorylated. It was not detectably labelled with 14C-amino acids added after infection and is therefore probably a cellular protein. The phosphorylated ribosomal proteins from HSV-1- and HSV-2-infected cells were indistinguishable electrophoretically and had an apparent mol. wt. of about 48 000. Phosphorylation of the 48K protein was detected 2 to 3 h after infection and reached a maximum rate at 4 to 5 h. It was prevented by adding cycloheximide at 2 h, or actinomycin at 1.5 h p.i., or azetidine at the beginning of infection. The phosphorylation did not occur on reversal of a cycloheximide block in the presence of actinomycin, confirming that it is not caused by a virus alpha-polypeptide. Virus that had been irradiated with u.v. light, although still able to suppress synthesis of cellular protein and DNA, did not induce phosphorylation of the 48K ribosomal protein. Therefore the phosphorylation is not responsible for the suppression of host synthesis. The alpha polypeptides ICP 4, 0, 22 and 27 are also phosphorylated but, in contrast to that of the ribosomal protein, their phosphorylation does not depend on the synthesis of beta and gamma polypeptides. It is probably mediated by a host enzyme.

Animals↗
PubMed1984

Synthesis of alpha (immediate-early) proteins in Vero cells infected with pseudorabies virus.

The synthesis of alpha (immediate-early) polypeptides in Vero cells infected with pseudorabies virus was studied. Cycloheximide was added at the beginning of infection and removed several hours later. The accumulated alpha mRNA was translated either in vivo in the presence of actinomycin D to prevent further mRNA synthesis, or in vitro. In intact cells three electrophoretically distinct virus-specific proteins were synthesized, with apparent molecular weights of approximately 180 000 (A), 190 000 (B) and 200 000 (C). The accumulation of B and C was prevented by the proline analogue azetidine. Only protein A was detected in vitro. Proteins B and C were not detected in normally infected cells. All three were associated with the nuclear fraction of cell homogenates and A and B were phosphorylated. The radioactivity of B and C declined during a chase period while that of A increased. This change was prevented by adding cycloheximide during the chase. The pattern of chymotrypsin digestion products suggested that A and B at least were similar proteins. It is presumed that protein A is the single immediate-early protein previously described and analogous to ICP 4 of herpes simplex virus. The significance and function, if any, of proteins B and C is not known but it is possible that they represent stages in the formation or transport of A within the cell and that the progression depends on an unstable protein which is depleted in cells treated with cycloheximide.

Animals↗
PubMed1988

On the control of immediate early (alpha) mRNA survival in cells infected with herpes simplex virus.

The alpha or immediate early mRNA of herpes simplex virus strain HSV-2(G) had a half-life of about 15 min if made in the absence of viral protein synthesis but was relatively stable if viral protein synthesis occurred, either freely or restricted by the presence of the proline analogue azetidine. In contrast, the alpha mRNA of other strains of the virus is stable, even in the absence of protein synthesis. Studies with recombinant viruses showed that the region of the viral DNA between 0.58 and 0.65 map units [which includes the gene (vhs, UL41) that controls virion-mediated shutoff of host protein synthesis] is important in determining the survival of alpha mRNA. In mixed infection experiments HSV-2(G) inhibited alpha as well as host protein synthesis but the shutoff activity appeared to be short-lived. Within 3 h after infection, as a result of protein synthesis, cells became completely resistant to shutoff by superinfecting virus.

Gene Expression Regulation↗
PubMed1981

Proline uptake in Candida albicans.

L-Proline entered both mycelial and yeast cells of Candida albicans by an active transport system of high specificity at low (less than 0.1 mM) external concentrations of substrate. The apparent Km value of this system was 0.1 mM for both types of cells, while the V value was 4 nmol min-1 (mg dry wt)-1 for mycelial cells and 1.4 nmol min-1 (mg dry wt)-1 for yeast cells. At L-proline concentrations greater than 0.1 mM, the amino acid appeared to enter both morphological forms by diffusion as well as active transport. As saturation was approached diffusion became increasingly important. The higher uptake rate of mycelial cells seemed not to be the result of an inducible system. The optimal pH and temperature for transport of L-proline were 7.0 and 37 degrees C, respectively. Sodium azide and the proline analogues sarcosine and L-azetidine-2-carboxylic acid inhibited L-proline uptake, while L-thiazolidine-4-carboxylic acid was less effective. The active transport system was highly specific for L-proline since neither ammonium ions, which inhibit the general amino acid transport system of fungi, nor 16 different amino acids interfered substantially with uptake.

Amino Acids↗
PubMed1984

Active transport of proline by Coxiella burnetii.

The obligate intracellular rickettsia, Coxiella burnetii, was shown to possess an energy dependent proline transport system which displayed a high degree of specificity and was highly dependent on pH. Transport was maximal at pH 3.0 to 4.5, a pH range approximately that of the host cell phagolysosome where the agent replicates. Transport was inhibited by the uncouplers carbonyl cyanide m-chlorophenylhydrazone and dinitrophenol, but not by sodium arsenite. In the presence of glutamate, a preferred energy source, proline uptake was enhanced more than two-fold. This enhancement of proline uptake was greatly decreased in the presence of sodium arsenite. The addition of glutamate decreased the apparent Km for proline transport from 45 microM to 15 microM, with the Vmax increasing from 3.6 pmol s-1 (mg dry wt)-1 to 4.8 pmol s-1 (mg dry wt)-1. Two proline analogues, furoic acid and azetidine-2-carboxylic acid, were effective inhibitors of proline transport. D-Proline, 4-hydroxyproline, glycine and proline amide inhibited transport minimally, while no inhibition was seen with succinate, pyruvate or glutamate.

2,4-Dinitrophenol↗
PubMed1993

Two Related Biosynthetic Pathways of Mugineic Acids in Gramineous Plants.

The biosynthesis of mugineic acids was studied by feeding 2H- or 13C-labeled compounds to water-cultured roots in several gramineous plants. The fate of labeled compounds was monitored by using 2H- and 13C-nuclear magnetic resonance. On investigating the proton changes during biosynthesis by feeding D,L-[3,3,4,4-d4]-methionine (98.6% 2H), 2H-labeled 2[prime]-deoxymugineic, mugineic, and 3-epihydroxymugineic acids were isolated from root washings of wheat (Triticum aestivum L. cv Minori), barley (Hordeum vulgare L. cv Minorimugi), and beer barley (Hordeum vulgare L. cv AM Nijo Tochigi), respectively. The 2H-nuclear magnetic resonance study indicated that 12 deuteriums were incorporated into the labeled 2[prime]-deoxymugineic acid, suggesting that three molecules of L-[3,3,4,4-d4]methionine were combined. In comparison, one of the deuteriums at C-2[prime] position in the mugineic acid, and one each of the deuteriums at C-2[prime] and C-3 positions in the 3-epihydroxymugineic acid, were lost. However, all other deuteriums were incorporated in a manner similar to that of the labeled 2[prime]-deoxymugineic acid. When [1,4[prime],4"-13C3]2[prime]-deoxymugineic acid (20% 13C) was fed to oat roots (Avena sativa L. cv Amuri II), avenic acid A, which was 13C enriched at the corresponding positions, was obtained. These results revealed that L-methionine was the precursor for all these mugineic acids and that cleavage of the azetidine ring or hydroxylation of the 2[prime]-deoxymugineic acid produced two related biosynthetic pathways in different gramineous plant species: L-methionine -> 2[prime]-deoxymugineic acid -> avenic acid A in oat; and L-methionine -> 2[prime]-deoxymugineic acid -> mugineic acid -> 3-epihydroxymugineic acid in barley and beer barley.

Journal Article↗
PubMed1996

Induction and Regulation of Heat-Shock Gene Expression by an Amino Acid Analog in Soybean Seedlings.

The effect of the proline analog azetidine-2-carboxylic acid (Aze) on the induction and the regulation of heat-shock (HS) mRNA accumulation and heat-shock protein (HSP) synthesis in soybean (Glycine max) seedlings was studied. Treatment with Aze elicited an HS-like response at the normal growth temperature, 28[deg]C, with seven of nine HS cDNA clones tested. Two cDNA clones, Gm-Hsp22.5 and pFS2033, share 78% identity; however, transcripts hybridizing to GmHsp22.5 but not pFS2033 accumulated with Aze treatment at 28[deg]C. Substantial incorporation of radioactive amino acid into high molecular weight HSPs but not low molecular weight HSPs was observed in vivo during Aze treatment at 28[deg]C. Low molecular weight HSPs were detected using antibodies raised against an abundant member of low molecular weight class I HSPs, indicating that low molecular weight HSPs were synthesized at normal growth temperatures during Aze treatment despite a lack of substantial in vivo radioactive amino acid incorporation. In summary, Aze treatment induced accumulation of most but not all HS mRNAs and HSPs in soybean seedlings; the observations presented here suggest differential regulation among various HS genes at the transcriptional and posttranscriptional levels.

Journal Article↗
PubMed1999

Overexpression of a gene that encodes the first enzyme in the biosynthesis of asparagine-linked glycans makes plants resistant to tunicamycin and obviates the tunicamycin-induced unfolded protein response.

The cytotoxic drug tunicamycin kills cells because it is a specific inhibitor of UDP-N-acetylglucosamine:dolichol phosphate N-acetylglucosamine-1-P transferase (GPT), an enzyme that catalyzes the initial step of the biosynthesis of dolichol-linked oligosaccharides. In the presence of tunicamycin, asparagine-linked glycoproteins made in the endoplasmic reticulum are not glycosylated with N-linked glycans, and therefore may not fold correctly. Such proteins may be targeted for breakdown. Cells that are treated with tunicamycin normally experience an unfolded protein response and induce genes that encode endoplasmic reticulum chaperones such as the binding protein (BiP). We isolated a cDNA clone for Arabidopsis GPT and overexpressed it in Arabidopsis. The transgenic plants have a 10-fold higher level of GPT activity and are resistant to 1 microg/mL tunicamycin, a concentration that kills control plants. Transgenic plants grown in the presence of tunicamycin have N-glycosylated proteins and the drug does not induce BiP mRNA levels as it does in control plants. BiP mRNA levels are highly induced in both control and GPT-expressing plants by azetidine-2-carboxylate. These observations suggest that excess GPT activity obviates the normal unfolded protein response that cells experience when exposed to tunicamycin.

Amino Acid Sequence↗
PubMed1977

Ammonium and amino acids as regulators of nitrate reductase in corn roots.

When amino acids or ammonia are added to plant systems, the effects on the development of nitrate-dependent nitrate reductase activity are variable. In addition, amino acids added singly or as casein hydrolysate may not support a normal growth. A physiologically correct mixture of amino acids, one similar in composition to amino acids released by the endosperm, has been shown to support normal growth and protein synthesis in corn (Zea mays) embryos. In this investigation, we have used the mixture of corn amino acids to determine whether amino acids have an effect on the appearance or disappearance of nitrate reductase activity. The results show that these amino acids partially inhibit the induction of nitrate reductase in corn roots. The effect is more pronounced in mature root than in root tip sections. When glutamine and asparagine are included along with the "corn amino acid mixture," the inhibition is more severe. Amino acids or amino acid analogues added singly to the induction medium have a similar effect: i.e. when the induction of nitrate reductase is inhibited in the root tips (lysine, canavanine, azaserine, azetidine-2-carboxylic acid, dl-4-azaleucine, asparagine, and glutamine), that inhibition is more severe in mature root sections. Arginine enhanced the recovery of nitrate reductase in root tips but inhibited it in mature root sections. The effect of the amino acids is apparently on some phase of the induction processes (i.e. the uptake or distribution of nitrate or a direct effect on the synthesis of the enzyme) and not on the turnover of the enzyme.

Journal Article↗
PubMed1982

Cryostorage of cloned amino Acid analog-resistant carrot and tobacco suspension cultures.

Five clones were isolated from five different amino acid analog-resistant Daucus carota L. var. Sativa and Nicotiana tabacum L. cv. Xanthi cell lines. The individual clones were similar in their resistance to dl-5-methyltryptophan, S-(2-aminoethyl)-l-cysteine, or azetidine-2-carboxylic acid, and in their corresponding free amino acid levels.The cell suspensions were stored using a controlled freezing rate at -196 degrees C with concentrations up to 40% of the four cryoprotectants: mannitol, proline, dimethylsulfoxide, glycerol, and combinations of dimethyl-sulfoxide and glycerol. No less than 55% post-thaw viability, determined by phenosafranin dye exclusion, was obtained after storage using a cryoprotectant mixture of 10% glycerol and 10% dimethylsulfoxide. Growth of the cryostored cells could be obtained consistently only by using feeder plate methodology with this combination of cryoprotectants. Post-thaw viability and percentage of cells demonstrating growth, as estimated by growth kinetics, were found to be similar. This indicates that little selection occurred during the freezing and recovery process. In addition, the amino acid analog-resistant traits were unaltered following cryostorage.Suspension cultures of Datura innoxia Mill. were frozen similarly with maximum post-thaw viability of 38%, but subsequent growth was not obtained.Protoplasts of D. innoxia, tobacco and carrot were also cryostored using a mixture of 10% dimethylsulfoxide and 10% glycerol as cryoprotectants. Viabilities of no less than 40% were obtained, however, only the carrot protoplasts regenerated cell walls and underwent cell division.

Journal Article↗
PubMed1985

Selection and characterization of chlorella mutants deficient in amino Acid transport : further evidence for three independent systems.

Six amino acids are transported at high rates across the plasmalemma of Chlorella vulgaris only after the induction of two specific transport systems. Induction is achieved either by pretreatment with glucose, glucose analogs, or by nitrogen starvation. Mutants for these transport systems were obtained after incubation of Chlorella cells in the presence of acridine orange or ethidium bromide, followed by a selection procedure using the toxic amino acid analogs l-canavanine (for l-arginine), and l-azetidine-2-carboxylic acid (for l-proline). Mutants isolated by this method had lost their ability to induce the corresponding transport system. Double mutants deficient in transport of both these amino acids still possess the general amino acid transport system, a third system which was described previously. Evidence for additional amino acid transport systems in Chlorella is discussed.

Journal Article↗
PubMed1987

Changes in k, rb, and na transport to shoots after anoxia.

The effect of anoxia on subsequent uptake and transport of K, Rb, and Na was examined with seedlings of barley (Hordeum vulgare L.), corn (Zea mays L.), and tall fescue (Lolium x Festuca hybrid derivative) to further our understanding of xylem loading. Roots were incubated in solutions depleted of O(2) by flushing with N(2) gas. After 1 hour exposure, plants were returned to aerated solutions for 16 hours prior to measuring uptake and transport. For each species, anoxia pretreatment significantly enhanced Na transport to the shoot. The rate of Na accumulation into roots, however, was not affected. There was no enhancement of either K or Rb accumulation in shoots, indicating specificity for Na transport. A minimum exposure to anoxia of 30 minutes and a minimum of 12 hours elapsed time was necessary to achieve the maximum rate of Na transport to the shoot in barley seedlings. Accumulation of Na in the shoot of both the control and anoxia pretreated barley plants was inhibited by anoxia and by addition of the proline analog, l-azetidine-2-carboxylic acid, during the uptake period. Enhancement of Na transport was associated with a proportional increase in the rate of synthesis of a membrane bound protein with a molecular weight of 78,000 daltons.

Journal Article↗
PubMed1987

Nitrogen Enhancement of Phosphate Transport in Roots of Zea mays L: II. Kinetic and Inhibitor Studies.

Exposure to 1 millimolar ammonium pretreatments increased V(max) for phosphorous uptake in dark-grown decapitated maize seedlings without a statistically measurable change in K(m). Sulfate uptake also was stimulated. The stimulation in phosphorous uptake due to ammonium pretreatment was greater in seedlings grown without phosphorous than in those grown with 25 micromolar phosphorous. The stimulus was not expressed unless the entire root system was pretreated with ammonium, and pretreatment of a part of the root system inhibited phosphorous uptake by the remaining part unless it also had been pretreated. Pretreatment with the amino acid analogs p-fluoro-dl-phenylalanine and l-azetidine-2-carboxylic acid (AZ) restricted phosphorous uptake in seedlings that were pretreated with ammonium and in those that were not, but the effect of ammonium pretreatment was not completely eliminated by the analogs. In general, translocation of the entering phosphorous was affected similarly to uptake by experimental treatments. Enhanced translocation, however, was not sufficient to account quantitatively for the increase in uptake, and an increased uptake was still evident when translocation was completely prevented by 50 micromolar AZ pretreatment.

Journal Article↗
PubMed1992

Induction of the 72-kD heat shock protein in organ-cultured normal human skin.

To study the induction of heat shock protein (HSP) of normal human skin, the indirect immunofluorescence method, using monoclonal antibody directed against 72-kD HSP, was applied in organ-cultured normal human skin that was treated with heat, UV, or chemicals. The present study provided new evidence that HSP 72 was induced not only by heat and chemical agents, such as L-azetidine 2-carboxylic acid, and sodium arsenite, but also by ultraviolet (UV B and C). The result suggests that normal human skin has an induced protective function against numerous environmental stresses.

Arsenic↗
PubMed1995

Nuclear accumulation of p53 in normal human fibroblasts is induced by various cellular stresses which evoke the heat shock response, independently of the cell cycle.

Nuclear accumulation of p53 is induced by various DNA damaging agents (the p53 response). Induction of nuclear accumulation of p53 after various cellular stresses, mostly other than DNA damage, including heat shock, was examined in normal human fibroblasts by immunostaining and flow cytometry using a mouse anti-p53 monoclonal antibody. Immunostaining revealed nuclear accumulation of p53 within 6 h after various stresses [heat shock, osmotic shock, heavy metal (Cd), blockers of the cellular respiratory system (NaN3), amino acid analogues (azetidine and canavanine), an inhibitor of protein synthesis (puromycin), and oxygen free radicals (H2O2)]. Heat shock proved to be one of the most effective inducers among these stresses. FACScan analysis revealed that this induction of p53 occurred regardless of the stage in the cell cycle and that accumulation of cells in G2/M occurred. As all of these stresses are known to induce the heat shock response, the mechanism of p53 induction after stresses and that of heat shock response may share, at least partly, some common signaling pathway(s).

Cell Cycle↗