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PubMed1999

Crystallization and preliminary X-ray diffraction studies of pyrrolidone carboxyl peptidase from the hyperthermophilic archaeon Thermococcus litoralis.

Pyrrolidone carboxyl peptidase from the hyperthermophilic archaeon Thermococcus litoralis has been crystallized in a form suitable for X-ray diffraction from ammonium sulfate or ammonium dihydrogen orthophosphate using the vapour-phase diffusion method. Crystals from both precipitants are of the orthorhombic space group P21212 with unit-cell dimensions a = 94.06, b = 149.06, c = 73.54 A. A complete data set to 2.8 A resolution has been collected from crystals grown from ammonium sulfate.

Crystallization↗
PubMed1983

Pyrrolidone carboxylic acid synthesis in guinea pig epidermis.

To establish the in vivo mechanism of synthesis and accumulation of epidermal pyrrolidone carboxylic acid (PCA), enzymes potentially capable of PCA synthesis have been quantified and located within the guinea pig epidermis. Intermediates in the synthesis of [3H]PCA from a pulse of [3H]glutamine have been identified and quantified to determine which of the several possible metabolic routes occurs in vivo. PCA appears to be synthesized from substrate derived from the breakdown within the stratum corneum of protein synthesized several days earlier. The predominant route is probably via the nonenzymic cyclization of free glutamine liberated from this protein. In view of the high activity of gamma-glutamyl cyclotransferase in the stratum corneum, a minor contribution to PCA formation by the action of the enzyme on gamma-glutamyl peptides cannot be excluded.

Animals↗
PubMed1992

Molecular characterization of pcp, the structural gene encoding the pyrrolidone carboxylyl peptidase from Streptococcus pyogenes.

This paper describes the cloning of a gene (pcp) coding for pyrrolidone carboxylyl peptidase (PYRase), an enzyme which selectively removes N-terminal pyroglutamic acid residues from polypeptides. This gene was isolated from Streptococcus pyogenes by construction of a gene library with a bacteriophage lambda-derived cosmid-Escherichia coli host system. Nucleotide sequence determination of a 1.3 kb restriction fragment revealed a 645 bp open reading frame encoding a 215-amino-acid product of M(r) 23,135 consistent with the 26 kDa polypeptide obtained from in vivo overexpression in E. coli. Southern hybridization confirmed that pcp is a single-copy gene on the S. pyogenes chromosome. 5' and 3' endpoint mapping of the 0.7 kb specific transcript observed by Northern analysis permitted the identification of transcriptional initiation and termination signals. Structural features of the pcp gene product from S. pyogenes are discussed and compared with that from Bacillus subtilis. The lack of sequence identity with any other known protein or nucleotide sequence suggests that this enzyme belongs to a new class of peptidase.

Amino Acid Sequence↗
PubMed1982

Weak acid-catalyzed pyrrolidone carboxylic acid formation from glutamine during solid phase peptide synthesis. Minimization by rapid coupling.

Formation of pyrrolidone carboxylic acid (pyroglutamic acid) residues from amino-terminal glutaminyl residues in peptides was shown to be catalyzed by weak acids, but not by strong acids. During dicyclohexylcarbodiimide-mediated coupling reactions the N alpha-protected amino acid reagent accelerated this cyclization and resulted in a significant amount of chain termination. The side reaction could be minimized by accelerating the coupling reaction and simultaneously reducing the time of exposure to weak acids. The most effective procedure was to couple in dimethylformamide with the preformed symmetric anhydride of the amino acid.

Chemical Phenomena↗
PubMed1971

1-Hydroxy-3-amino-pyrrolidone-2(HA-966): a new GABA-like compound, with potential use in extrapyramidal diseases.

1. The drug HA-966 (1-hydroxy-3-amino-pyrrolidone-2), which chemically resembles the cyclic form of GABA, has been studied for neuro-pharmacological properties and for effects on the catecholamine content of the corpus striatum.2. The acute effects on spontaneous behaviour of rodents included flaccid catalepsy and reversible tranquillization in doses which were 5% or less of the lethal dose. Long lasting depression of the CNS, followed by complete recovery, was produced in the cat and the dog. In the monkey HA-966 caused periodical sleeping episodes.3. The exploratory behaviour and the amphetamine-induced motor activity in mice were blocked by HA-966. The toxicity of amphetamine in aggregated mice was only moderately reduced, suggesting that HA-966 differs from neuroleptics.4. Tremors induced by chemical agents (nicotine, zinc and tremorine) were markedly inhibited by HA-966. The muscarinic effects of tremorine were not reduced by HA-966, indicating a selective central antitremor effect.5. HA-966 elevated the threshold to strychnine convulsions and abolished the ipsilateral flexor reflex, while not having motor endplate blocking properties. It is suggested that HA-966 depresses central internuncial neurones.6. In rats and rabbits HA-966 produced synchronous EEG and inhibited the sensory arousal in doses not causing sedation. In the monkey the drug caused a periodical dissociation between ;sleep-EEG' and behaviour.7. In rat brain, HA-966 selectively elevated the dopamine content in the corpus striatum, while no changes in noradrenaline and 5-hydroxytryptamine contents could be demonstrated. The effect was still present when dopa synthesis was inhibited with alpha-methyl-p-tyrosine.8. Several effects of intravenously administered HA-966 became manifest after an appreciable delay and in hepatectomized mice the effects were much reduced. It is postulated that HA-966 is converted to a pharmacologically active metabolite.9. The results are discussed in the light of current views on drug therapy in extrapyramidal conditions and a GABA-related hypothesis as to the mode of action of HA-966 is presented.

Acoustic Stimulation↗
PubMed2005

Effects of Nefiracetam, a novel pyrrolidone-type nootropic agent, on the amygdala-kindled seizures in rats.

PURPOSE: Nefiracetam (NEF) is a novel pyrrolidonetype nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the effects of NEF in amygdala-kindled seizures and its potential for antiepileptic therapy. METHODS: Effects of NEF on fully amygdala-kindled seizures and development of amygdala-kindled seizures were investigated in rats and compared with those of levetiracetam (LEV), a pyrrolidone-type antiepileptic drug (AED). RESULTS: In fully amygdala-kindled rats, NEF (25, 50, and 100 mg/kg, p.o.) decreased afterdischarge induction, afterdischarge duration, seizure stage, and motor seizure duration in a dose-dependent manner. LEV (25, 50, and 100 mg/kg, p.o.) had no effects on afterdischarge induction and slightly decreased afterdischarge duration, whereas it markedly decreased seizure stage and motor seizure duration. In contrast to the results in fully amygdala-kindled rats, NEF (25 and 50 mg/kg/day, p.o.) had few or no effects on the development of amygdala-kindled seizures. As well as fully amygdala-kindled seizures, LEV (50 mg/kg/day, p.o.) markedly inhibited the development of behavioral seizures without reducing daily afterdischarge duration. CONCLUSIONS: Although NEF possesses potent anticonvulsant effects on fully amygdala-kindled seizures, it has few or no effects on the development of amygdala-kindled seizures. LEV shows marked anticonvulsant effects on both phases of kindling. In fully amygdala-kindled rats, NEF inhibits both electroencephalographic and behavioral seizures, whereas LEV inhibits only behavioral seizures. This double dissociation suggests that NEF has a distinct anticonvulsant spectrum and mechanisms from those of LEV.

Administration, Oral↗
PubMed1989

Immediate contact reactions to benzoic acid and the sodium salt of pyrrolidone carboxylic acid. Comparison of various skin sites.

Benzoic acid (BA) and the sodium salt of pyrrolidone carboxylic acid (NaPCA) were tested in 13 healthy persons to obtain information about, firstly, the irritant properties of NaPCA and, secondly, the reactivity of various skin sites. BA at 16, 8, and 4 mM pet., and NaPCA at 50, 25, 12.5, and 6.25% in water, were applied to the forehead, cheek, neck and upper back. Erythema reactions were observed visually, and the changes in the skin blood flow were monitored using a laser-Doppler flowmeter. BA at 16 mM increased blood flow on the cheek of 12 test subjects, and on the neck, forehead and upper back of 6 subjects, but 8 and 4 mM BA elicited reactions only on the cheek. NaPCA caused reactions on the upper back of 3 test subjects only, but not on other test sites.

Adult↗
PubMed1992

Irritant cutaneous reactions to N-methyl-2-pyrrolidone (NMP).

Several workers in a small electrotechnical company in Norway experienced irritant reactions of the skin after a few days of working with the solvent N-methyl-2-pyrrolidone (NMP). Due to concern about the health risk of commonly-used organic solvents, the company had chosen to use NMP when one of its products had to be treated with a solvent. After 2 days of work with NMP, 10 of the 12 involved workers displayed acute irritant contact dermatitis of the hands. According to published reports, NMP is not considered to be particularly irritant to the skin. The Safety Data Sheet of a Norwegian sales firm contained no information on cutaneous hazards, but the Safety Data Sheet of an American producer of NMP stated the risk of severe dermatitis upon prolonged contact. NMP seems to be more irritant to the human skin than reported thus far.

Dermatitis, Irritant↗
PubMed1993

Changes in expression of the albumin, fibronectin and type I procollagen genes in CCl4-induced liver fibrosis: effect of pyridoxol L,2-pyrrolidon-5 carboxylate.

The protective activity of pyridoxol L,2-pyrrolidon-5 carboxylate (metadoxine) was investigated in a rat model of carbon tetrachloride (CCL4)-induced hepatic fibrosis. After 6 weeks of CCl4 treatment, the animals developed fibrosis and inflammation of the liver while those treated with CCl4 + metadoxine had less severe lesions (P < 0.05). Since in liver fibroplasia there are quantitative changes of the extracellular matrix components and almost invariably a decrease in albumin synthesis, we have also investigated by Northern blot analysis the expression of the cellular fibronectin, pro-alpha 2(I)collagen and albumin genes. There were striking increases in fibronectin and pro-alpha 2(I)collagen mRNA contents in the livers of CCL4-treated animals and these enhancements were less evident in the metadoxine-treated rats. In contrast, albumin mRNA levels, almost identical in control and metadoxine-treated rats, were lower in the CCl4-treated animals. These data suggest that metadoxine might slow the development of CCl4-mediated liver fibrosis.

Albumins↗
PubMed1988

Macrophage clearance of 125I-labelled polyvinyl pyrrolidone in the horse: effect of ovarian steroids and persistent endometritis.

The rate of clearance of 125I-labelled polyvinyl pyrrolidone (PVP) from blood was measured in mares as an indicator of macrophage function. In three out of four cycling mares, PVP clearance was slower during oestrus than dioestrus. Similarly, administration of oestrogen to four ovariectomised mares tended to depress PVP clearance compared with clearance from the same mares before they received oestrogen. However, the effect of oestrogen was not statistically significant. Mares susceptible to persistent endometritis had rates of PVP clearance which were similar to those of genitally normal mares.

Animals↗
PubMed1985

Absorption through human skin of ibuprofen and flurbiprofen; effect of dose variation, deposited drug films, occlusion and the penetration enhancer N-methyl-2-pyrrolidone.

The penetration of ibuprofen and flurbiprofen, non-steroidal anti-inflammatory agents, was investigated from drug films deposited by acetone evaporation on cadaver skin in an open cell 'in-vivo mimic' design. Increased dosage did not produce a proportional increase in the permeation and maximizing the skin-drug contact did not increase penetration: both factors indicate that absorption from deposited drug films was dissolution rate-limited. Occlusion of the skin did not increase the dissolution rate of the deposited drug film, but did elevate the penetration of drug already present within the skin at the time of occlusion. The diffusion coefficients for both drugs were calculated by two methods, yielding 1.8 +/- 1.3 X 10(-11) cm2 s-1 and 1.0 +/- 0.56 X 10(-11) cm2 s-1 for ibuprofen and 1.9 +/- 0.59 X 10(-11) cm2 s-1 and 0.77 +/- 0.23 X 10(-11) cm2 s-1 for flurbiprofen. Increasing the acetone-skin contact time from 2 min to 2 h did not significantly alter the permeability of the skin. Absorption of flurbiprofen was similar from 10 and 100% saturated aqueous solutions, suggesting that the skin has a limited capacity for flurbiprofen transport beyond which further increase in drug penetration may be difficult. N-Methyl-2-pyrrolidone enhanced the penetration flux of ibuprofen sixteenfold and flurbiprofen, over threefold. The 'in-vivo mimic' design for permeation experiments has thus proved to be useful for evaluating the kinetics of topical therapy and the mechanism of action of potential penetration enhancers.

Acetone↗
PubMed1969

The use of [125-I] polyvinyl pyrrolidone K. 60 in the quantitative assessment of the uptake of macromolecular substances by the intestine of the young rat.

1. A method has been developed which allows the quantitative estimation of the uptake of labelled polyvinyl pyrrolidone (PVP) of mean mol. wt. 160,000 (K. 60) by the wall of the small intestine of young rats.2. Four hours after feeding a standard dose of [(125)I]PVP by stomach tube, the small intestine was thoroughly washed out, and the radioactivity of the intestinal wall measured. Under these conditions, the small intestine of animals less than 18 days old took up more than 50% of the radioactivity which had left the stomach. There was no increase in PVP uptake if the duration of absorption exceeded 4 hr. The PVP was taken up by the epithelial cells of the villus, and its intracellular localization has been demonstrated by fluorescence microscopy and can be related to vacuolation in the cells.3. In animals between 18 and 20 days old the uptake of PVP declined progressively, until, in animals more than 20 days old, less than 5% of the radioactivity was taken up by the intestinal wall.4. There is good agreement between the reported age of termination of antibody absorption in young rats and the age at which PVP uptake ceased in the present experiments. It is suggested that the loss of ability of the intestine to take up substances of high mol. wt. may be the factor which limits the duration of the period of antibody absorption in this species.

Animals↗
PubMed1969

The absorption of polyvinyl pyrrolidone by the new-born pig intestine.

1. The intestinal absorption of [(131)I]polyvinyl pyrrolidone of mean mol. wt. 160,000 (K. 60) and 40,000 (K. 30) after oral administration has been measured in unsuckled conscious pigs less than 20 hr old. Absorption was assessed by the measurement of the concentration of [(131)I]PVP in venous blood during the 6 hr after feeding and also by the distribution at the end of the experiment of [(131)I]PVP between homogenates of the alimentary tract and homogenates of the rest of the animal.2. The concentration of [(131)I]PVP in the peripheral blood after feeding was dependent upon the mol. wt. of the polymer, when comparable amounts had been absorbed from the intestine. PVP K. 60 attained higher blood concentrations than PVP K. 30 and the blood concentrations of PVP K. 60 were close to the values to be expected if all the material which had left the intestine had remained in the blood. The lower blood concentrations found when PVP K. 30 was fed were associated with the disappearance of labelled solute from the gut and were thus the consequence of the relatively rapid escape of labelled solute from the plasma after absorption had taken place.3. The ability of the intestine to absorb [(131)I]PVP K. 60 declined progressively after birth but did not terminate abruptly unless the animal was fed colostrum. In unsuckled animals the rate and extent of absorption at 3 hr was much greater than at 20 hr after birth, but some absorption was still present at least 65 hr after birth.4. The transfer of PVP K. 60 to the peripheral blood was dependent upon factors in sow colostrum, since significant absorption did not occur when PVP was fed in water or simple salt solutions.5. The factors which accelerated absorption were present in colostrum from the goat, cow and ewe as well as that from the sow; they remained in the whey, but, in contrast to the factors which accelerate absorption in the calf, were largely inactivated by boiling. Similarly, neither phosphate, lactate, pyruvate, nor lower volatile fatty acid salts, which were effective in the calf, accelerated absorption in the pig.6. The absorption of [(131)I]PVP K. 30 was found to be much less dependent upon the composition of the solvent than the absorption of [(131)I]PVP K. 60, although absorption was most rapid when PVP K. 30 was fed in colostrum.

Age Factors↗
PubMed1970

Structural changes in the small intestine associated with the uptake of polyvinyl pyrrolidone by the young ferret, rabbit, guinea-pig, cat and chicken.

1. The entry of [(125)I]polyvinyl pyrrolidone (PVP) of mean mol. wt. 160,000 (K. 60) into the epithelial cells of the small intestine has been measured in new-born animals of five species.2. The distribution along the intestine of cells capable of taking up [(125)I]PVP and the decrease and eventual cessation of uptake (closure) with increasing age have been investigated, and have been related to changes in the histological appearance of the small intestine.3. The small intestine of the ferret took up PVP readily until 33-34 days after birth. From 34 to 37 days of age PVP uptake declined sharply and disappeared completely by 40-45 days.4. In the ferret, unlike other species studied, some PVP was taken up by the duodenum. This continued for the first 4 weeks after birth. Thereafter PVP uptake gradually became confined to the terminal ileum.5. In the guinea-pig, PVP uptake was limited to the first 48 hr after birth. During this period the site of uptake was progressively restricted to the terminal ileum.6. In the rabbit, PVP could be taken up in the distal two-thirds of the small intestine for at least 20 days after birth. A decline in uptake occurred between 20 and 22 days after birth in most animals.7. Wide individual variations were seen in the kitten, but PVP uptake was seen in some animals up to 14 days after birth.8. Newly hatched chicks and chicks tested 48 hr after hatching did not take up PVP.9. Histological examination of the small intestine with the light microscope demonstrated that in all species PVP uptake was associated with the presence of vacuoles in the epithelial cells of the villus.10. In the young guinea-pig, large PAS-positive granules were seen in the macrophages of the lamina propria. These appeared to migrate through the epithelium into the intestinal lumen. The significance of this finding and its relation to macromolecular uptake remain unclear.

Age Factors↗
PubMed1971

Factors influencing the uptake of [ 125 I]polyvinyl pyrrolidone by the intestine of the young rat.

1. The uptake of orally administered [(125)I]polyvinyl pyrrolidone (PVP) of mean mol. wt. 160,000 (K. 60) by the small intestine of young rats was determined 4 hr after feeding by measurement of the radioactivity remaining in the wall after flushing out the intestinal contents.2. PVP uptake was proportional to the administered dose of PVP for doses of 1 mg and below. At higher doses, uptake was no longer in linear proportion, suggesting a degree of saturation of uptake.3. Litters were reared in one of three environmental temperatures: 13, 20 and 30 degrees C, and were tested to determine the age at which PVP uptake ceased (;closure'). The results were evaluated statistically (see Appendix).4. There was no significant difference between the time of closure in animals reared at 20 and 30 degrees C, but, relative to these groups, closure was significantly delayed, by approximately 48 hr, in animals reared at 13 degrees C.5. Once closure had begun, there were no significant differences in the rate of decline in PVP uptake with age between animals reared at different environmental temperatures.6. Separation of the young rats from their mother both before and after the test-feed of PVP caused a considerable reduction in PVP uptake. Provided that the body temperature of the young rats was maintained, the main factor contributing to the reduction in PVP uptake appeared to be the absence of milk, rather than separation from the mother.

Animals↗
PubMed2003

Toxicokinetics and metabolism of N-[(14)C]N-methyl-2-pyrrolidone in male Sprague-Dawley rats: in vivo and in vitro percutaneous absorption.

Neat N-methyl-2-pyrrolidone (NMP) rapidly penetrated into the skin of male Sprague-Dawley rats after in vivo and in vitro topical application. At the two topical doses tested in vivo, no steady state was observed. The maximal absorption fluxes were 10 and 20 mg/cm(2)/h for 20 microl/cm(2) and 40 microl/cm(2), respectively. Similar results were observed after in vitro topical application of neat [(14)C]NMP (25-400 microl/cm(2)) in fresh full-thickness skin. Whatever the dose tested, the percutaneous absorption fluxes increased with exposure time to reach a maximum value (F(max)) and then decreased. F(max) and the time to reach it (T(max)) increased as the dose increased. At the highest dose, which may be considered as an "infinite dose," the maximal flux (7.7 +/- 1.1 mg/cm(2)/h, n = 12) occurred 6 h after the topical application of NMP. The decrease on percutaneous absorption flux was correlated with the dilution of neat NMP with water from the receptor fluid. A semi-quantitative mathematical model was developed to describe the absorption flux of NMP taking into account the transfer of water through the skin. The K(p) values determined from the different aqueous solutions of NMP (1:1 to 1:32, v/v) were not significantly different. The mean value was 6.4 (10(-3) cm/h) (range, 4.7 to 7.6). Occlusion did not affect the percutaneous absorption flux of neat NMP. Desquamation increased the percutaneous absorption of NMP slightly. The skin did not metabolize NMP. The flux was dependent on the thickness of the skin and was proportional to the concentration of NMP. These findings suggest a passive diffusion of NMP through the skin.

Administration, Cutaneous↗
PubMed1977

Pyrrolidone carboxylyl peptidase in Streptococcus cremoris: dependence on an interaction with membrane components.

A study of the distribution of pyrrolidone carboxylyl peptidase (PCP) activity among cell fractions of Streptococcus cremoris HP revealed that this enzyme is associated with a particulate fraction, which mainly consists of membrane material. This location could only be established using a gentle nonmechanical method for the disruption of spheroplasts under the conditions of which intracellular marker enzymes are released. The effect of monovalent anions and treatments, which do not destroy covalent binding, suggests an association of the enzyme with surrounding structures determined by both hydrophobic and electrostatic interactions. The activity of PCP associated with cells harvested from different growth phases and in the solubilized state was studied as a function of the temperature in the absence and in the presence of the membrane-interfering agent n-butanol. A decrease in the apparent activation energy, inherent to the solubilized enzyme, is induced in situ at a lower transition temperature. Only with logarithmic-phase cells is this transition followed (mid-logarithmic cells) or accompanied (late logarithmic cells) by a secondary decrease in the energy of activation. n-Butanol appeared to decrease the lower transition temperature of the enzyme activity in situ, and additionally it exerted an effect on the manifestation of the secondary transition. Thecorganization of membrane components, mainly the lipids.

Aminopeptidases↗
PubMed1994

Characterization of the pcp gene of Pseudomonas fluorescens and of its product, pyrrolidone carboxyl peptidase (Pcp).

The gene pcp, encoding pyrrolidone carboxyl peptidase (Pcp), from Pseudomonas fluorescens MFO was cloned and its nucleotide sequence was determined. This sequence contains a unique open reading frame (pcp) coding for a polypeptide of 213 amino acids (M(r) 22,441) which has significant homology to the Pcps from Streptococcus pyogenes, Bacillus subtilis, and Bacillus amyloliquefaciens. Comparison of the four Pcp sequences revealed two highly conserved motifs which may be involved in the active site of these enzymes. The cloned Pcp from P. fluorescens was purified to homogeneity and appears to exist as a dimer. This enzyme displays a Michaelis constant of 0.21 mM with L-pyroglutamyl-beta-naphthylamide as the substrate and an absolute substrate specificity towards N-terminal pyroglutamyl residues. Studies of inhibition by chemical compounds revealed that the cysteine and histidine residues are essential for enzyme activity. From their conservation in the four enzyme sequences, the Cys-144 and His-166 amino acids are proposed to form a part of the active site of these enzymes.

Amino Acid Sequence↗