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PubMed1980

Studies on the accumulation of L-pyroglutamic acid in guinea pig epidermis.

The activities and properties of the enzymes involved in the formation and degradation of pyroglutamic acid (2-pyrrolidone-5-carboxylic acid, 5-oxoproline) in guinea pig epidermis have been studied. The enzyme pattern was characterized by an extremely high activity of gamma-glutamyl cyclotransferase. The epidermal extracts possessed a measurable, but rather low activity of pyroglutamate hydrolase. It is suggested that the only major pathway by which pyroglutamate may be formed in epidermal tissue is from L-glutamate by a 2-step reaction, the first involving the formation of a gamma-glutamyl peptide by the action of gamma-glutamyl-cysteine synthetase, and the second cyclization of the gamma-glutamyl moiety by the action of gamma-glutamyl cyclotransferase. Abundant substrate supply, the extremely high cyclotransferase activity and the rather low capacity to degrade pyroglutamate may be the factors responsible for the accumulation of this compound in epidermal tissue. A relatively low content of reduced glutathione may also be a contributing factor.

Animals↗
PubMed1988

A new endogenous anxiolytic agent: L-pyroglutamic acid.

By use of a simple anticonflict procedure (Vogel test), it was demonstrated that L-pyroglutamic acid (L-pyrrolidone carboxylic acid [L-PCA]), an amino acid naturally occurring in mammalian tissues and fluids, possesses anxiolytic activity. This tissues and fluids, possesses anxiolytic activity. This effect was stereospecific (D-PCA was inactive) and, in the rat, it was not associated with a decrease in motor activity. Ro 15-1788, a benzodiazepine antagonist, did not modify L-PCA actions. Furthermore, anxiolytic doses of the amino acid did not change the content of 5-hydroxytryptamine (5-HT) or of 5-hydroxyindoleacetic acid (5-HIAA) in the rat cortex and hippocampus. These results suggest that the mechanism of the anxiolytic activity of L-PCA is different from that of the benzodiazepines and of 5-HT1a agonists.

Animals↗
PubMedDate not supplied

Pyroglutamic acid improves learning and memory capacities in old rats.

The effects of the arginine salt of pyroglutamic acid (2-oxo-pyrrolidone carboxylic acid, PCA) on learning and memory capacities of old rats were studied in a subchronic treatment schedule (i.p. injection of 0.1 and 1 g/kg/day for 15 days). The acquisition and extinction of active avoidance behaviour were studied in a pole-jumping test situation. The retention of passive avoidance response was examined in a step-through passive avoidance task. PCA facilitated the rate of acquisition of pole-jumping response, and inhibited the extinction of the response. The dose of 1 g/kg was more potent than 0.1 g/kg in this respect. Also in the passive avoidance task, the treatment with PCA was followed by an improvement of avoidance retention. These results indicate that PCA is a behaviourally active compound in that it improves learning and memory capacities in old rat.

Aging↗
PubMed2006

Effect of pyrrolidone-pyroglutamic acid composition on blood flow in rat middle cerebral artery.

We compared the effects of a pyrrolidone-pyroglutamic acid composition and nimodipine on blood circulation in the middle cerebral artery in rats. The composition produced a strong effect on blood supply to the brain, stimulated blood flow in the middle cerebral artery (by 60 +/- 9%) and decreased blood pressure (by 25.0 +/- 2.7%). The cerebrovascular effects of this composition differed from those of nimodipine. Nimodipine not only increased middle cerebral artery blood flow, but also decreased cerebral blood flow in the early period after treatment.

Animals↗
PubMed1982

Accumulation of pyroglutamic acid (5-oxoproline) in homocystinuria.

A 12-year-old boy with homocystinuria due to a cystathionine synthetase defect was shown to accumulate large amounts of pyroglutamic acid (pyroglu). In four different urine samples the concentration ranged between 4.1 and 9.7 mol/mol of creatinine. The pyroglu concentration in plasma was 1.6 mmol/l, and in erythrocytes 750 nmol/g cells. Normally only trace amounts are present. The pyroglu levels normalized during treatment with pyridoxine and folic acid. Accumulation of pyroglu has not previously been described in homocystinuria. Homocysteine can replace cysteine as a substrate for gamma-glutamylcysteine synthetase, an enzyme involved in the biosynthesis of glutathione, giving gamma-glutamylhomocysteine. This dipeptide is efficiently split by gamma-glutamylcyclotransferase to pyroglu and homocysteine. This reaction sequence most likely explains the accumulation of pyroglu in our patient. Ten other homocystinuria patients, who all had lower plasma levels of homocysteine, did not accumulate pyroglu. Our patient might either be a new variant, or more likely the pyroglu formation occurs only high levels of homocysteine.

Amino Acids↗
PubMed1999

L-pyroglutamic acid protects rat cortical neurons against sodium glutamate-induced injury.

AIM: To evaluate the effects of L-pyroglutamic acid (L-PGA, L-5-oxo-2-pyrrolidinecaroxylic acid) on sodium glutamate-induced neurotoxicity in rat cortical neurons. METHODS: In primary cortical cultures from 16-d-old fetal rat, neuronal viability and contents of nitrite in the bathing medium after transient exposure to sodium glutamate (Glu) were measured; with Fura 2-AM as an intracellular calcium indicator, AR-CM-MIC cation measurement system was used to examine cytosolic free calcium ([Ca2+]i). RESULTS: L-PGA 10-80 mumol.L-1, inhibited Glu (500 mumol.L-1)-induced neuronal loss in a concentration-dependent manner with IC50 value of (41 +/- 9) mumol.L-1 (95% confidence limits: 30.3-54.7 mumol.L-1). L-PGA also attenuated Glu-induced NO release. L-PGA 1, 3, 10, 30, and 100 mumol.L-1 depressed Glu-caused [Ca2+]i elevation by 20.5%, 34.4%, 47.7%, 70.6%, and 80.4%, respectively. CONCLUSION: L-PGA protects cortical neurons against Glu-induced neurotoxity which may be related to inhibition of NO formation or suppression of the rise in [Ca2+]i.

Animals↗
PubMed1984

Pyroglutamic acid administration modifies the electrocorticogram and increases the release of acetylcholine and GABA from the guinea-pig cerebral cortex.

Pyroglutamic acid (1-PCA), a cyclic derivative of glutamic acid, was administered i.p. (7.7 mmol/kg) or intracerebroventricularly (25 - 50 mumol) to freely moving guinea-pigs, provided with semi-permanently implanted epidural cups. The effect of this compound on cortical Acetylcholine (ACh) and GABA outflow, as well as on gross behaviour and electrocorticogram (E.Co.G.) was investigated. 1-PCA increased the release of ACh and GABA from the cortical surface, did not change their cortical content, decreased the spontaneous motor activity and synchronized the E.Co.G.. These results suggest that 1-PCA increases GABA release, possibly by changing amino acid transport through the biological barrier or by acting as antagonist on the receptors for glutamic acid. In turn, the activation of the GABA system increases, as previously demonstrated, the cortical ACh release and causes mild sedation and E.Co.G. synchronization.

Acetylcholine↗
PubMed1979

N-alpha-Cocoyl-L-arginine ethyl ester, DL-pyroglutamic acid salt, as an inactivator of hepatitis B surface antigen.

N-alpha-Cocoyl-L-arginine ethyl ester, DL-pyroglutamic acid salt (CAE), exhibited a strong inactivating effect on hepatitis B surface antigen. Concentrations of CAE required for 50 and 100% inactivation of the antigen were 0.01 to 0.025% and 0.025 to 0.05% respectively. CAE completely inactivated hepatitis B surface antigen at the lowest concentration compared with various compounds including about 500 amino acid derivatives, sodium hypochlorite, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, and some detergents. Furthermore, CAE inactivated vaccinia virus, herpes simplex virus, and influenza virus, whereas poliovirus was not inactivated at all. The results suggest that the inactivating effects of CAE are related to interaction with lipid-containing viral envelopes.

Antiviral Agents↗
PubMed1994

[Synthesis of N-(4-carbomethoxy-4-phthalimidobutanoyl)-N-substituted glycines, proline and pyroglutamic acid].

This paper reports the synthesis of eleven N-(4-carbomethoxy-4-phthalimidobutanoyl)-N-substituted glycines (VII1-9), proline (VII10) and pyroglutamic acid (VII11) expected to have inhibitory activity on angiotensin converting enzyme. All of the compounds mentioned above and the corresponding t-butyl esters of VII1-9 were not reported in the literature previously. The structures were confirmed through their IR, 1HNMR, MS spectra and elemental analysis. In preliminary test in rats, compounds VII8, VII9 and VII10 showed marked hypotensive activity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

L-pyroglutamic acid inhibits energy production and lipid synthesis in cerebral cortex of young rats in vitro.

In the present study we investigated the effects of L-pyroglutamic acid (PGA), which predominantly accumulates in the inherited metabolic diseases glutathione synthetase deficiency (GSD) and gamma-glutamylcysteine synthetase deficiency (GCSD), on some in vitro parameters of energy metabolism and lipid biosynthesis. We evaluated the rates of CO2 production and lipid synthesis from [U-14C]acetate, as well as ATP levels and the activities of creatine kinase and of the respiratory chain complexes I-IV in cerebral cortex of young rats in the presence of PGA at final concentrations ranging from 0.5 to 3 mM. PGA significantly reduced brain CO2 production by 50% at the concentrations of 0.5 to 3 mM, lipid biosynthesis by 20% at concentrations of 0.5 to 3 mM and ATP levels by 52% at the concentration of 3 mM. Regarding the enzyme activities, PGA significantly decreased NADH:cytochrome c oxireductase (complex I plus CoQ plus complex III) by 40% at concentrations of 0.5-3.0 mM and cytochrome c oxidase activity by 22-30% at the concentration of 3.0 mM, without affecting the activities of succinate dehydrogenase, succinate:DCPIP oxireductase (complex II), succinate:cytochrome c oxireductase (complex II plus CoQ plus complex III) or creatine kinase. The results strongly indicate that PGA impairs brain energy production. If these effects also occur in humans, it is possible that they may contribute to the neuropathology of patients affected by these diseases.

Animals↗
PubMed2002

Pseudopeptide foldamers: the homo-oligomers of pyroglutamic acid.

As a part of a program evaluating substituted gamma-lactams as conformationally constrained building blocks of pseudopeptide foldamers, we synthesized the homo-oligomers of L-pyroglutamic acid up to the tetramer level by solution methods. The preferred conformation of this pseudopeptide series in structure-supporting solvents was assessed by FT-IR absorption, 1H NMR and CD techniques. In addition, the crystal structure of the N alpha-protected dimer was established by X-ray diffraction. A high-level DFT computational modeling was performed based on the crystallographic parameters. In this analysis, we demonstrated that an alpha C-H...O=C intramolecular hydrogen bond is responsible for the stabilization of the s-trans L-pGlu-L-pGlu conformation by 1.4 kcal mol-1. This effect can be easily detected by 1H NMR spectroscopy, owing to the anomalous chemical shifts of the alpha CH protons present in all of the oligomers. In summary, we have developed a new polyimide-based, foldameric structure that, if appropriately functionalized, has promise as a rigid scaffold for novel functions and applications.

Crystallography, X-Ray↗
PubMed1987

Effect of pyroglutamic acid stereoisomers on ECS and scopolamine-induced memory disruption and brain acetylcholine levels in the rat.

The acquisition of a passive avoidance conditioned response was disrupted in the rat by electroconvulsive shock (ECS) and scopolamine administration. D,L-pyroglutamic acid (D,L-PCA) 500 and 1000 mg/kg, administered as arginine salt 120 min before the retest, prevented both the ECS and scopolamine-induced amnesia. Arginine alone was ineffective. Scopolamine brought about a 52 and 39% decrease, respectively, in cortical and hippocampal acetylcholine (ACh) levels, measured by means of a gas-chromatographic method. D,L-PCA 500 and 1000 mg/kg also prevented the decrease in brain ACh level. When the two isomers were studied separately, D-PCA was more effective than L-PCA and antagonized scopolamine-induced amnesia at the doses of 250 and 500 mg/kg. In conclusion, D,L-PCA is active on cortical and hippocampal cholinergic mechanisms and, like other 2-oxopyrrolidone derivatives, shows cognition-enhancing properties.

Acetylcholine↗
PubMed2006

Modifications of the pyroglutamic acid and histidine residues in thyrotropin-releasing hormone (TRH) yield analogs with selectivity for TRH receptor type 2 over type 1.

Thyrotropin-releasing hormone (TRH) analogs in which the N-1(tau) or the C-2 position of the imidazole ring of the histidine residue is substituted with various alkyl groups and the l-pyroglutamic acid (pGlu) is replaced with the l-pyro-2-aminoadipic acid (pAad) or (R)- and (S)-3-oxocyclopentane-1-carboxylic acid (Ocp) were synthesized and studied as agonists for TRH receptor subtype 1 (TRH-R1) and subtype 2 (TRH-R2). We observed that several analogs were selective agonists of TRH-R2 showing relatively less or no activation of TRH-R1. For example, the most selective agonist of the series 13, in which pGlu is replaced with the pAad and histidine residue is substituted at the N-1 position with an isopropyl group, was found to activate TRH-R2 with a potency (EC(50)=1.9microM) but did not activate TRH-R1 (potency>100 microM); that is, exhibited >51-fold greater selectivity for TRH-R2 versus TRH-R1. Analog 8, in which pGlu is replaced with pAad and histidine is substituted at the N-1(tau) position with a methyl group, exhibited a binding affinity (K(i)=0.0032 microM) to TRH-R1 that is similar to that of [Ntau(1)-Me-His]-TRH and displayed potent activation of TRH-R1 and TRH-R2 (EC(50)=0.0049 and 0.0024 microM, respectively). None of the analogs in which pGlu is replaced with the bioisosteric (R)- and (S)-(Ocp) and the imidazole ring is substituted at the N-1(tau) or C-2 position were found to bind or activate either TRH-R1 or TRH-R2 at the highest test dose of 100 microM.

Histidine↗
PubMed1990

Oxiracetam and D-pyroglutamic acid antagonize a disruption of passive avoidance behaviour induced by the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovalerate.

Intracerebroventricular administration (6 micrograms/2 microliters) of D-2-amino-5-phosphonovalerate (AP-5), a specific antagonist of the NMDA receptors, prior to training impaired the passive avoidance in a retention test in rat. Pretreatment with oxiracetam and D-pyroglutamic acid at doses ranging from 50 to 500 mg/kg SC dose-dependently prevented the disruptive effect of AP-5. This finding indicates that an interaction with excitatory amino acid NMDA type receptors may be important in behavioural effects of the two pyrrolidinone derivatives.

Animals↗
PubMed1997

Pyroglutamic acid and iron regulate the expression of the pcp gene in Pseudomonas fluorescens MFO.

Pyrrolidone carboxyl peptidase (Pcp) is an aminopeptidase (EC 3.4.11.8) able to specifically remove the L-pyroglutamyl residue from the amino-terminus of polypeptides. Since nothing was known concerning the regulation and function of Pcps, a mutant of a milk-isolated strain lacking Pcp activity (Pseudomonas fluorescens MB1), was constructed by homologous recombination using a transcriptional fusion between pcp and a reporter gene (uidA). The wild-type and mutant strains were grown in synthetic media and in milk to investigate the environmental effects on pcp transcription. The expression of pcp and of the transcriptional fusion pcp::uidA was not sensitive to environmental conditions like temperature, osmolarity or nitrogen and phosphate starvation but was induced by the product of the enzymatic activity, pyroglutamic acid (pGlu). The expression of the native gene and the fusion in inducing conditions was also controlled by the iron concentration. The identification in the pcp promoter sequence of putative ferric uptake regulator (Fur) binding sites suggests a transcriptional regulation in a Fur-dependent fashion. Two other putative regulatory stretches, corresponding to inverted repeated sequences with perfect and imperfect symmetry, were also identified. pGlu and iron are therefore at least two of the transcriptional effectors of pcp expression.

Amino Acid Sequence↗
PubMed2004

Virtually complete control of simple and face diastereoselectivity in the Michael addition reactions between achiral equivalents of a nucleophilic glycine and (S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones: practical method for preparation of beta-substituted pyroglutamic acids and prolines.

This study demonstrates a new strategy for controlling the stereochemical outcome of the Michael addition reactions between nucleophilic glycine equivalents and alpha,beta-unsaturated carboxylic acid derivatives: The addition reactions between achiral Ni(II)-complex of the Schiff base of glycine with o-[N-alpha-pycolylamino]acetophenone and (S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones were shown to occur at room temperature in the presence of nonchelating organic bases and, most notably, with very high stereoselectivity at both newly formed stereogenic centers. Thus, the chiral 4-phenyl-1,3-oxazolidin-2-one moiety was found to control efficiently both face diastereoselectivities of the glycine derived enolate and the C,C double bond of the Michael acceptor. The new strategy developed in this work is methodologically superior to previous methods, most notably in terms of generality and synthetic efficiency. Excellent chemical yields and diastereoselectivities, combined with the simplicity of the experimental procedures, render the present method of immediate use for preparing various 3-substituted pyroglutamic acids and related amino acids (glutamic acids, glutamines, prolines, etc.) available via conventional transformations of the former.

Glycine↗