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PubMed1991

Rapid kidney changes resulting from glycosphingolipid depletion by treatment with a glucosyltransferase inhibitor.

The ceramide analog, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, inhibits the glucosylation of ceramide and thus, by virtue of the normal catabolism of the higher glucosphingolipids, leads to a general depletion of cellular glucolipids. In a previous study with chronic administration of this inhibitor in mice, it was found that the kidneys and liver, particularly the former, grew more poorly than the organs of control mice. This study shows that the inhibitor produces rapid decreases in glucolipid concentration in kidney which are maintained for at least 5 days without noticeable harm. The changes were enhanced by inclusion of L-cycloserine in the injection scheme. Cycloserine blocks ketosphinganine synthase and thus slows the synthesis of all sphingolipids. However, sphingomyelin levels did not drop significantly in this study. The glucosyltransferase inhibitor also produced a small decrease in kidney beta-D-glucuronidase and distinct increases in the levels of glucocerebrosidase, galactocerebrosidase and sphingomyelinase. It also produced a small but distinct decrease in the level of glucosyltransferase, after a delay of a few hours, possibly because the inhibitor was metabolized to a covalently inactivating product. Comparison with kidney, liver and brain showed that the kidney was more sensitive to the action of the morpholino inhibitor.

Animals↗
PubMed1995

Putative cognition enhancers reverse kynurenic acid antagonism at hippocampal NMDA receptors.

Oxiracetam, aniracetam and D-cycloserine, three putative cognition enhancers, were examined in a functional assay for NMDA receptors. Rat hippocampal slices or synaptosomes were labeled with [3H]noradrenaline and exposed to NMDA or glutamate in superfusion. NMDA (100 microM) elicited a remarkable rise (about 500%) in the release of [3H]noradrenaline from slices. The effect of NMDA was antagonized by the glutamate receptor blocker, kynurenic acid. The antagonism by 100 microM kynurenate was reduced by submicromolar concentrations of oxiracetam and totally reversed by 1 microM of the drug. The concentration-antagonism curve for kynurenic acid was shifted to the right in the presence of 0.2 or 1 microM oxiracetam. Aniracetam and D-cycloserine, as well as glycine and D-serine, behaved similarly to oxiracetam: all compounds, tested at 1 microM, reversed the antagonism by 100 microM kynurenate of the NMDA-evoked [3H]noradrenaline release. In superfused hippocampal synaptosomes, 100 microM NMDA or glutamic acid elicited the release of [3H]noradrenaline; the evoked release was enhanced by glycine, but not by oxiracetam. In this preparation 1 microM glycine or 1 microM oxiracetam prevented the antagonism by kynurenate of the NMDA- or the glutamate-evoked [3H]noradrenaline release. As kynurenic acid is an endogenous glutamate receptor antagonist whose brain levels are known to increase in conditions associated to cognitive deficits, it is proposed that the putative cognition enhancers tested may act in vivo by relieving the antagonism produced by excessive endogenous kynurenate.

Animals↗
PubMed1995

Effects of putative cognition enhancers on the NMDA receptor by [3H]MK801 binding.

Piracetam, aniracetam, and D-cycloserine were tested for their ability to reduce inhibition of [3H]MK801 (dizocilpine) binding by 100 microM kynurenate. Piracetam (100 microM-1 mM) failed to reduce inhibition by kynurenate but stimulated [3H]MK801 binding in the absence of kynurenate. In contrast, D-cycloserine (30 microM-1 mM) and aniracetam markedly reduced this inhibition by kynurenate. Thus, cognition enhancers might function via at least some subtypes of NMDA receptors.

Animals↗
PubMed1995

Inactivation of gamma-aminobutyric acid aminotransferase by L-3-chloroalanine hydroxamate.

The mechanism of inactivation of gamma-aminobutyric acid aminotransferase (GABA-AT) by L-3-chloroalanine hydroxamate (1) was investigated. Inactivation of [3H]PLP-reconstituted GABA-AT with 1 followed by denaturation gave no PMP or enamine adduct to the PLP; however, a new unknown metabolite was observed which was identical to the metabolite formed upon inactivation of GABA-AT by L-cycloserine. Time-dependent inactivation occurs, but the kinetics are second order; the rate of inactivation increases with time. After inactivation occurs the addition of fresh enzyme results in a faster rate of inactivation than prior to the initial inactivation. This indicates that the actual inactivator is generated from L-3-chloroalanine hydroxamate, and is not L-3-chloroalanine hydroxamate itself. Added gabaculine-inactivated enzyme to fresh enzyme does not increase the rate of inactivation, suggesting that the conversion of L-3-chloroalanine hydroxamate to the active form is not catalyzed by peripheral amino acid residues. L-3-Chloroalanine hydroxamate was shown to undergo buffer-catalyzed cyclization to L-cycloserine, which is the actual inactivator of GABA-AT.

4-Aminobutyrate Transaminase↗
PubMed2006

Characterization of cycA mutants of Escherichia coli. An assay for measuring in vivo mutation rates.

Quantitative assessment of the spontaneous or induced genomic mutation rate, a fundamental evolutionary parameter, usually requires the use of well-characterized mutant selection systems. Although there is a great number of genetic selection schemes available in Escherichia coli, the selection of D-cycloserine resistant mutants is shown here to be particularly useful to yield a general view of mutation rates and spectra. The combination of a well-defined experimental protocol with the Ma-Sandri-Sarkar maximum likelihood method of fluctuation analysis results in reproducible data, adequate for statistical comparisons. The straightforward procedure is based on a simple phenotype-genotype relationship, and detects mutations in the single-copy, chromosomal cycA gene, involved in the uptake of D-cycloserine. In contrast to the widely used rifampicin resistance assay, the procedure selects mutations which are neutral in respect of cell growth. No specific genetic background is needed, and practically the entire mutation spectrum (base substitutions, frameshifts, deletions, insertions) can simultaneously be measured. A systematic analysis of cycA mutations revealed a spontaneous mutation rate of 6.54 x 10(-8) in E. coli K-12 MG1655. The mutation spectrum was dominated by point mutations (base substitutions, frameshifts), spread over the entire gene. IS insertions, caused by IS1, IS2, IS3, IS4, IS5 and IS150, represented 24% of the mutations.

Amino Acid Transport Systems↗
PubMed2005

Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of glutamatergic drugs, acting agonistically on the N-methyl-D-aspartate (NMDA) or the non-NMDA receptors, in schizophrenia. METHOD: All relevant randomized controlled trials of glutamatergic drugs for schizophrenia were obtained from the Cochrane Schizophrenia Group's Register of Trials without any language or year limitations. Trials were classified according to their methodological quality. For binary and continuous data, relative risks and weighted (WMD) or standardized mean differences (SMD) were calculated, respectively. RESULTS: Eighteen short-term trials with 343 randomized patients were included in the meta-analysis. In all of these trials, glycine, D-serine, D-cycloserine or ampakine CX516 was used to augment antipsychotics. NMDA receptor co-agonists glycine and D-serine are effective in reducing negative symptoms (N = 132, fixed effect model SMD = -0.66, 95% CI -1.02 to -0.29, p = 0.0004) of schizophrenia, the magnitude of the effect is moderate. D-Cycloserine, a partial agonist of NMDA receptors, is less effective towards negative symptoms (N = 119, fixed effect model SMD = -0.11, 95% CI -0.48 to 0.25, p = 0.6). Positive symptoms fail to respond to glutamatergic medication. Available derived data on cognitive functioning do not indicate a significant effect of glycine or D-serine (N = 80, random effect model WMD = -2.79, 95% CI -6.17 to 0.60, p = 0.11). CONCLUSIONS: In the current limited data set, a moderate amelioration of negative symptoms of schizophrenia was found, but no other statistically significant beneficial effects on symptoms of schizophrenia.

Clozapine↗
PubMedDate not supplied

Deficits in water escape performance and alterations in hippocampal cholinergic mechanisms associated with neonatal monosodium glutamate treatment in mice.

Mice treated neonatally with monosodium glutamate (MSG) were found to have learning and memory deficits in performing a non-spatial water escape task. Scopolamine impaired the water-escape performance of the control mice but not that of the MSG-treated mice. It was suggested that the water-escape performance deficit in the MSG-treated mice was a result of impaired central cholinergic mechanisms. As such, scopolamine was unable to further incapacitate an already impaired cholinergic system. This is strongly supported by the decreased affinity of the sodium-dependent high-affinity choline uptake observed in the hippocampus. D-Cycloserine, a partial agonist at the glycine site of the NMDA receptor, did not affect the water-escape performance of the MSG-treated and control mice; nor did it alter the effects of scopolamine. This lack of effect of D-Cycloserine may imply that the NMDA receptors are not involved in non-spatial learning, in contrast to their reported involvement in spatial learning.

Animals↗
PubMed1973

Streptomyces DD-carboxypeptidases as transpeptidases. The specificity for amino compounds acting as carboxyl acceptors.

The ability of the water-soluble dd-carboxypeptidases of Streptomyces strains albus G, R61, K11 and R39 to perform transpeptidation was studied. The donor was diacetyl-l-lysyl-d-alanyl-d-alanine, and a whole range of amino acids, peptides and structurally related amino compounds were tested for acceptor function. No compound tested was an acceptor for the enzyme from strain albus G whereas the enzymes from strains R61 and K11 could utilize with varying efficiency a wide range of substances including peptides with N-terminal glycine or d-alanine, omega-amino acids, aminohexuronic acids, 6-aminopenicillanic acid and d-cycloserine. Certain peptides, when present in higher concentration, inhibited the transpeptidation observed at lower concentration. The enzyme from strain R39 would not use any dipeptide as an acceptor, but a few compounds that were not glycine or alpha-amino acids of the d-configuration did function thus. These were d-cycloserine and the lactams of meso- or racemic-diaminoadipic acid.

Carbon Isotopes↗
PubMed1996

Antimycobacterial activities of antisense oligodeoxynucleotide phosphorothioates in drug-resistant strains.

Strains of Mycobacterium smegmatis, a mycobacterium which shares genetic sequences, grows more rapidly, and is nonpathogenic in man as compared with Mycobacterium tuberculosis, were utilized for the initial development of new antimycobacterial therapy. Drug-resistant strains of M. smegmatis which are known to arise in a manner identical to the emergence of drug-resistant strains of M. tuberculosis were isolated and utilized as models for the antimycobacterial activities of modified and unmodified oligodeoxynucleotide phosphorothioates in broth cultures. Under normal conditions, oligodeoxynucleotide phosphorothioates do not enter mycobacteria, and several strategies were successfully utilized to afford entry of oligonucleotides into the mycobacterial cells. One involved the presence of very low levels of ethambutol, which enables the entry of oligonucleotides into mycobacteria because of its induced alterations in the cell wall, and another involved the utilization of oligonucleotides covalently attached to a D-cycloserine molecule, whereby entry into the mycobacterial cell is achieved by a receptor-mediated process. Another low molecular weight, covalently attached ligand that enabled the entry and subsequent antimycobacterial activities of oligodeoxynucleotide phosphorothioates in the absence of a cell wall modifying reagent was biotin. Significant sequence-specific growth inhibition of wild-type, as well as of drug-resistant, M. smegmatis was obtained by modified oligonucleotides complementary in sequence to a specific region of the mycobacterium aspartokinase (ask) gene when utilized in combinations with ethambutol (as compared to ethambutol alone) or as D-cycloserine or biotin covalent adducts without the presence of any other cytotoxic or cytostatic agent.

Antitubercular Agents↗
PubMed2006

Molecular dynamics simulations of the ligand-binding domain of an N-methyl-D-aspartate receptor.

The mechanism of partial agonism at N-methyl-D-aspartate receptors is an unresolved issue, especially with respect to the role of protein dynamics. We have performed multiple molecular dynamics simulations (7 x 20 ns) to examine the behavior of the ligand-binding core of the NR1 subunit with a series of ligands. Our results show that water plays an important role in stabilizing different conformations of the core and how a closed cleft conformation of the protein might be stabilized in the absence of ligands. In the case of ligand-bound simulations with both full and partial agonists, we observed that ligands within the binding cleft may undergo distinct conformational changes, without grossly influencing the degree of cleft closure within the ligand-binding domain. In agreement with recently published crystallographic data, we also observe similar changes in backbone torsions corresponding to the hinge region between the two lobes for the partial agonist, D-cycloserine. This observation rationalizes the classification of D-cycloserine as a partial agonist and should provide a basis with which to predict partial agonism in this class of receptor by analyzing the behavior of these torsions with other potential ligands.

Animals↗
PubMed2004

Pharmacological treatments of cerebellar ataxia.

The confirmed pharmacological treatment of cerebellar ataxia is still lacking. In a recent preliminary trial, we showed that D-cycloserine, a partial NMDA allosteric agonist, may relieve the symptoms. In this paper, major clinical trials to relieve ataxic symptoms are reviewed. Previous studies showed some efficacy of physostigmine in ataxic patients. However, physostigmine did not improve the ataxia in a recent double-blind crossover study. The replacement therapy of the deficient cholinergic system with choline or choline derivatives was tried in patients with Friedreich's ataxia and other ataxic patients, but the result was not definitive. A levorotatory form of hydroxytryptophan (a serotonin precursor), a serotoninergic 5-HT1A agonist, a serotoninergic 5-HT3 antagonist, and a serotonin reuptake inhibitor were also used for the therapy for ataxia. In a double-blind randomized study, buspirone, a 5-HT1A agonist was active in cerebellar ataxia, but the effect is partial and not major. The effects of the studies with the other serotoninergic drugs were not consistent. The effect of sulfamethoxazole-trimethoprim therapy in spinocerebellar ataxia type3/Machado-Joseph disease (MJD) was reported, although the therapy improved spasticity or rigidity, rather than ataxia. In contrast to previous studies, sulfamethoxazole-trimethoprim therapy in MJD had no effect in a 2001 double-blind crossover study. The thyrotropin-releasing hormone, D-cycloserine, and acetazolamide for SCA6 may have some efficacy. However, a well-designed double-blind crossover trial is needed to confirm the effect.

Cerebellar Ataxia↗
PubMed1999

Prepulse inhibition of the startle reflex in rats: effects of compounds acting at various sites on the NMDA receptor complex.

Prepulse inhibition (PPI) of the startle reflex in rats is disrupted by N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists (phencyclidine-like compounds). In order to explore more thoroughly the control exerted by NMDA receptors on PPI, we assessed the effects of i.p. administration, in Sprague-Dawley rats, of compounds acting as antagonists or agonists at the five binding sites of the NMDA receptor complex. The non-competitive NMDA receptor antagonists phencyclidine (1-6 mg/kg) and MK-801 (dizocilpine: 0.05-0.2 mg/kg) robustly and dose-dependently disrupted PPI. A similar effect was obtained with the competitive NMDA receptor antagonists CGS 19755 (1-20 mg/kg) and CPP (3-20 mg/kg), but not with the cation Mg2+ (100 and 200 mg/kg), the glycine/NMDA binding site antagonist L-701,324 (1-10 mg/kg), or the polyamine/NMDA binding site antagonist eliprodil (3-20 mg/kg). Potentiation of glutamatergic neurotransmission by NMDA (10-50 mg/kg), and the glycine/NMDA site partial agonist d-cycloserine (1-30 mg/kg) also failed to modify PPI, though d-cycloserine diminished PPI at higher doses (50-200 mg/kg). Co-administration of sub-threshold doses of CPP (3 mg/kg) and phencyclidine (2 mg/kg) resulted in an additive effect, disrupting PPI. In contrast, co-administration of L-701,324 (6 mg/kg) with phencyclidine (2 mg/kg), eliprodil (20 mg/kg), or CPP (3 mg/kg), did not disrupt PPI. These results demonstrate that PPI-disrupting effects can only be obtained with phencyclidine-like compounds and NMDA receptor competitive antagonists. Treatment with compounds that potentially augment glutamatergic tone were without effect. Finally, despite the permissive control of the glycine/NMDA binding site on glutamatergic neurotransmission, the glycine/NMDA binding site antagonist L-701,324 did not produce synergistic activity when combined with antagonists at the glutamate, polyamine/NMDA or phencyclidine-like compound binding sites.

Acoustic Stimulation↗
PubMed2001

Effects of N-methyl-D-aspartate agonists and antagonists in rats discriminating amphetamine.

The present study assessed the interactions between N-methyl-D-aspartate (NMDA) agonists or antagonists and the discriminative stimulus effects of amphetamine. Adult male Sprague-Dawley rats were trained to discriminate 0.5 mg/kg (i.p.) of amphetamine from saline under a two-lever fixed-ratio schedule of food reinforcement. During test sessions, i.p. injections of the glycine site agonist D-cycloserine, the ion-channel blocker dizocilpine and the competitive antagonist CGP 43487 were coadministered with i.p. saline or with a full range of doses of amphetamine. D-Cycloserine did not substitute for amphetamine and attenuated the cueing effects of the drug. Both dizocilpine and CGP 43487 engendered intermediate levels of amphetamine-appropriate responses and potentiated the stimulus properties of amphetamine; however, the effects of CGP 43487 were very small and not dose-dependent. In an ancillary experiment, the training dose of amphetamine was reduced to 0.25mg/kg; under these conditions dizocilpine, but not CGP 43487, produced full substitution for the discriminative stimulus effects of amphetamine. These results show that drugs affecting NMDA receptor-based neurotransmission can modulate the discriminative stimulus effects of amphetamine.

2-Amino-5-phosphonovalerate↗
PubMed1992

Peptidoglycan biosynthesis in Escherichia coli: variations in the metabolism of alanine and D-alanyl-D-alanine.

The in vivo functioning of the alanine/D-alanyl-D-alanine pathway of Escherichia coli was investigated by determining precursor pool levels and specific enzyme activities under various growth conditions. Cells grown on D- or L-alanine showed several remarkable features compared with cells grown on other carbon sources: 10-fold higher values of the D-alanyl-D-alanine and the UDP-MurNAc-pentapeptide pools, a 240-fold increase of the alanine racemase activity, and the absence of bacteriolysis after treatment with D-cycloserine at high concentrations (50 micrograms ml-1). In cells grown on glucose, D-cycloserine (1 micrograms ml-1) led to depletion of the D-alanyl-D-alanine pool and to lysis, which was efficiently antagonized by chloramphenicol. A threefold increase of the dipeptide pool was observed when cells were treated with chloramphenicol alone. The alanine racemase activity was lowest in glucose-grown cells and the D-alanine:D-alanine ligase and D-alanyl-D-alanine-adding activities were the same whatever the carbon source. Molecular masses of 53-56 kDa and 56-60 kDa were estimated for the partially purified inducible alanine racemase and D-alanine:D-alanine ligase respectively.

Alanine↗
PubMed2006

The occurrence of free D-alanine and an alanine racemase activity in Leishmania amazonensis.

Free D-amino acids are implicated in several biological functions. This study examined the presence of D-alanine in Leishmania amazonensis. Measuring chiral amino acid content by high-performance liquid chromatography we detected a significant amount of free D-alanine in promastigotes of these parasites. D-alanine accounts for 8.9% of total free alanine and is found primarily in the soluble fraction. Specific racemization of L-alanine to D-alanine was detected in cell lysates and this enzyme activity was inhibited by D-cycloserine, an alanine racemase inhibitor. Furthermore, we were able to decrease this pool of D-amino acid by treating our cultures with D-cycloserine. We demonstrate for the first time the existence of a significant amount of free D-alanine in L. amazonensis and an alanine racemase activity present in cell lysates. The restriction of D-alanine to bacteria, some fungi and now in L. amazonensis opens a new perspective on treatment of diseases caused by these microorganisms.

Alanine↗
PubMed2002

Use of the alr gene as a food-grade selection marker in lactic acid bacteria.

Both Lactococcus lactis and Lactobacillus plantarum contain a single alr gene, encoding an alanine racemase (EC 5.1.1.1), which catalyzes the interconversion of D-alanine and L-alanine. The alr genes of these lactic acid bacteria were investigated for their application as food-grade selection markers in a heterologous complementation approach. Since isogenic mutants of both species carrying an alr deletion (Deltaalr) showed auxotrophy for D-alanine, plasmids carrying a heterologous alr were constructed and could be selected, since they complemented D-alanine auxotrophy in the L. plantarum Deltaalr and L. lactis Deltaalr strains. Selection was found to be highly stringent, and plasmids were stably maintained over 200 generations of culturing. Moreover, the plasmids carrying the heterologous alr genes could be stably maintained in wild-type strains of L. plantarum and L. lactis by selection for resistance to D-cycloserine, a competitive inhibitor of Alr (600 and 200 micro g/ml, respectively). In addition, a plasmid carrying the L. plantarum alr gene under control of the regulated nisA promoter was constructed to demonstrate that D-cycloserine resistance of L. lactis is linearly correlated to the alr expression level. Finally, the L. lactis alr gene controlled by the nisA promoter, together with the nisin-regulatory genes nisRK, were integrated into the chromosome of L. plantarum Deltaalr. The resulting strain could grow in the absence of D-alanine only when expression of the alr gene was induced with nisin.

Anti-Bacterial Agents↗
PubMed2004

Selection and characterization of conditionally active promoters in Lactobacillus plantarum, using alanine racemase as a promoter probe.

This paper describes the use of the alr gene, encoding alanine racemase, as a promoter-screening tool for the identification of conditional promoters in Lactobacillus plantarum. Random fragments of the L. plantarum WCFS1 genome were cloned upstream of the promoterless alr gene of Lactococcus lactis in a low-copy-number plasmid vector. The resulting plasmid library was introduced into an L. plantarum Deltaalr strain (MD007), and 40,000 clones were selected. The genome coverage of the library was estimated to be 98%, based on nucleotide insert sequence and restriction analyses of the inserts of randomly selected clones. The library was screened for clones that were capable of complementing the D-alanine auxotroph phenotype of MD007 in media containing up to 10, 100, or 300 micro g of the competitive Alr inhibitor D-cycloserine per ml. Western blot analysis with polyclonal antibodies raised against lactococcal Alr revealed that the Alr production level required for growth increased in the presence of increasing concentrations of D-cycloserine, adding a quantitative factor to the primarily qualitative nature of the alr complementation screen. Screening of the alr complementation library for clones that could grow only in the presence of 0.8 M NaCl resulted in the identification of eight clones that upon Western blot analysis showed significantly higher Alr production under high-salt conditions than under low-salt conditions. These results established the effectiveness of the alanine racemase complementation screening method for the identification of promoters on their conditional or constitutive activity.

Alanine Racemase↗
PubMed1974

Production of flavine-adenine dinucleotide from riboflavine by a mutant of Sarcina lutea.

A study was made to develop a new method for the production of flavine-adenine dinucleotide (FAD) from riboflavine and adenine by a mutant of Sarcina lutea deficient in the enzyme adenosine deaminase. It was found that this strain could convert exogenously supplemented riboflavine to extracellular FAD. The yields of FAD were increased by addition of D-cycloserine in the culture medium. The culture conditions for FAD production were investigated under the addition of D-cycloserine, and increased production of FAD was observed with the addition of an appropriate amount of thiamine, acetate, and sodium ion. The yield of 0.7 g/liter was obtained in the optimal culture in 5 days. Accumulated FAD was readily isolated by adsorption chromatography and ion-exchange chromatography in a 70% yield.

Acetates↗