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PubMed1982

s-Cis...and s-trans isomerism in acylproline analogs. Models for conformationally locked proline peptides.

N-Acetyl-2,3-dehydroproline, N-acetyl-5-oxo-L-proline, N-acrylyl-L-proline, N-acetyl-L-azetidine-2-carboxylic acid and N-acetyl-D,L-pipecolic acid have been examined in 2H2O by 1H and 13Cn.m.r. for the purpose of finding s-cis or s-trans locked acylprolines. Conformationally locked acylprolines could be incorporated into proline-containing peptide hormones such as angiotensin and thyroliberin in order to determine the rotational state of the peptide bond to proline in the hormone receptor complex. The populations of trans and cis rotational isomers were determined as a function of p2H in order to assign the trans and cis isomers and to compare the populations in all the acylprolines at neutral p2H, where the cis isomer is normally present. Proton spectra were also recorded at from 7 degrees to 75 degrees in order to qualitatively determine the exchange rate between the isomers. The majority of these analogs exhibit a cis-trans isomerization similar to that of N-acetyl-L-proline in the ratio of trans to cis rotational isomer found at neutral p2H (about 1:1), the temperature dependence of the population ratio (none), and the coalescence temperature for proton resonances (greater than 75 degrees). However, N-acetyl-5-oxo-L-proline was found to be greater than 98% s-trans at neutral pH, compared to 50% s-trans in N-acetyl-L-proline, and therefore a good candidate for synthesis of an s-trans locked peptide hormone. N-Acetyl-2,3-dehydroproline rapidly exchanges between s-cis and s-trans in contrast to all other proline analogs examined and exhibits coalescence of the beta-proton cis and trans resonances at 45 degrees. Titration with the shift reagent Pr+++ was employed to confirm the assignments of the cis and trans methyl resonances of all of the N-acetyl compounds except N-acetyl-5-oxo-L-proline.

Magnetic Resonance Spectroscopy↗
PubMed1995

Synthesis of dipeptide 4-nitroanilides containing non-proteinogenic amino acids.

A series of tert-butyloxycarbonyl amino acid 4-nitroanilides, including N-alkylated amino acids and (R)-thiazolidine-4-carboxylic acid, (S)-oxazolidine-4-carboxylic acid. (4S,5S)-5-methyloxazolidine-4-carboxylic acid, (4S,5R)-5-methyloxazolidine-4-carboxylic acid, (S)-azetidine-2-carboxylic acid, (S)-pipecolic acid and (S)-3,4-dehydroproline, were prepared conveniently by the isocyanate method or the mixed anhydride procedure. The resulting amino acid 4-nitroanilides were extended to corresponding dipeptide 4-nitroanilides with tert-butyloxycarbonyl-(S)-alanine. In the case of sterically hindered amino acid 4-nitroanilides the mixed anhydride procedure with diphenylphosphinyl chloride was successful.

Amino Acids↗
PubMed1988

Extracellular matrix synthesis is required for the movement of sclerotome and neural crest cells on collagen.

During early embryogenesis cells of several different populations disperse by active cell movement from one location to another. Preexisting extracellular materials are major determinants of these dispersal patterns, but the cells are also able to modify their substrata by synthesizing and secreting extracellular matrix molecules as they move. In order to determine the contribution made by these deposited materials, several tissues from the early chick embryo have been cultured in the presence of inhibitors of extracellular matrix synthesis and secretion. The tissues examined were sclerotome cells from differentiated somites and neural crest cells. For comparison, undifferentiated somites were also cultured. The movement of these cells was compared in type I collagen gel culture and in conventional culture on artificial substrata. Inhibitors of collagen synthesis were used (cis-hydroxy proline and L-azetidine-2-carboxylic acid) in addition to a proteoglycan inhibitor (p-nitrophenyl-xylopyranoside) and a secretion inhibitor (monensin). Results indicate that sclerotome cells require collagen synthesis for movement in a collagen matrix. Reversal of the effects of collagen inhibitors, by proline and type II collagen, suggest that sclerotome cells normally condition the type I matrix in order to move in it. Inhibition of proteoglycan synthesis produced the greatest effect on the movement of neural crest cells regardless of the substratum, confirming an important role for these molecules in the crest migratory routes. The attachment of all cells to collagen was highly sensitive to the presence of monensin, which is known to reduce the deposition of glycosaminoglycans and fibronectin. These results suggest that conditioning of the extracellular matrix by newly synthesized material is required for cell attachment and movement during early development.

Animals↗
PubMed1996

Ser57 in the Na+/proline permease of Escherichia coli is critical for high-affinity proline uptake.

Ser57 in the Na+/proline permease of Escherichia coli has been replaced with alanine, cysteine, glycine, or threonine, and properties of the corresponding putP mutants have been analyzed. Although Ser57 is not essential for activity, the amino acid side chain at this position is critical for proline uptake. Thus, alanine, cysteine, glycine, or threonine in place of Ser57 reduces the initial rate of proline transport under standard conditions to less than 10% of the wild-type value. In addition, substitution of Ser57 in the Na+/proline permease reduces the sensitivity of E. coli cells to the toxic proline analogs L-azetidine-2-carboxylate and 3.4-dehydro-D.L-proline. Replacement of Ser57 with alanine or cysteine results in apparent affinities for proline that are reduced by more than two orders of magnitude, and permeases with threonine and glycine in place of Ser57 yield apparent affinities reduced by a factor of 60 and 18 respectively, relative to wild-type. In contrast, all of the Ser57 replacements analyzed cause only small changes in Vmax values. All permease molecules containing Ser57 substitutions are inserted into the membrane in amounts comparable to the wild-type protein as shown by immunoblot analysis. These results indicate that alterations of proline transport and sensitivity to toxic proline analogs have to be attributed primarily to defects in substrate binding. It is suggested that the serine residue at position 57 of the permease is located within the substrate-binding domain of the protein.

Amino Acid Sequence↗
PubMed1995

Activation of class II or III metabotropic glutamate receptors protects cultured cortical neurons against excitotoxic degeneration.

Trans-1-aminocyclopentane-1,3-dicarboxylic acid, a mixed agonist of all metabotropic glutamate receptor (mGluR) subtypes, is known to produce either neurotoxic or neuroprotective effects. We have therefore hypothesized that individual mGluR subtypes differentially affect neurodegenerative processes. Selective agonists of subtypes which belong to mGluR class II or III, such as (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)-glycine (DCG-IV) (specific for subtypes mGluR4, 6 or 7), were highly potent and efficacious in protecting cultured cortical neurons against toxicity induced by either a transient exposure to N-methyl-D-aspartate (NMDA) or a prolonged exposure to kainate. In contrast, agonists that preferentially activate class I mGluR subtypes (mGluR1 or 5), such as quisqualate or trans-azetidine-2,3-dicarboxylic acid, were inactive. DCG-IV was still neuroprotective when applied to cultures after the toxic pulse with NMDA. This delayed rescue effect was associated with a reduction in the release of endogenous glutamate, a process that contributes to the maturation of neuronal damage. We conclude that agonists of class II or III mGluRs are of potential interest in the experimental therapy of acute or chronic neurodegenerative disorders.

Animals↗
PubMed1998

Antagonists for group I mGluRs attenuate excitotoxic neuronal death in cortical cultures.

Activation of ion channel-linked glutamate receptors, especially N-methyl-D-aspartate (NMDA) receptors, mediates the excitotoxic effects of glutamate upon central neurons. We examined the hypothesis that activation of group I metabotropic glutamate receptors (mGluRs) would increase NMDA receptor-mediated cortical neuronal death. Addition of the selective group I mGluR agonists, dihydroxyphenylglycine (DHPG) or trans-azetidine-2,4-dicarboxylic acid (t-ADA) potentiated NMDA-induced neuronal death, and application of the group I mGluR-selective antagonist, aminoindan-1,5-dicarboxylic acid (AIDA), as well as the non-selective antagonists methyl-4-carboxyphenylglycine (MCPG) or 4-carboxyphenylglycine (4CPG) reduced NMDA- and kainate-induced neuronal death in murine cortical cultures. The pro-excitotoxic effect of group I mGluR activation may be mediated largely by enhancement of glutamate release, as DHPG potentiated high potassium-stimulated glutamate release, and the protective effects of both AIDA and MCPG were abolished when NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors were blocked immediately after toxic NMDA receptor overstimulation. The present data support the possibility that antagonizing group I mGluRs may be a useful strategy for attenuating excitotoxic neuronal death in certain disease states.

Animals↗
PubMed1996

Sensitivity of Escherichia coli to proline analogues during osmotic stress and anaerobiosis.

The sensitivity of wild-type Escherichia coli K-12 to a series of proline analogues was determined in cultures containing increasing concentrations of NaCl under both aerobic and anaerobic conditions. The bacteria were most sensitive to L-azetidine-2-carboxylate and L-thiazolidine-4-carboxylate. The minimum inhibitory concentrations for these compounds decreased progressively during osmotic stress, but the bacteria were much more sensitive to these proline analogues under aerobic conditions than during anaerobiosis. The reduced sensitivity under anaerobic conditions did not reflect degradation of the compounds in the culture medium. Since both urine and medullary renal tissue contain relatively low oxygen concentrations, these results raise doubts about the potential use of proline or glycine betaine analogues in treating urinary tract infections.

Anaerobiosis↗
PubMed1979

Transport of L-proline and its regulation in Leishmania tropica promastigotes.

Leishmania tropica promastigotes transport L-proline through an active uptake system that has saturation kinetics, temperature dependence, a requirement for metabolic energy and transport against a concentration gradient. In experiments lasting 10 min, less than 10% of the proline transported is incorporated into macromolecules. The remainder is largely unaltered proline with an intracellular concentration nearly 60 times that in the reaction mixture. The uptake system has a relatively broad specificty; it is competitively inhibited by D-proline as well as by alanine, methionine, valine, azetidine-2-carboxylate, thioproline, 3,4-dehydropoline, hydroxyproline and alpha-aminoisobutyric acid. Pre-established intracellular proline pools exchange with external proline as well as compounds that compete with it for uptake. Evidence is presented that feedback inhibition and transinhibition may regulate proline uptake in this organism.

Amino Acids↗
PubMedDate not supplied

Further studies on substrates inducing metacyclogenesis in Trypanosoma cruzi.

Epimastigotes of Trypanosoma cruzi, Peru strain, incubated in Contreras' artificial triatomine urine transformed into metacyclic trypomastigotes when 10 mM L-glutamine, L-asparagine or D-fructose was added to the medium. Metacyclogenesis with these substrates was comparable to the percent metacyclic morphotype formation induced by L-proline and significantly greater than that stimulated by 10 mM D-glucose. Sodium acetate (10 mM) increased transformation induced by L-proline, and L-hydroxyproline (10 mM) increased transformation induced by D-fructose. Phosphoenolpyruvate (10 mM) inhibited L-proline-induced metacyclic trypomastigote stage formation. Three antimetabolites, azetidine 2-carboxylate (5 mM), malonic acid (1 mM), and desthiobiotin (5 mM), completely inhibited D-fructose-induced but not L-proline-induced transformation. The Costa Rica, Y, and CL strains of T. cruzi showed different patterns of percent metacyclogenesis with substrates that induce transformation in the Peru strain.

Amino Acids↗
PubMed1988

Expression of heat stress proteins by human periodontal ligament cells.

The purpose of the present report was to document the stress response produced by physical and chemical abuses to human periodontal ligament cells, and to review some of the known functions of stress response proteins produced as a result of such treatments. For these studies human PDL cells were exposed to sublethal challenges of 43 degrees C heat, sodium arsenite and the amino acid analog L-azetidine-2-carboxylic acid (AZC). The cells were labelled with [35S]-methionine and the proteins produced were examined by autofluorography of SDS-PAGE gels. Heat challenges were shown to induce hsps with an apparent mol. wts. of 90K, 68-72K, 41-47K, and 36 K. Arsenite-treated cells produced similar hsps including a 30k protein not produced by other forms of stress. AZC treatment resulted in the production of apparent functionless hsps with apparent molecular weights of 90,000, 72,000, 68,000 and 36,000. The function of these proteins and their possible role in periodontal disease is discussed.

Arsenic↗
PubMed1978

Comparative physiological effects of incorporated amino acid analogs in Escherichia coli.

The relative toxicities of several incorporated analogs of phenylalanine, methionine, arginine, and proline were assessed by a variety of criteria in a derivative of Escherichia coli 15 requiring the antagonized amino acids. Toxicity of the analog-substituted cell protein was most consistently indicated by its insolubility at graded temperatures, its increased breakdown, the relative suppression of further cell growth, and lethality. The relative toxicity of poorly utilized analogs could be judged clearly only by the first two criteria. Toxicity generally increased as follows: selenomethionine < 2,5-dihydrophenylalanine and m-fluorophenylalanine < o-fluorophenylalanine and norleucine < ethionine < p-fluorophenylalanine < azetidine-2-carboxylate < canavanine. The overall perturbation of cell protein structure indicated by the toxicity of the methionine and phenylalanine analogs correlated with their alteration of charge and bulk and was greatly modified by minor positional modifications of fluorine. Among the more specific functional impairments, the activity and heat stability of beta-galactosidase were lowered in parallel by substitutions of phenylalanine and methionine analogs, but not in the usual order of toxicity. Flagella were transiently motile with p-fluorophenylalanine, moderately motile with m-fluorophenylalanine, and fully motile with all methionine analogs. Usually the analog incorporations were no more than bacteriostatic in E. coli strains, canavanine killing only the E. coli 15 substrain extensively in minimal media. Selenomethionine supported indefinite growth of procaryotes such as Bacillus subtilis and certain E. coli strains, but only upon supplementation, at least initially, with many nonessential metabolites.

Amino Acids↗
PubMed1991

In vitro and in vivo antibacterial activities of E-4497, a new 3-amine-3-methyl-azetidinyl tricyclic fluoroquinolone.

The in vitro and in vivo antibacterial activities of a new tricyclic fluoroquinolone, E-4497 [S(-)-9-fluoro-3-methyl-10-(3-amine-3-methyl-azetidin-1-yl)-7-oxo- 2,3-dihydro- 7H-pyrido-(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid], were evaluated in comparison with those of DR-3355 [S-(-)-ofloxacin], norfloxacin, and ciprofloxacin. E-4497 was more potent than norfloxacin and as potent as or more potent than DR-3355 and ciprofloxacin against Staphylococcus spp., Streptococcus spp., and Enterococcus faecalis. With the exception of Providencia spp., E-4497 inhibited 90% of the Enterobacteriaceae at less than or equal to 0.25 micrograms/ml. Against enteric bacteria, E-4497 was similar in potency to norfloxacin but less potent than DR-3355 and ciprofloxacin. For Pseudomonas aeruginosa, the MICs of E-4497, DR-3355, norfloxacin, and ciprofloxacin for 90% of strains were 2, 2, 4, and 0.5 micrograms/ml, respectively. Against Clostridium perfringens and Bacteroides fragilis, E-4497 (MICs for 90% of strains, 2 and 8 micrograms/ml, respectively) was two- to fourfold more active than norfloxacin and ciprofloxacin. E-4497 activity decreased moderately in the presence of 10 mM Mg2+. Urine at pH 5.5 caused a significant decrease in activity compared with urine at pH 7.2. However, the presence of serum either had no effect or increased the activity of E-4497. In general, E-4497 was bactericidal at the MIC. In systemic infections with Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa in mice, the protective effect of E-4497 was generally greater than that of norfloxacin and comparable to those of DR-3355 and ciprofloxacin.

Animals↗
PubMed1985

Proline-hyperproducing strains of Serratia marcescens: enhancement of proline analog-mediated growth inhibition by increasing osmotic stress.

Proline-producing strains of Serratia marcescens were more osmotolerant than wild-type strains. Growth inhibition by proline analogs was significantly enhanced by increasing the osmotic stress of the medium. Mutants resistant to azetidine-2-carboxylate were derived from a proline-producing strain, SP126, under a high osmotic condition. One of the mutants, strain SP187, produced 56 mg of L-proline per ml of medium containing sucrose and urea. This amount was ca. 3 times larger than that produced by strain SP126. The intracellular glutamate content which decreased in strain SP126 was restored in strain SP187. The glutamate dehydrogenase level of strain SP187 was 5 times higher than that of strain SP126.

Glutamate Dehydrogenase↗
PubMed2001

Mutations in the listerial proB gene leading to proline overproduction: effects on salt tolerance and murine infection.

The observed sensitivity of Listeria monocytogenes to the toxic proline analogue L-azetidine-2-carboxylic acid (AZ) suggested that proline synthesis in Listeria may be regulated by feedback inhibition of gamma-glutamyl kinase (GK), the first enzyme of the proline biosynthesis pathway, encoded by the proB gene. Taking advantage of the Epicurian coli mutator strain XL1-Red, we performed random mutagenesis of the recently described proBA operon and generated three independent mutations in the listerial proB homologue, leading to proline overproduction and salt tolerance when expressed in an E. coli (DeltaproBA) background. While each of the mutations (located within a conserved 26-amino-acid region of GK) was shown to confer AZ resistance (AZ(r)) on an L. monocytogenes proBA mutant, listerial transformants failed to exhibit the salt-tolerant phenotype observed in E. coli. Since proline accumulation has previously been linked to the virulence potential of a number of pathogenic bacteria, we analyzed the effect of proline overproduction on Listeria pathogenesis. However, our results suggest that as previously described for proline auxotrophy, proline hyperproduction has no apparent impact on the virulence potential of Listeria.

Amino Acid Sequence↗
PubMed1975

Specificity of the Escherichia coli proline transport system.

The presence of both the carbonyl portion of the carboxyl group at position 2 of the pyrrolidine ring and a secondary amine was essential for uptake of a compound by the proline permease of Escherichia coli. The permease possessed a high affinity for azetidine-2-carboxylic acid and for compounds with ring structures smaller than the pyrrolidine ring. Pipecolic acid, the higher homologue of proline, and its derivatives were not transported. Cis- and trans-3,4-methano-prolines, also six-membered ring structures, behaved anomolously in that they possessed a high affinity for the permease. The difference between the methano-prolines and other six-membered ring structures probably resides in the fact that the former exist in the "boat" configuration whereas the latter possess the "chair" configuration. In general, substituted prolines in the cis configuration displayed a higher affinity for the permease than did corresponding trans isomers, though the affinity for substituted prolines was influenced by the position, size, and polar or nonpolar nature of the substituent group. At O C many analogues with affinity for proline permease exchanged with intracellular proline, but some analogues, notably trans-3-methyl- and trans-4-methyl-L-prolines, though possessing high affinity for the permease, showed an almost complete inability to exchange with intracellular proline.

Binding Sites↗
PubMed1981

Genetics of L-proline utilization in Escherichia coli.

L-Azetidine-2-carboxylate (AC) and 3,4-dehydro-D,L-proline (DHP) are toxic L-proline analogs that can be used to select bacterial mutants defective for L-proline transport. Mutants resistant to AC and DHP are defective for proline transport alone (putP mutants), and mutants resistant to AC but not to DHP are defective both in putP and in the closely linked proline dehydrogenase gene putA. Proline dehydrogenase oxidizes DHP but not AC, probably detoxifying the former compound. These observations were exploited in preparing an otherwise isogenic set of Escherichia coli K-12 strains with well-defined defects in the putP and putA genes. The results of this study suggest that the genetic and biochemical characteristics of proline utilization in E. coli K-12 are closely analogous to those of Salmonella typhimurium.

Chromosome Mapping↗
PubMed1981

Proline transport in Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae is capable of utilizing proline as the sole source of nitrogen. Mutants of S. cerevisiae with defective proline transport were isolated by selecting for resistance to either of the toxic proline analogs L-azetidine-2-carboxylate or 3,4-dehydro-DL-proline. Strains carrying the put4 mutation are defective in the high-affinity proline transport system. These mutants could still grow when given high concentrations of proline, due to the operation of low-affinity systems whose existence as confirmed by kinetic studies. Both systems were repressed by ammonium ions, and either was induce by proline. Low-affinity transport was inhibited by histidine, so put4 mutants were unable to grow on a medium containing high concentrations of proline to which histidine has been added.

Amino Acids↗
PubMed1986

Proline transport and osmotic stress response in Escherichia coli K-12.

Proline is accumulated in Escherichia coli via two active transport systems, proline porter I (PPI) and PPII. In our experiments, PPI was insensitive to catabolite repression and was reduced in activity twofold when bacteria were subjected to amino acid-limited growth. PPII, which has a lower affinity for proline than PPI, was induced by tryptophan-limited growth. PPII activity was elevated in bacteria that were subjected to osmotic stress during growth or the transport measurement. Neither PPI nor uptake of serine or glutamine was affected by osmotic stress. Mutation proU205, which was similar in genetic map location and phenotype to other proU mutations isolated in E. coli and Salmonella typhimurium, influenced the sensitivity of the bacteria to the toxic proline analogs azetidine-2-carboxylate and 3,4-dehydroproline, the proline requirements of auxotrophs, and the osmoprotective effect of proline. This mutation did not influence proline uptake via PPI or PPII. A very low uptake activity (6% of the PPII activity) observed in osmotically stressed bacteria lacking PPI and PPII was not observed when the proU205 lesion was introduced.

Amino Acid Transport Systems, Neutral↗