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PubMed2006

Genetically modified cyanobacterium Nostoc muscorum overproducing proline in response to salinity and osmotic stresses.

In the parent Nostoc muscorum an active proline oxidase enzyme is required to assimilate exogenous proline as a fixed nitrogen source. Cyanobacterial mutants, resistant to growth inhibitory action of proline analogue L-azetidine-2-carboxylate (Ac-R), were deficient in proline oxidase activity, and were over-accumulators of proline. Proline over-accumulation, resulting either from mutational acquisition of the Ac-R phenotype, or from salinity-induced uptake of exogenous proline, confirmed enhanced salinity/osmotic tolerance in the mutant strain. The nitrogenase activity and photosynthetic O 2 evolution of the parent were sensitive to both salinity as well as osmotic stresses than of Ac-R mutant strain. In addition, the mutation to Ac-resistant phenotype showed no alteration in salinity inducible potassium transport system in the cyanobacterium.

Azetidinecarboxylic Acid↗
PubMed1986

Effects of antifibrotic substances on pancreatic fibrosis following acute necrotizing pancreatitis.

This study was designed to search for a way to inhibit pancreatic fibrosis following acute pancreatitis. Experimental necrotizing pancreatitis was induced by a freezing procedure in the pancreas of male Wistar rats. After the freezing procedure, the rats were divided into 3 groups: nothing addition was done to the control group, while the other 2 groups received daily intraperitoneal administration of antifibrotic substances (colchicine or L-azetidine-2-carboxylic acid (AZC)) for 6 weeks. Pancreatic enzymes in the serum were not markedly influenced by administration of antifibrotic substances, and there were no differences in the ratios of dry to wet weights of the pancreas between groups with and without these drugs. After freezing, the hydroxyproline levels in the pancreas of the control group increased from 1 to 4 weeks and then decreased during the 5th and 6th weeks. All groups receiving colchicine or AZC exhibited a significant decrease in the hydroxyproline levels at 2 to 4 weeks compared with the control group (P less than 0.01). Histological examination also showed the inhibition of pancreatic fibrosis, agreeing with changes in the hydroxyproline levels in groups receiving colchicine or AZC. These results suggest that administration of antifibrotic substances, colchicine and AZC, have the possibility of inhibiting pancreatic fibrosis following acute pancreatitis.

Animals↗
PubMed1998

Modulation of sensory inhibition in the ventrobasal thalamus via activation of group II metabotropic glutamate receptors by 2R,4R-aminopyrrolidine-2,4-dicarboxylate.

Recordings were made from single neurones responsive to somatosensory input in the ventrobasal thalamus of the anaesthetised rat. GABAergic afferent inhibition arising from the thalamic reticular nucleus was evoked using a condition-test vibrissal stimulation paradigm. Local iontophoretic application of the group II metabotropic glutamate receptor (mGluR) agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC) in the vicinity of the recorded neurones produced a reduction of the afferent inhibition (from 78+/-3.0% to 25+/-5.3%), presumably via a presynaptic mechanism. This effect could be antagonised by LY307452, a known group II mGluR antagonist. In contrast, two selective group I mGluR agonists, (S)-3,5-dihydroxyphenylglycine (DHPG) and trans-azetidine-2,4-dicarboxylate (tADA), were without effect on the GABAergic inhibition. These data show that group II but not group I mGluRs can have a significant role in the modulation of GABAergic afferent inhibition in the ventrobasal thalamus. This could be of importance in the control of sensory discriminative processes and functions of sleep, arousal and seizure generation.

Animals↗
PubMed2006

Substrate specificity of the amino acid transporter PAT1.

The proton coupled amino acid transporter PAT1 expressed in intestine, brain, and other organs accepts L- and D-proline, glycine, and L-alanine but also pharmaceutically active amino acid derivatives such as 3-amino-1-propanesulfonic acid, L-azetidine-2-carboxylic acid, and cis-4-hydroxy-D-proline as substrates. We systematically analyzed the structural requirements for PAT1 substrates by testing 87 amino acids, proline homologs, indoles, and derivatives. Affinity data and effects on membrane potential were determined using Caco-2 cells. For aliphatic amino acids, a blocked carboxyl group, the distance between amino and carboxyl group, and the position of the hydroxyl group are affinity limiting factors. Methylation of the amino group enhances substrate affinity. Hetero atoms in the proline template are well tolerated. Aromatic alpha-amino acids display low affinity. PAT1 interacts strongly with heterocyclic aromatic acids containing an indole scaffold. The structural requirements of PAT1 substrates elucidated in this study will be useful for the development of prodrugs.

Amino Acid Transport Systems↗
PubMed2005

Characterization of the genomic structures and selective expression profiles of nine class I small heat shock protein genes clustered on two chromosomes in rice (Oryza sativa L.).

The cytosolic class I small heat shock proteins (sHSP-CI) represent the most abundant sHSP in plants. Here, we report the characterization and the expression profile of nine members of the sHSP-CI gene family in rice (Oryza sativa Tainung No.67), of which Oshsp16.9A, Oshsp16.9B, Oshsp16.9C, Oshsp16.9D and Oshsp17.9B are clustered on chromosome 1, and Oshsp17.3, Oshsp17.7, Oshsp17.9A and Oshsp18.0 are clustered on chromosome 3. Oshsp17.3 and Oshsp18.0 are linked by a 356-bp putative bi-directional promoter. Individual gene products were identified from the protein subunits of a heat shock complex (HSC) and from in vitro transcription/ translation products by two-dimensional gel electrophoreses (2-DE). All sHSP-CI genes except Oshsp17.9B were induced strongly after a 2-h heat shock treatment. The genes on chromosome 3 were induced rapidly at 32 and 41 degrees C, whereas those on chromosome 1 were induced slowly by similar conditions. Seven of these genes, except Oshsp16.9D and Oshsp17.9B, were induced by arsenite (As), but only genes on chromosome 3 were strongly induced by azetidine-2-carboxylic acid (Aze, a proline analog) and cadmium (Cd). A similar expression profile of all sHSP-CI genes at a lower level was evoked by ethanol, H2O2 and CuCl2 treatments. Transient expression assays of the promoter activity by linking to GUS reporter gene also supported the in vivo selective expression of the sHSP-CI genes by Aze treatment indicating the differential induction of rice sHSP-CI genes is most likely regulated at the transcriptional level. Only Oshsp16.9A abundantly accumulated in mature dry seed also suggested additionally prominent roles played by this HSP in development.

Azetidinecarboxylic Acid↗
PubMed1987

Translational repression by chemical inducers of the stress response occurs by different pathways.

The mechanism by which chemical inducers of the stress response inhibit protein synthesis was examined. All the chemicals tested principally inhibit the initiation phase of translation. Covalent modification of the initiation factor proteins does not constitute a common mechanism. Eukaryotic initiation factor (eIF)-2 alpha phosphorylation is moderately to strongly induced by Na arsenite and diamide, but only slightly to imperceptibly affected by iodoacetamide, azetidine carboxylic acid, and canavanine. eIF-4B dephosphorylation does not occur in any case. The only consistent change detected is the hyperphosphorylation of the 28,000 Da heat stress protein. These results indicate that these diverse chemicals, all of which enhance the transcription of the stress mRNAs, do not inhibit translation by a common, recognized mechanism; it is likely that several distinct pathways leading to inhibition exist.

Arsenic↗
PubMed1982

L-Proline transport in Saccharomyces cerevisiae.

Transport of L-proline into Saccharomyces cerevisiae K is mediated by two systems, one with a KT of 31 microM and Jmax of 40 nmol . s-1 . (g dry wt.)-1, the other with KT greater than 2.5 mM and Jmax of 150-165 nmol . s-1 . (g dry wt.)-1. The kinetic properties of the high-affinity system were studied in detail. It proved to be highly specific, the only potent competitive inhibitors being (i) L-proline and its analogs L-azetidine-2-carboxylic acid, sarcosine, D-proline and 3,4-dehydro-DL-proline, and (ii) L-alanine. The other amino acids tested behaved as noncompetitive inhibitors. The high-affinity system is active, has a sharp pH optimum at 5.8-5.9 and, in an Arrhenius plot, exhibits two inflection points at 15 degrees C and 20-21 degrees C. It is trans-inhibited by most amino acids (but probably only the natural substrates act in a trans-noncompetitive manner) and its activity depends to a considerable extent on growth conditions. In cells grown in a rich medium with yeast extract maximum activity is attained during the stationary phase, on a poor medium it is maximal during the early exponential phase. Some 50-60% of accumulated L-proline can leave cells in 90 min (and more if washing is done repeatedly), the efflux being insensitive to 0.5 mM 2,4-dinitrophenol and uranyl ions, the pH between 3 and 7.3, as well as to the presence of 10-100 mM unlabeled L-proline in the outside medium. Its rate and extent are increased by 1% D-glucose and by 10 micrograms nystatin per ml.

2,4-Dinitrophenol↗
PubMed1984

Variable denaturation of ovalbumin by incorporation of amino acid analogs.

Denaturation of hen ovalbumin synthesized in a cell-free system was assayed by examining its sensitivity to trypsin. The native ovalbumin resisted digestion by trypsin, and it remained resistant to digestion when some amino acid analogs, including azetidine-2-carboxylic acid and meta-flourotyrosine, were incorporated into its peptide chain. However, when other amino acid analogs such as beta-hydroxyleucine and 4-thiaisoleucine were incorporated during protein systhesis, ovalbumin became very lablie to trypsin. These experiments demonstrate a sensitive system for detecting protein denaturation and suggest a variable effect of different amino acid analogs on the native conformation of a protein.

Animals↗
PubMed1990

A novel 40-kDa protein induced by heat shock and other stresses in mammalian and avian cells.

When HeLa cells were exposed to heat shock or other stresses, a 40-kDa protein (p40) was induced in addition to the classical heat shock proteins with molecular sizes of 110-, 90-, 70-, and 47-kDa. The p40 was induced not only by heat shock but by arsenite and 2-azetidine carboxylic acid. Also, it was induced in rat, mouse and chick cells by these stresses. The p40 was a basic protein (pI divided by 9.2) as judged by two-dimensional gel electrophoresis. To our knowledge, p40 is a novel heat shock protein in mammalian and avian cells.

Animals↗
PubMed1986

Zetidoline metabolism by rat liver microsomes. Formation of metabolites with potential neuroleptic activity.

1-(3'-Chlorophenyl)-3-[2-(3,3-dimethyl-1-azetidinyl)ethyl] imidazolidin-2-one, zetidoline, a new neuroleptic agent, when incubated with rat liver microsomes was rapidly metabolized to six free (mets B, D, I, L, M and N) and two conjugated metabolites (mets E and F). Sites of the metabolic attack (oxidation) were primarily the aromatic moiety, then the imidazolidinone and the azetidine rings. The metabolites were purified and structures assigned by means of EI-MS, 1H-NMR and chemical synthesis (mets B, D, L and M). The main metabolites, zetidoline, some chemical analogues and a few known dopamine antagonists were tested as in vitro inhibitors of 3H-zetidoline and 3H-spiperone binding to rat striatal membranes, and as in vivo inducers of prolactin release in female rats (inhibition of the estrus cycle). Two zetidoline metabolites, namely 4'-hydroxy zetidoline (met. B) and 5-hydroxy zetidoline (met. L), were found to have both in vitro and in vivo activities comparable to those of the parent drug. Identification of these active hydroxylated metabolites appears important both in the search of new leads of neuroleptics and for designing pro-drugs derivatives with improved pharmacokinetic profiles.

Animals↗
PubMed1978

L-Proline and related compounds: correlation of structure, amnesic potency and anti-spreading depression potency.

The effects of L-proline, D-proline, and L-azetidine-2-carboxylic acid (L-A.2.C., the lower homolog of L-proline) have been compared in two systems. L-Proline is more potent than either analog in causing amnesia of one-trial avoidance conditioning of the 2-day-old chick and in preventing mechanically induced spreading depression in the retina isolated from 2-3-week-old chicks. The results suggest that the L-configuration and the proper molecular size are essential for the effects of L-proline upon memory and upon spreading depression. This level of specificity is greater than that involved in protein synthesis because L-A.2.C. is incorporated into protein in place of L-proline, in several protein-synthesizing systems.

Animals↗
PubMed1987

Gastrulation in the sea urchin embryo requires the deposition of crosslinked collagen within the extracellular matrix.

This study demonstrates that a collagenous extracellular matrix (ECM) is necessary for gastrulation in the sea urchin embryo. The approach taken was to disrupt collagen processing with two types of agents (a lathyritic agent, beta-aminopropionitrile (BAPN), and three types of proline analogs: dehydroproline, cis-OH-proline, and azetidine carboxylic acid) and to assess the effect on embryogenesis by morphological, immunological, and biochemical criteria. Embryos chronically exposed to either of the agents following fertilization displayed no detectable developmental abnormalities before the mesenchyme blastula stage. These embryos, however, did not gastrulate nor differentiate any further and remained at the mesenchyme blastula stage for at least 36 hr. Upon removal of the agents, the embryos resumed a normal developmental schedule and formed pluteus larvae that were indistinguishable from control embryos. By immunofluorescence studies with monospecific antibodies to type I and type IV collagens it is seen that the lathyritic agent BAPN reduces the accumulation of collagens within the ECM. This effect is confirmed and quantitated by use of an ELISA and by a biochemical determination of OH-proline. When the agents are removed from the inhibited embryos, collagen deposition returns to normal, coincident with gastrulation. Western-blot analysis, using monospecific antibodies to collagen, demonstrates that the effect of the lathyritic agent is to reduce the stability of the extracellular collagen by inhibiting the intra- and intermolecular crosslinking of collagen molecules. BAPN exhibits a dose-dependent effect on morphogenesis, but has no effect on respiration nor on protein synthesis of the embryos throughout development. Although the lathyritic agent affects collagen deposition, it is shown to not affect the expression of other molecules of the ECM, nor that of several cell surface molecules. However, a cell surface molecule that is expressed specifically in the endoderm, termed Endo 1, is not expressed in the inhibited embryos. Endo 1 is expressed after removal of the lathyritic agent and its appearance is coincident with gastrulation in the recovered embryos. These results suggest that a collagenous ECM is important for gastrulation and subsequent differentiation in the sea urchin, but not for earlier developmental processes. In addition, the dependence of Endo 1 expression on the collagenous ECM raises the possibility that this cell surface molecule is in some way regulated by interactions of the presumptive endodermal cells with the ECM.

Aminopropionitrile↗
PubMed1982

The pharmacological assessment of a new, potent oxotremorine analogue in mice and rats.

Some of the central and peripheral effects of oxotremorine (OT) and its azetidine analogue, N-[4-azetidinyl)-2-butynyl]-2-pyrrolidone (BM 120), were compared in mice and rats. BM 120 was found to be about twice as potent as OT and to have a somewhat longer duration of action. All its effects were antagonized by pretreatment with atropine sulphate. BM 120 acted as powerful muscarinic agonist on the isolated guinea pig ileum.

Animals↗
PubMed1984

Collagen metabolism and spicule formation in sea urchin micromeres.

The role of collagen or collagen-like protein(s) in the in vitro formation of the sea urchin embryonic skeleton was investigated using isolated micromeres of Strongylocentrotus purpuratus. Micromeres were cultured in sea water containing 4% horse serum on tissue culture plastic or an extracellular matrix of type I collagen. The effect of proline analogs and an inhibitor of collagen hydroxylation on in vitro spicule formation in both culture systems was monitored. When micromeres are cultured in the presence of proline analogs L-azetidine-2-carboxylic acid and L-3, 4-dehydroproline which disrupt collagen metabolism, spicule formation is significantly less inhibited on a collagen substratum than on plastic. Culturing micromeres on plastic in the presence of alpha, alpha'-dipyridyl, an inhibitor of collagen hydroxylation, resulted in almost complete inhibition of spicule formation. The inhibition by alpha, alpha'-dipyridyl can be overcome by culturing micromeres on collagen substratum. These results do not support the idea of collagen being the calcified organic matrix of the spicule. Rather, they suggest that micromeres synthesize a collagen-like extracellular matrix which is necessary for spicule formation. Inhibition of this activity by proline analogs or a collagen processing inhibitor can be overcome by providing the cells with a previously deposited extracellular matrix.

2,2'-Dipyridyl↗
PubMed1986

Basal lamina inhibition suppresses synthesis of calcium-dependent proteins associated with mammary epithelial cell spreading.

Spreading of mouse mammary epithelial cells on collagen gels is closely correlated with the synthesis of a group of putative calcium-binding proteins (CBP) (Braslau et al., Exp cell res 155 (1984) 213). Collagen synthesis was shown to occur during cell spreading, while omission of serum prevented cell spreading and the synthesis of collagen. The proline analogues cis-hydroxyproline and L-azetidine-2-carboxylic acid were shown to inhibit epithelial cell spreading and to suppress the collagen synthesis that occurs during serum-supported cell spreading. Inhibition of collagen synthesis resulted in the inhibition of CBP synthesis associated with cell spreading. In contrast, the collagen cross-linking inhibitor B-aminopropionitrile did not inhibit cell spreading nor did it suppress collagen synthesis; CBP synthesis was also normal during treatment with this inhibitor. Thus, mammary epithelial cell spreading on collagen gels and CBP synthesis can both be suppressed by inhibition of collagen synthesis indicating that they may be integrated in some manner. It is suggested that inhibition of cell spreading during inhibition of collagen synthesis results from failure to assemble a normal basal lamina; this may in turn signal suppression of CBP synthesis.

Animals↗
PubMed1988

Metabolic inhibitors and intermediate filament organization in human fibroblasts.

A number of metabolic inhibitors including the mRNA transcription inhibitor actinomycin D; the protein synthesis inhibitors emetine, cycloheximide, and puromycin; the energy metabolism inhibitors sodium azide and oligomycin; the amino acid analog L-azetidine-2-carboxylic acid; sodium fluoride; and acrylamide each cause the collapse of vimentin filament organization while leaving microtubule organization apparently unaffected in the human fibroblastic cell line MCH23. The protein kinase inhibitor N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H8) caused a partial collapse of vimentin organization but its effect was more difficult to discern, since it also induced a dramatic change in cellular morphology. Each of these drugs produced a significant inhibition of protein synthesis at concentrations that affected vimentin organization. The mechanisms by which these drugs affect intermediate filament organization are unclear, but our results demonstrate that intermediate filament organization in MCH23 cells is affected by a wide range of drugs and that such drugs cannot be used without great caution as reagents for the study of intermediate filament organization and function.

Acrylamide↗
PubMed1988

The relationship of heat-shock proteins, thermotolerance, and protein synthesis.

The relationship of heat-induced inhibition of protein synthesis (HIIPS) and thermotolerance, the transient ability to survive otherwise lethal heat treatments, was studied in HA-1 Chinese hamster fibroblasts exposed to various treatments. A mild heatshock or exposure to sodium arsenite induced a refractoriness to HIIPS, while exposure to the amino acid analog of proline, azetidine, did not. The development and decay of refractoriness to HIIPS after exposure to heat or sodium arsenite paralleled in the increase and decrease of the rate of synthesis of the heat-shock proteins (HSP), and was associated with neither the persistence of elevated levels of HSP nor the persistence of the thermotolerant state. Refractoriness to HIIPS was not associated with the elevated synthesis of HSP in the presence of amino acid analogs regardless of the mode of induction, indicating a requirement for functional HSP for the effect. The refractoriness to HIIPS was also found in heat-resistant variants of HA-1 cells that express elevated levels of hsp 70, implicating a role for this protein in this process. Our observation establish an unique biological effect associated with the period of elevated synthesis of the HSP, especially the hsp 70.

Animals↗
PubMed1984

Cotransport of proline and Li+ in Escherichia coli.

Uptake of Li+ induced by the addition of proline to a cell suspension of Escherichia coli was detected using an Li+-selective electrode. This Li+ uptake was inhibited by L-azetidine 2-carboxylic acid, a competitive inhibitor of the proline transport system. Thus, direct evidence for Li+-proline cotransport via the proline transport system was obtained. Kinetic parameters of the Li+ uptake were determined.

Azetidinecarboxylic Acid↗