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PubMed1989

[Post-proline hydrolysis activities in cerebrospinal fluid].

Post-proline hydrolytic-activity exists in various tissues and body fluids of human organism. Using electrophoretic techniques, column chromatographic methods and kinetic investigations two peaks of proteolytic activity towards glycyl-prolyl-p-nitroanilide were detected in human cerebrospinal fluid. The identity of one enzyme with dipeptidylpeptidase IV (EC 3.4.14.5) must now constitute proof of this. Among 650 patients with cerebral diseases, characterised by post-proline hydrolytic activity in cerebrospinal fluid, high enzyme activity coincide with bacterial meningitis. Furthermore, all bacteria which could be isolated from cerebrospinal fluid exhibit high activities of post-proline cleaving hydrolases. Until now, the origin of the cerebrospinal post proline hydrolytic activity is not clear, although our investigations suggested, that lymphocytes, cerebral parenchyma and bacteria may be involved in the enzyme secretion.

Dipeptidyl-Peptidases and Tripeptidyl-Peptidases↗

PubMed1978

Metabolism of proline in a human leukemic lymphoblastoid cell line.

Amino acid analysis of the culture medium was carried out in a human leukemic lymphoblastoid cell line (REH) established from the lymphoblasts of a patient with acute lymphoid leukemia. The results are compared with those of a reference cell line (LHN13) established from normal human lymphocytes. The most striking difference between these two cell lines concerns proline. In LHN13 the concentration of this amino acid in the culture medium increases by 40 microgram/ml/10(6) cells during a 72-hr incubation. In REH there is a decrease under the same culture conditions. In both cell lines proline is derived from glutamic acid and from arginine, as found with the use of 14C-labeled precursors. Synthesis of proline in the REH line represents approximately 26% of the value measured in LHN13 when the precursor is glutamic acid and 15% when the precursor is arginine. The radioisotopic assay for delta1-pyrroline-5-carboxylate reductase showed that there is a deficiency of this enzyme in the REH cells. The defect in proline synthesis of REH was found at the establishment of this line and constitutes a metabolic marker that has persisted for more than 2 years.

Amino Acids↗

PubMed1988

Site-specific alteration of cysteine 281, cysteine 344, and cysteine 349 in the proline carrier of Escherichia coli.

Cys-281, Cys-344, or Cys-349 in the proline carrier of Escherichia coli was changed to a serine residue by site-specific mutagenesis. The activities of the resultant mutants for uptake of proline were as great as that of the wild-type strain. These mutant carriers were all as sensitive as the wild-type carrier to the proline analogue azetidine 2-carboxylate. However, the mutant carriers with Ser-281 and Ser-344 were resistant to N-ethylmaleimide, whereas the mutant carrier with Ser-349 was as sensitive as the wild-type carrier to this reagent. These results indicate that these cysteine residues are not essential for proline transport and that Cys-281 and Cys-344 may be close to the substrate-binding site that contains an N-ethylmaleimide-sensitive residue.

Amino Acid Transport Systems, Neutral↗

PubMed1988

Proline binding to mouse brain synaptosomes.

L-proline has been shown to exert a variety of physiological and behavioral effects that are consistent with its possible role as a neuromodulator in the mammalian brain. The binding of l-proline to mouse brain synaptosomes has been partially characterized. Preliminary kinetic analysis shows the presence of at least two binding sites in the submicromolar range, and one in the nanomolar range. While more detailed studies are necessary as to determine the biological significance of proline binding to mouse brain synaptosomes, these results further support the possible role of proline as a neuromodulator.

Amino Acid Transport Systems, Neutral↗

PubMed1987

The availability of dietary nitrate for the endogenous nitrosation of L-proline.

Urinary excretion of N-nitrosoproline (NPRO) following ingestion of a high-nitrate salad meal, without then with an oral dose of 500 mg L-proline, was investigated in 16 healthy volunteers. The mean excretion rate following consumption of the high-nitrate meal alone was significantly lower than that measured after ingestion of the salad plus proline. Supplementation of the same meal (plus proline) with vitamin C from dietary sources resulted in a significant decrease in mean urinary NPRO levels in healthy subjects. The nitrosation-inhibiting effect of vitamin C was not affected by an increase in the fat content of the meal. Supplementation of the high-nitrate salad with alcohol or coffee did not affect subsequent urinary NPRO levels. No significant difference was observed in the urinary NPRO concentrations of smokers and nonsmokers after ingestion of high-nitrate salad (with or without vitamin C) plus proline.

Ascorbic Acid↗

PubMed1985

[Antagonism of piracetam with proline in relation to mnestic effects].

Based on the authors' previous data showing that the lipophylic cethyl group promotes the penetration of amino acids through the blood-brain barrier, proline cethyl ester was synthesized and studied as a neuropharmacological tool. The substance administered to rats systemically (intraperitoneally) was shown to be able to provoke a deep amnesia when tested by the conditioned avoidance performance. Piracetam abolished the amnestic effect of proline cethyl ester while sodium hydroxybutyrate administered in the dosage range provoking the nootropic effect did not change that amnesia. The data suggest that proline may be considered as one of the possible endogenous amnestic factors. The close structural similarity of the piracetam cyclic fragment to proline, which resulted in their competition, appears to be one of the reasons for piracetam antiamnestic activity.

Animals↗

PubMed1985

Induction of proline-rich glycoprotein synthesis in mouse salivary glands by isoproterenol and by tannins.

Glycoproteins which contain about 45 mol% proline were dramatically induced in mouse parotid and submandibular glands by isoproterenol treatment, but these unusual proteins were not detected in control animals. These acid-soluble substances were obtained by extracting tissues with 10% trichloroacetic acid, as reported previously for isolating proline-rich proteins from rat submandibular glands (Mehansho, H., and Carlson, D.M. (1983) J. Biol. Chem. 258, 6616-6620). Three major proline-rich glycoproteins were induced in parotid glands with apparent molecular weights of 66,000 (GP-66p), 45,000 (GP-45p), and 27,000 (GP-27p), whereas only one such protein was expressed by the submandibular glands (66,000 (GP-66sm]. Both GP-66p and GP-66sm contained about 19% carbohydrate with the following molar ratios, respectively; GalNAc, 1.0, 1.0; Gal, 1.6, 2.3; GlcNAc, 0.8, 1.1; sialic acid, 0.9, 1.9. The peptide chains of GP-66p and GP-66sm appear to be identical by amino acid compositions, glycopeptide analysis, and preliminary amino acid sequencing data. Northern blot analysis of RNAs from parotid glands of normal and isoproterenol-treated rats, probed with a 32P-labeled proline-rich protein cDNA, confirmed that control animals were devoid of mRNAs encoding these proteins and that isoproterenol treatment dramatically induced expression of these genes. Feeding sorghum high in tannins caused changes in the parotid glands similar to those observed upon isoproterenol treatment, as noted earlier with rats (Mehansho, H., Hagerman, A., Clements, S., Butler, L., Rogler, J., and Carlson, D.M. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 3948-3952). These glycoproteins have high affinities for tannins as demonstrated by competitive binding curves.

Amino Acids↗

PubMed1985

Amino acid sequence of a proline-rich phosphoglycoprotein from parotid secretion of the subhuman primate Macaca fascicularis.

The complete amino acid sequence of the macaque proline-rich phosphoglycoprotein (MPRP) was determined by automated Edman degradation of the protein, fragments F-1 and F-2 derived from the protein by an intrinsic salivary protease, and chymotryptic, tryptic, Staphylococcus aureus V8 protease, and endoproteinase lysine-C peptides. MPRP contains 115 amino acid residues including phosphorylated serine at residues 1, 2, 6, 12, and 15, and 6 O-glycosidic carbohydrate units at residues 69, 75, 87 (threonine) and 96, 103, and 106 (serine). The Mr of the polypeptide moiety of the protein is 12,656. The amino-terminal domain contains all 5 phosphoserine residues and most of the other negatively charged and hydrophilic residues, whereas the carboxyl-terminal domain contains 24 of 25 proline residues, and 6 O-glycosidic oligosaccharides. Comparison of MPRP with the four major anionic proline-rich proteins (PRPs) from human glandular secretion shows that 57% of the amino acid residues are identical if gaps are introduced to maximize homology, suggesting that these proteins are phylogenetically related. Significant structural and functional differences occur between the macaque and human proteins. MPRP has 5 phosphoserines, PRPs have 2. MPRP is a glycoprotein, PRPs are not. MPRP inhibits the spontaneous precipitation (primary precipitation) of calcium phosphate salts from supersaturated solutions in addition to inhibiting seeded crystal growth (secondary precipitation) (Oppenheim, F. G., Offner, G. D., and Troxler, R. F. (1982) J. Biol. Chem. 257, 9271-9282), whereas PRPs inhibit only secondary precipitation. MPRP is the only major anionic proline-rich protein in macaque glandular secretion; in contrast, there are four major anionic PRPs and these display a genetic polymorphism. The significance of these structural differences with respect to biological function and the possible relationship of MPRP to salivary mucins are discussed.

Amino Acid Sequence↗

PubMed1979

The complete primary structure of a proline-rich phosphoprotein from human saliva.

The complete amino acid sequence of a calcium-binding "proline-rich phosphoprotein," named Protein A, from human saliva was determined by automated and manual Edman degradation of peptides obtained by enzymatic and chemical cleavage of the intact protein. The NH2-terminal pyrrolidone carboxylic acid was identified by means of NMR. The protein consists of 106 amino acids, including 24 residues of proline. The NH2-terminal 32 residues contain 13 of the 15 negatively charged residues including 2 phosphoserines, but only 1 proline. In spite of a high concentration of proline in the COOH-terminal part of the molecule, the longest oligoproline sequence is tetraproline. The protein contains a number of repeated sequences and there are also several sequences of 3 or 4 residues identical with known sequences of collagen, but the characteristic occurrence of glycine in every third position in collagen is not found in salivary Protein A.

Amino Acid Sequence↗

PubMed1982

The effects of 1-amino-D-proline on the production of carnitine from exogenous protein-bound trimethyllysine by the perfused rat liver.

Following receptor-mediated endocytosis of trimethyllysine-labeled asialofetuin and agalacto-orosomucoid by liver parenchymal and nonparenchymal cells, respectively, the glycoproteins are degraded and the methylated lysine residues released. The free intracellular trimethyllysine is then converted, in addition to 2-N-acetyl-6-N-trimethyllysine, to 4-N-trimethylaminobutyrate, carnitine, and acetylcarnitine. In the presence of 1-amino-D-proline, a vitamin B6 antagonist, the total production from protein-bound trimethyllysine of 4-N-trimethylaminobutyrate, the immediate precursor of carnitine, carnitine, and its acetylated derivative was depressed by as much as 60-80% in perfused rat liver. The decreased synthesis of carnitine was accompanied by an accumulation of 3-hydroxy-6-N-trimethyllysine, and intermediate in the carnitine biosynthetic pathway. The extent of 3-hydroxy-6-N-trimethyllysine accumulation, which was not evident in the absence of added 1-amino-D-proline, depended on the dose of 1-amino-D-proline perfused through the liver. In addition, those effects of 1-amino-D-proline were almost completely reversed by inclusion of pyridoxine in the perfusing medium. These results support the suggestion of a requirement for pyridoxal 5'-phosphate in the biosynthesis of carnitine by the liver.

Animals↗

PubMed1983

Fascioliasis: bile duct collagen induced by proline from the worm.

We investigated whether collagen increases occur in the bile duct during fascioliasis, and their relationship to the release of proline by the worm. Experiments showed increased levels of collagen in the bile ducts of rats following 2 wk of infusion with proline or i.p. implantation with Fasciola. The increase in bile duct collagen in proline-infused animals and in worm-implanted animals could be completely inhibited to the amount in controls by 3,4-dehydroproline. These effects suggest that the hyperplasia of the bile duct that is induced by liver flukes involves stimulation of collagen deposition through their release of proline.

Animals↗

PubMed1982

New evidences for the role of secretory ameloblasts in the removal of proline labelled proteins from young enamel as visualized by autoradiography.

Eight mice (M. musculus, albinus), two hours old, were sacrificed from 1 to 168 hours following the administration of a single dose of 1 microCi/g body weight of 3H-Thymidine. An other group of six mice received a single dose of 5 microCi/g body weight of 3H-Proline and the animals were killed from 20 min. to 120 h after the injection. The unfixed hemi-jaws containing one incisor tooth, were processed to obtain frozen cross serial sections. With time, as the tooth grows, the 3H-Thymidine labelled ameloblasts move away from the apical end of the incisor at a daily rate of 550 micrometer. By determining the silver grains content over ameloblasts and related enamel matrix in animals which received 3H-Proline, using serial sections separated from each other by 550 micrometers, it was shown that : 1) The silver grains concentration over secretory ameloblasts, which was maximum 20 min. after 3H-Proline administration, showed a decrease after 24 h and a new increase between 48 and 72 h and a further decrease at later time intervals ; 2) such second reactive peak was not observed in post-secretory ameloblasts; 3) the radioactive reaction over the enamel matrix after reaching a maximum 24 h after the injection, decreased at 48 h and another increase in radioactivity was detected at 96 h when the matrix moved incisally but was still related to secretory ameloblasts. The results were interpreted as indicative of the participation of the secretory ameloblasts in the removal of proline-containing protein, which can be considered either as one of the steps of enamel maturation, or also as evidence of a distinct process by which there would be a partial turnover of the organic matter in young enamel.

Ameloblasts↗

PubMed1977

Evidence for selective axon-terminal uptake and retrograde transport of label in cortico- and rubrospinal systems after injection of 3H-proline.

In tracing the macaque's ascending spinal connections by anterograde axonal flow, perikaryal labelling was also observed within the n. ruber pars magnocellularis as well as in the sensorimotor cortex. While neuropil labelling was demonstrated after single injections of leucine or proline, labelling of perikarya was only evident following proline injections. Perikaryal labelling is most likely to be due to uptake of label by axons and/or axons terminals within the injection field and subsequent retrograde axonal transport of radioactive compound to the parent cell bodies. Advantages and disadvantages of the uptake of label by axon terminals are discussed in relation to the use of 3H-proline for tracing neuronal connections. The selectively of this event and its relationship to the suggested inhibitory functional role of proline and its metabolites is not clear and needs further investigation.

Afferent Pathways↗

PubMedDate not supplied

[Aggregation of poly-L-proline in aqueous solution].

Infrared spectra were measured for both aqueous (D2O) solution and the solid state of form II poly-L-proline in the amide I region as a function of the temperature. The temperature range includes the region where a precipitation is known to occur. From the analysis of spectra of hydrated films and aqueous solutions at different temperatures one can see that there are some peptide C = O-groups which are bounded with water. From this study it has been concluded that poly-L-proline exists in aggregate form even at temperatures lower that required for precipitation. It is supposed that poly-L-proline forms the aggregates including at least 40--50 polypeptide chains with hexagonal packing. At heating crystallisation of such aggregates occurred and it causes precipitation of poly-L-proline II.

Kinetics↗

PubMed1994

A proline-rich region of the third intracellular loop imparts phenotypic beta 1-versus beta 2-adrenergic receptor coupling and sequestration.

beta-Adrenergic receptor (beta AR) subtypes differ not only by characteristic ligand affinities but also in the manner and extent to which they mediate agonist-promoted events such as activation of adenylyl cyclase and receptor sequestration. We utilized mutagenesis and recombinant expression in Chinese hamster fibroblasts to examine the effect of an unusual proline-rich 24-amino acid sequence (PARPPSPSPSPVPAPAPPPGPPRP) present in the third intracellular loop of the beta 1AR, but not in the beta 2AR, on the aforementioned receptor-mediated events. Cells expressing the wild-type beta 2AR stimulated adenylyl cyclase in response to the agonist isoproterenol with an EC50 approximately 5-fold lower than that observed with the beta 1AR (0.53 +/- 0.14 versus 2.47 +/- 0.52 nM, p < 0.01). Deletion of the proline-rich sequence from the beta 1AR resulted in an improvement in isoproterenol-stimulated adenylyl cyclase to an EC50 value intermediate to that observed in the wild-type receptors (1.14 +/- 0.08 nM, p < 0.05 versus wild-type beta 1AR). In contrast, insertion of this sequence into the beta 2AR impaired its ability to mediate this process. Similar results were observed for receptor sequestration. Wild-type beta 1-and beta 2AR underwent maximal agonist-promoted sequestration of 25.9 +/- 4.0 and 60.0 +/- 3.3%, respectively. Deletion of the proline-rich region from the beta 1AR improved maximal sequestration to 43.0 +/- 2.7% (p < 0.01 versus wild-type beta 1AR), while insertion of the sequence into the beta 2AR impaired sequestration to 33.9 +/- 2.7% (p < 0.001 versus wild-type beta 2AR). We conclude that the distinct phenotypic patterns observed for these two agonist-promoted events in the beta 1AR and beta 2AR subtypes are partially due to the conformational effects of this proline-rich third intracellular loop sequence. Such regions, which are also found in some other G-protein-coupled receptors, may represent a general motif responsible for attenuating certain agonist-promoted receptor events.

Adenylyl Cyclases↗

PubMed1993

Cloning of ornithine delta-aminotransferase cDNA from Vigna aconitifolia by trans-complementation in Escherichia coli and regulation of proline biosynthesis.

Proline prototrophy was restored to an Escherichia coli proBA proline auxotroph by ornithine and a mothbean (Vigna aconitifolia) cDNA expression library. This novel strategy, "trans-complementation," allowed isolation of a cDNA encoding ornithine delta-aminotransferase (delta-OAT). This enzyme transaminates ornithine to glutamic-gamma-semialdehyde (GSA), thereby bypassing the block in GSA synthesis from glutamate in the proBA mutant. The identity of the mothbean enzyme was confirmed by its high sequence homology to mammalian and yeast delta-OATs as well as to a family of bacterial and fungal omega-aminotransferases and an absence of significant homology to various alpha-aminotransferases. The V. aconitifolia OAT cDNA encodes a polypeptide of 48.1 kDa. The native enzyme expressed in E. coli appears to be a monomer with Km of 2 mM for ornithine and 0.75 mM for alpha-ketoglutarate. Levels of mRNA in V. aconitifolia for delta 1-pyrroline-5-carboxylate synthetase (P5CS) and delta-OAT, the two key enzymes for proline synthesis, were monitored under different physiological conditions. Salt stress and nitrogen starvation induced P5CS mRNA levels and depressed OAT mRNA levels. Conversely, OAT mRNA level was elevated in plants supplied with excess nitrogen while the P5CS mRNA level was reduced. These data suggest that the glutamate pathway is the primary route for proline synthesis in plants during conditions of osmotic stress and nitrogen limitation whereas the ornithine pathway assumes prominence under high nitrogen input.

1-Pyrroline-5-Carboxylate Dehydrogenase↗

PubMed1993

Reciprocal effects of proline and glutamine on glycogenesis from glucose and ureagenesis in isolated, perfused rat livers.

L-Proline and L-glutamine were used to probe the inverse relationship between glycogenesis and ureagenesis in isolated, perfused livers from 48-h fasted rats. Both amino acids may provide nitrogen in the form of NH+4 for carbamyl-P synthesis. However, one molecule of glutamine may provide additionally for the synthesis of one molecule of the urea cycle substrate L-aspartate, but proline can provide for the synthesis of a molecule of NH+4 or one molecule of aspartate on an either/or basis only. In all perfusates, glucose was initially 30 mM (to favor phosphotransferase activity of glucose-6-phosphatase) and 0.5 mM 3-mercaptopicolinate was present (to inhibit glyconeogenesis from endogenous substrates, from the added amino acids, and via the indirect pathway). Glycogenesis from glucose, perfusate and hepatic urea formation, and levels of hepatic glucose-6-P, citrulline, PPi, and carbamyl-P were measured. The addition of glutamine to the perfusate markedly stimulated the urea cycle, but not glycogenesis. Hepatic urea level, perfusate urea concentration, and hepatic citrulline and PPi increased while carbamyl-P content decreased. In contrast, proline stimulated glycogenesis from glucose, but not ureagenesis. In the proline-supplemented compared with glutamine group, hepatic glycogenesis and carbamyl-P content increased; hepatic glucose-6-P levels showed a tendency toward increase; and hepatic urea formation, hepatic citrulline, and PPi levels were decreased. These observations are interpreted to support an hepatic mechanism whereby the relative availability of carbamyl-P to the urea cycle and as a substrate for glucose phosphorylation via phosphotransferase activity of the glucose-6-phosphatase system preliminary to glycogenesis from glucose is a major metabolic determinant.

Animals↗

PubMed1993

Substrate recognition by ceramide-activated protein kinase. Evidence that kinase activity is proline-directed.

Signal transduction for tumor necrosis factor-alpha and interleukin-1 involves sphingomyelin hydrolysis to ceramide and stimulation of a ceramide-activated serine/threonine protein kinase (Mathias, S., Younes, A., Kan, C., Orlow, I., Joseph, C., and Kolesnick, R. (1993) Science 259, 519-522). Kinase activity is detected by phosphorylation of a 19-amino acid peptide derived from the sequence surrounding Thr669 of the epidermal growth factor receptor. Thr669 is contained within a -Pro-Leu-Thr-Pro- motif, which conforms to a known recognition sequence for the proline-directed class of serine/threonine protein kinases. The present studies used peptides with single-site amino acid substitutions within this sequence to assess substrate recognition by ceramide-activated protein kinase. Substitution of alanine for the C-terminal but not the N-terminal proline reduced kinase activity by 80%. Similarly, substitution of basic residues for the leucine residue reduced kinase activity by 90%. Substitution of acidic residues for leucine, or its removal, also markedly reduced kinase activity. Surprisingly, addition of a leucine residue between threonine and the C-terminal proline enhanced kinase activity 3-4 fold. The Vmax(app) of the enzyme toward the control peptide containing -Pro-Leu-Thr-Pro- (200 +/- 11 pmol of peptide phosphorylated/min/mg of membrane protein) was enhanced 2.3-fold by ceramide. However, ceramide had no effect on the Km (2.0 +/- 0.4 mM). Membranes containing ceramide-activated protein kinase showed minimal activity toward peptides derived from substrates for casein kinase II, S6 kinase, protein kinase C, and cAMP-dependent protein kinase, but possessed substantial activity toward a calmodulin kinase substrate. However, activities toward these substrates were not enhanced by ceramide. These results suggest that ceramide-activated protein kinase may be a member of the proline-directed class of protein kinases and display specificity for -Leu-Thr-Pro- as a minimal substrate recognition motif.

Alanine↗