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PubMed1982

The effect of azaserine upon the proline and methyl alpha-D-glucoside transport systems of rat renal brush-border membranes.

An inhibitory effect of azaserine on Na+ dependent proline and methyl alpha-D-glucoside transport of the rat renal brush-border membrane vesicles has been demonstrated. The inhibitory effects of azaserine were not the results of the drug disrupting the membrane vesicles as shown in osmolarity studies, nor did it affect the transport systems' affinities for Na+. Azaserine acts as a non-competitive inhibitor for the proline transport system in renal brush-border membranes by lowering 37% and 27% in the Vmax1 and Vmax2, respectively, when compared to that of control proline transport system. Azaserine had no effect upon the two Km values for proline uptake. Azaserine inhibition of methyl alpha-D-glucoside uptake by vesicles in the presence of 7.2 mM azaserine at 22 degrees C resulted in 66% increase in Km1 value and 44% decrease in Vmax1 as compared to that of control vesicles. There was no detectable effect upon the Km2 and Vmax2 of the methyl alpha-D-glucoside transport system. No effect of the drug was observed when sodium was equilibrated across the membrane, indicating that azaserine altered the driving force exerted by a sodium gradient. Azaserine only slightly affected the relative contribution of the two Km systems to total proline uptake. Contrary to the observed effect of azaserine upon the proline transport system, azaserine exerted a distinct effect upon the relative contribution to total uptake by the two Km systems in the low methyl alpha-D-glucoside concentration range. In the presence of 7.2 mM azaserine, the low-affinity, high-Km transport system becomes the major contributor to total methyl alpha-D-glucoside uptake by isolated renal brush-border vesicles.

Animals↗
PubMed1979

Immunological comparison of proline-rich proteins from human and primate parotid secretion.

Antisera raised in response to proline-rich proteins purified from parotid secretions of man and the primate Macaca fascicularis were employed to investigate the interrelationships of these proteins by immunodiffusion, immunoelectrophoresis and the combined use of disc gel acrylamide electrophoresis with radial immunodiffusion. The major human proline-rich proteins, PRP I, PRP II, PRP III and PRP IV as well as several minor proline-rich proteins cross-react with antiserum to PRP I or PRP III. Similarly primate parotid saliva contains several components cross-reacting with antiserum directed against a purified primate proline-rich protein, MPRP. Antiserum to PRP I or PRP III cross-reacted with MPRP and primate parotid saliva protein, whereas antiserum to MPRP cross-reacted only with human parotid saliva protein and not with the isolated human proline-rich proteins. The immunological relationships of these salivary proline-rich proteins within and between species suggest their origin from a common precursor molecule.

Animals↗
PubMed1977

Reutilization of precursor following axonal transport of [3H]proline-labeled protein.

In further studies on axonally transported protein in the goldfish visual system, the turnover of rapidly transported [3H]proline-labeled protein was examined. It was found that: (1) a fraction of the rapidly transported protein has a relatively short half-life; (2) [3H]proline released following proteolysis of transported protein is efficiently reutilized for tectal protein synthesis, as inferred from an increased labeling of nuclear protein in the contralateral tectum (COT) relative to that in the ipsilateral tectum (IOT); (3) a small amount of [3H]proline arrives in the COT by axonal flow of the free amino acid; and (4) [3H]leucine and [3H]asparagine are less efficiently reutilized than [3H]proline. These findings may relate to the phenomenon of transneuronal transfer of radioactivity which has been observed with [3H]proline as precursor. The extensive reutilization of [3H]proline may account for part or all of the labeling at secondary synaptic sites. The results suggest that asparagine may be highly suitable for radioautographic identification of primary neuronal fields.

Acetohexamide↗
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↗
PubMedDate not supplied

Proline hydroxylase activity and collagen content of pigeon aortas with naturally-occurring and cholesterol-aggravated atherosclerosis.

Proline hydroxylase activity and collagen content were determined in atherosclerotic plaque, fatty streak, and normal tissue from aortas of White Carneau pigeons with naturally-occurring of cholesterol-aggravated atherosclerosis. Little increase in collagen content or proline hydroxylase activity occurred in fatty streaks or plaques from birds with cholesterol-aggravated atherosclerosis. This is consistent with the morphologic observation of the presence of little or no "fibromuscular cap" in these cholesterol-aggravated lesions. Both normal and plaque tissue from arotas of birds with naturally-occurring atherosclerosis contained more collagen than did similar tissues from control birds or birds with cholesterol-aggravated lesions. The largest proportion of this increase in collagen content probably represented an age effect since it occurred in normal as well as atherosclerotic tissue. Plaques from aortas of birds with naturally-occurring atherosclerosis did contain, however, significantly more collagen than normal tissue from the same aortas. This is consistent with the presence of a prominent "fibromuscular cap" in these naturally-occurring lesions. Proline hydroxylase activity was less in these lesions than in normal tissue from the same aortas. Consequently increased proline hydroxylase activity and collagen content are not greatly altered in association with development of cholesterol-aggravated atherosclerotic lesions in pigeons. On the other hand, well-developed naturally-occurring lesions contained increased concentrations of collagen but showed no increase proline hydroxylase activity. This is not to say though, that active collagen synthesis and presukably increased proline hydroxylase activity did not take place at some point in the development of these naturally-occurring lesions.

Animals↗
PubMed1990

Role of two proline-containing turns in the folding of porcine ribonuclease.

Unfolded ribonuclease (RNase) from porcine pancreas consists of a mixture of fast and slow-refolding species. The equilibrium distribution of these species differs strongly from other homologous RNases, because an additional proline residue is present at position 115 of the porcine protein. The major slow-folding species of porcine RNase contains incorrect proline isomers at Pro93 and at Pro114-Pro115. Both positions are presumably part of beta-turn structures in the native protein, as deduced from the structure of the homologous bovine RNase A. The folding kinetics of these molecules depend strongly on the conditions used. Under unfavorable conditions (near the unfolding transition), refolding is virtually blocked by the presence of the incorrect proline peptide bonds and partially folded intermediates with incorrect isomers could not be detected. As a consequence, folding is very slow under such conditions and the re-isomerization of Pro114-Pro115 is the first and rate-limiting step of folding. Under strongly native conditions (such as in the presence of ammonium sulfate), refolding is much faster. A largely folded intermediate accumulates with the turns around Pro93 and Pro114-Pro115 still in the non-native conformation. These results suggest that incorrect proline isomers strongly influence protein folding and that, under favorable conditions, the polypeptide chain can fold with two beta-turns locked into a non-native conformation. We conclude, therefore, that early formation of correct turn structure is not necessarily required for protein folding. However, the presence of incorrect turns, locked-in by non-native proline isomers, strongly decreases the rate of refolding. Alternative pathways of folding exist. The choice of pathway depends on the number and distribution of incorrect proline isomers and on the folding conditions.

Ammonium Sulfate↗
PubMedDate not supplied

Proline incorporation by cultured skin fibroblasts from patients with duchenne muscular dystrophy.

The incorporation of proline by cultured skin fibroblasts derived from normal individuals and patients with Duchenne muscular dystrophy (DMD) was analyzed by SDS-gel electrophoresis combined with a double-labeling procedure [Pediatr. Res., 12: 887 (1978)]. DMD fibroblasts showed increased proline incorporation into protein of approximately 130 000 daltons which could be degraded partially by collagenase. This difference was observed only at 7 days after seeding, and may be due to slight differences in growth rate as comparison of cells harvested at 2 and 7 days indicated that increased proline incorporation into high molecular weight protein was associated with day 7 cells, whether normal or DMD. During 14 days in culture normal and DMD strains did not differ in protein content, doubling time or incorporation of [3H]leucine and [14C]proline into cellular protein, although the ratio of [14C]proline to [3H]leucine incorporated was greater for DMD fibroblasts at 7 days. Incorporation of [14C]proline and [3H]leucine into extracellular proteins was greater in DMD fibroblast cultures. These subtle differences support the hypothesis that the DMD gene is expressed in fibroblasts.

Cell Differentiation↗
PubMed1980

Amnestic potency of proline analogs correlates with anti-spreading depression potency.

L-Proline and some of its analogs have been shown to prevent spreading depression (SD) in the chick retina at relatively low concentrations and to impair memory processing without provoking toxic or electrophysiological disturbances. Both effects are hypothesized to be caused by inhibition of the effects of glutamate released into the extracellular space. L-Proline, its D-enantiomer, six proline analogs including two homologs (L-azetidine-2-carboxylic acid and DL-pipecolic acid), and five other compounds were examined for their effects on spreading depression and their amnestic and electrophysiological effects. L-Proline, L-baikiain, DL-3,4-dehydroproline, and L-4-hydroxyproline all reduced the incidence of SD in the chick retina and proved to be amnestic. D-Proline, L-pyroglutamic acid, L-azetidine-2-carboxylic acid, DL-pipecolic acid, L-glutamic acid diethylester, L-isoleucine and L-norleucine neither depressed SD nor caused retrograde amnesia. L-Prolyl-L-proline and L-glutamine did not depress SD at low concentrations but had significant amnestic effects. None of the listed compounds induced EEG disturbances. Implications for memory mechanisms are discussed in the light of these results.

Amnesia↗
PubMed1985

High proline levels in the brains of mice as related to specific learning deficits.

Hyperprolinemic PRO/Re mice have been studied as potential models for hyperprolinemia in man. In addition to high proline levels, some heretofore unreported amino acid abnormalities in the brains of PRO/Re mice are described. The T-maze and shuttlebox learning abilities of PRO/Re mice were compared with those of CD-1 mice having normal proline levels. PRO/Re mice had a significant deficit for T-maze learning, but a significantly greater aptitude for shuttlebox learning when compared to CD-1 mice. By studying the F3 progency of the PRO/Re X CD-1 cross, these strain-specific differences in learning ability for different tasks were shown to be unrelated to the differences in brain proline levels. F3 mice could be subdivided into two distinct groups: those with high proline (HP+) and low proline (HP-) titers. Other amino acids in brain tissues were essentially identical in both groups. A comparison of learning abilities of these HP+ mice with their HP- littermates showed no meaningful differences. However, the slightly slower rate at which HP+ mice acquired shuttlebox learning was sufficiently consistent over the 8 day training period so that it became significant. These results do not support the hypothesis that high levels of proline in brain tissues and blood are necessarily accompanied by impaired learning and memory, but are in agreement with those studies of hyperprolinemia in man that suggest no consistent learning deficits in hyperprolinemic subjects. The results seem to validate the suitability of the PRO/Re mouse as a model for hyperprolinemia in man. The data suggest also that the altered amino acid pattern in brains of PRO/Re mice has multiple etiologies.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1984

Formation of long-lived hydroxyl free radical adducts of proline and hydroxyproline in a Fenton reaction.

Proline and hydroxyproline when exposed to the hydroxyl free radical generating system of ADP-Fe(II)-H2O2 yielded long-lived free radicals. An analysis of the electron paramagnetic resonance spectra of the long-lived hydroxyl free radical adducts of proline and hydroxyproline is consistent with a free electron on a nitroxyl group interacting with the nitrogen atom as well as with three separate protons. In the case of proline, nitroxide formation was observed under the influence of tert-butyl-hydroperoxide, giving a similar EPR spectrum (Lin, J.S., Tom, T.C. and Olcott, H.S. (1974) J. Agr. Food Chem. 22, 526-528); however, the hydroxyl free radical adduct of hydroxyproline has not been described yet. In the case of the proline nitroxide radical, two of the three protons involved interact with the free electron equivalently. The coupling constants for the hydroxyl free radical adduct of proline are AN = 1.58 mT, AH1 beta = AH2 beta = 2.13 mT, AH3 beta = 1.77 mT and for hydroxyproline are AN = 1.54 mT, AH1 beta = 2.56 mT, AH2 beta = 2.03 and AH3 beta = 1.51. The data are consistent with the amine nitrogen of proline and hydroxyproline being oxidized to a nitroxyl group and the free electron of the nitroxyl interacting with the beta-protons of these amino acid hydroxyl free radical adducts.

Adenosine Diphosphate↗
PubMed1988

Catalysis of proline isomerization during protein-folding reactions.

The enzyme peptidylprolyl cis-trans isomerase (PPI) is known to catalyze proline isomerization in short proline-containing peptides. If PPI can be shown to generally catalyze isomerization of proline residues in proteins, then it would be a valuable diagnostic reagent for recognition of isomerization, which has proven to be extremely difficult to characterize by other methods. In this study, the catalytic effect of PPI on the slow refolding reactions of seven different proteins has been studied, and in only two cases (RNase T1 and cytochrome c) could significant catalysis be seen. PPI also caused no enhancement in the rate for the 'subtle' conformational changes of native concanavalin A or native Fragment I of prothrombin, which have been suggested to be rate-limited by proline isomerization. There was a small effect of PPI observed for the generation of native RNAase A from the fully-reduced form when the glutathione concentration was low. The conclusion from these studies is that PPI can weakly catalyze some protein processes which are rate-limited by proline isomerization, but probably exhibits no measureable catalysis toward others. This somewhat limits the usefulness of PPI as a diagnostic reagent for proline isomerization.

Amino Acid Isomerases↗
PubMed1993

Specificity for various imino-acid-residues of a proline-specific dipeptidylcarboxypeptidase from a Streptomyces species.

A proline-specific dipeptidylcarboxypeptidase, which removes diproline from the C-terminus of the proline-containing peptides, such as Boc-Pro-Pro-Pro-Pro and Leu-Pro-Pro-Pro-Pro-Pro, has recently been purified from a Streptomyces sp. The specificity of the enzyme for various imino acid-containing synthetic peptide substrates was further studied. The peptides with proline, hydroxyproline, or dehydroproline at the P2' position were found to be good substrates, while those with pipecolic acid, D-proline or other usual amino acids at the P2' position were scarcely hydrolyzed. The peptides with proline, dehydroproline, pipecolic acid, or N-methyl-alanine at the P1' position were well-hydrolyzed, while those with hydroxyproline or D-proline at the P1' position were not hydrolyzed. Utilizing this high specificity for imino acids, Boc-Pro-Pro-Pro-Pro was synthesized by the enzyme using Boc-Pro-Pro as the acidic component and Pro-Pro as the basic component.

Amino Acid Sequence↗
PubMed1990

Proline uptake in Streptomyces clavuligerus.

Streptomyces clavuligerus was able to accumulate proline intracellularly throughout a wide range of external proline concentrations. Kinetic analysis of proline uptake indicated that this phenomenon is mediated by two saturable systems. One of them was a high-affinity system (Km = 11 microM), with low uptake capacity and specific for proline. The second system had lower affinity for proline (Km = 10.2 mM), higher uptake capacity, and was inhibited by several amino acids. Proline was not required as an inducer of the systems, which were neither repressed nor inhibited by ammonium.

Kinetics↗
PubMed2004

Hydrophytes lack potential to exhibit cadmium stress induced enhancement in lipid peroxidation and accumulation of proline.

Investigations were carried out to evaluate if hydrophytes (viz. Ceratophyllum, Wolffia, and Hydrilla) can be used as markers to assess the level of heavy metal pollution in aquatic bodies. The potential of these hydrophytes for lipid peroxidation and accumulation of proline in response to cadmium (Cd2+) pollution was studied. Hydrophytes were raised in artificial pond water (APW) supplemented with various levels of Cd2+. Interestingly, unlike mesophytes none of the hydrophytes showed ability to accumulate proline. Infact, in response to Cd2+ pollution hydrophytes exhibited a decline in proline levels in comparison to controls but mesophytes (viz. Brassica juncea, Vigna radiata and Triticum aestivum) showed progressive increase in the level of proline with increase in the extent of Cd2+ pollution. Mesophytes showed six to nine-fold increase in the level of proline in response to 1 mM Cd2+. The potential of the above hydrophytes for lipid peroxidation was also low under Cd2+ stress. In contrast, as expected a significant enhancement in the lipid peroxidation was observed in all three mesophytes in response to their exposure to Cd2+. About two-fold increase in production of malondialdehyde (a cytotoxic product of lipid peroxidation) was recorded in mesophytes exposed to 1 mM Cd2+. However, a decline in chlorophyll (Chl a and Chl b) levels was recorded in response to Cd2+pollution both in hydrophytes as well as mesophytes. In summary, hydrophytes neither have potential to accumulate proline nor have ability to accelerate lipid peroxidation under heavy metal stress. This suggests that the adaptive mechanism(s) existing in hydrophytes to tackle heavy metal stress is distinct from that in mesophytes.

Cadmium↗
PubMed2004

Structural mechanism governing cis and trans isomeric states and an intramolecular switch for cis/trans isomerization of a non-proline peptide bond observed in crystal structures of scorpion toxins.

Non-proline cis peptide bonds have been observed in numerous protein crystal structures even though the energetic barrier to this conformation is significant and no non-prolyl-cis/trans-isomerase has been identified to date. While some external factors, such as metal binding or co-factor interaction, have been identified that appear to induce cis/trans isomerization of non-proline peptide bonds, the intrinsic structural basis for their existence and the mechanism governing cis/trans isomerization in proteins remains poorly understood. Here, we report the crystal structure of a newly isolated neurotoxin, the scorpion alpha-like toxin Buthus martensii Karsch (BmK) M7, at 1.4A resolution. BmK M7 crystallizes as a dimer in which the identical non-proline peptide bond between residues 9 and 10 exists either in the cis conformation or as a mixture of cis and trans conformations in either monomer. We also determined the crystal structures of several mutants of BmK M1, a representative scorpion alpha-like toxin that contains an identical non-proline cis peptide bond as that observed in BmK M7, in which residues within or neighboring the cis peptide bond were altered. Substitution of an aspartic acid residue for lysine at residue 8 in the BmK M1 (K8D) mutant converted the cis form of the non-proline peptide bond 9-10 into the trans form, revealing an intramolecular switch for cis-to-trans isomerization. Cis/trans interconversion of the switch residue at position 8 appears to be sequence-dependent as the peptide bond between residues 9 and 10 retains its wild-type cis conformation in the BmK M1 (K8Q) mutant structure. The structural interconversion of the isomeric states of the BmK M1 non-proline cis peptide bond may relate to the conversion of the scorpion alpha-toxins subgroups.

Amino Acid Sequence↗
PubMed2005

Destabilization of human IAPP amyloid fibrils by proline mutations outside of the putative amyloidogenic domain: is there a critical amyloidogenic domain in human IAPP?

Islet amyloid polypeptide (IAPP; amylin) is responsible for amyloid formation in type-2 diabetes. Not all organisms form islet amyloid, and amyloid formation correlates strongly with variations in primary sequence. Studies of human and rodent IAPP have pointed to the amino acid residues 20-29 region as the important amyloid-modulating sequence. The rat 20-29 sequence contains three proline residues and does not form amyloid, while the human sequence contains no proline and readily forms amyloid. This has led to the view that the 20-29 region constitutes a critical amyloidogenic domain that dictates the properties of the entire sequence. The different behavior of human and rat IAPP could be due to differences in the 20-29 region or due simply to the fact that multiple proline residues destabilize amyloid fibrils. We tested how critical the 20-29 region is by studying a variant identical with the human peptide in this segment but with three proline residues outside this region. We designed a variant of the amyloidogenic 8-37 region of human IAPP (hIAPP(8-37) 3xP) with proline substitutions at positions 17, 19 and 30. Compared to the wild-type, the 3xP variant was much easier to synthesize and had dramatically greater solubility. Fourier transform infra red spectroscopy, transmission electron microscopy, Congo red staining and thioflavin-T binding indicate that this variant has a reduced tendency to form beta-sheet structure and forms deposits with much less structural order than the wild-type. Far-UV CD studies show that the small amount of beta-sheet structure developed by hIAPP(8-37) 3xP after long periods of incubation dissociates readily into random-coil structure upon dilution into Tris buffer. The observation that proline substitutions outside the putative core domain effectively abolish amyloid formation indicates that models of IAPP aggregation must consider contributions from other regions.

Amino Acid Sequence↗
PubMed2002

Effects of proline analog binding on the spectroscopic and redox properties of PutA.

The PutA flavoprotein regulates proline metabolism in Escherichia coli by performing two distinct functions. First, in the cytoplasm, PutA represses transcription of the put (proline utilization) regulon. Second, PutA associates with the membrane to oxidize proline to glutamate using discrete proline dehydrogenase and Delta(1)-pyrroline-5-carboxylate dehydrogenase domains. Here, we identify a proline analog that will be useful for testing the role substrate binding has in regulating PutA functions. L-Tetrahydro-2-furoic acid (L-THFA) was found to display simple competitive inhibition of proline dehydrogenase activity in PutA (apparent K(i)=0.2mM) and to perturb the flavin adenine dinucleotide (FAD) absorbance spectrum upon complexation to PutA. At pH 7.5, a reduction potential (E(m)) of -0.089V for the FAD/FADH(2) couple in L-THFA-complexed PutA was determined by potentiometric titrations. The E(m) value for L-THFA-complexed PutA is 12mV more negative than the E(m) for uncomplexed PutA (E(m)=-0.077V, pH 7.5) and corresponds to just a twofold increase in the dissociation constant of L-THFA with PutA upon reduction of FAD.

Bacterial Proteins↗
PubMed2003

Proline can have opposite effects on fast and slow protein folding phases.

Proline isomerization is well known to cause additional slow phases during protein refolding. We address a new question: does the presence of prolines significantly affect the very fast kinetics that lead to the formation of folding intermediates? We examined both the very slow (10-100 min) and very fast (4 micro s-2.5 ms) folding kinetics of the two-domain enzyme yeast phosphoglycerate kinase by temperature-jump relaxation. Phosphoglycerate kinase contains a conserved cis-proline in position 204, in addition to several trans-prolines. Native cis-prolines have the largest effect on folding kinetics because the unfolded state favors trans isomerization, so we compared the kinetics of a P204H mutant with the wild-type as a proof of principle. The presence of Pro-204 causes an additional slow phase upon refolding from the cold denatured state, as reported in the literature. Contrary to this, the fast folding events are sped up in the presence of the cis-proline, probably by restriction of the conformational space accessible to the molecule. The wild-type and Pro204His mutant would be excellent models for off-lattice simulations probing the effects of conformational restriction on short timescales.

Enzyme Activation↗