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PubMed2004

Direct observation of self-trapped vibrational states in alpha-helices.

Femtosecond infrared pump-probe spectroscopy of the N-H mode of a stable alpha-helix reveals two excited-state absorption bands, which disappear upon unfolding of the helix. A quantitative comparison with polaron theory shows that these two bands reflect two types of two-vibron bound states connected to the trapping of two vibrons at the same site and at nearest neighbor sites, respectively. The latter states originate from an acoustic phonon in the helix, which correlates adjacent sites.

Amino Acids↗
PubMed1992

Physical and biological properties of a new synthetic amino acid copolymer used as wound dressing.

A new synthetic amino acid copolymer has been evaluated as wound covering. It is permeable to water vapor in the region of 4.1 kg/m2/24 h, it does not allow microbial proliferation after in vitro inoculation, it is impermeable to bacteria, and is stable and flexible. In vivo experiments were designed to provide qualitative and quantitative evaluation on its possible use as a skin substitute in full-thickness skin excision in the guinea pig. Two excisions, approximately 12-14 cm2 were performed on each side of the spine, leaving the panniculus carnosus. One site was treated with the membrane, the other with gauze. Each animal served as its own control. Photographs with a fixed focal-length camera were taken in identical conditions for all wounds immediately and 7, 14, and 21 days after excision. They were analyzed by planimetry. Histological studies were performed at 7, 14, and 21 days. The rate of healing between 0 and 21 days of the wounds treated with the copolymer membrane was significantly accelerated in comparison with wounds covered with a dry dressing (p less than 0.05). This increased epithelialization rate was confirmed by histology, which also suggested a reduction of the inflammatory response of the wound. In vivo biodegradation studies were also performed by subcutaneous implantation in the rat followed at 15, 30, 60, and 90 days by histology and physicochemical analyses. The results demonstrate that the membrane is not biodegradable.

Animals↗
PubMed1995

Prediction of polyelectrolyte polypeptide structures using Monte Carlo conformational search methods with implicit solvation modeling.

Many interesting proteins possess defined sequence stretches containing negatively charged amino acids. At present, experimental methods (X-ray crystallography, NMR) have failed to provide structural data for many of these sequence domains. We have applied the dihedral probability grid-Monte Carlo (DPG-MC) conformational search algorithm to a series of N- and C-capped polyelectrolyte peptides, (Glu)20, (Asp)20, (PSer)20, and (PSer-Asp)10, that represent polyanionic regions in a number of important proteins, such as parathymosin, calsequestrin, the sodium channel protein, and the acidic biomineralization proteins. The atomic charges were estimated from charge equilibration and the valence and van der Waals parameters are from DREIDING. Solvation of the carboxylate and phosphate groups was treated using sodium counterions for each charged side chain (one Na+ for COO-; two Na for CO(PO3)-2) plus a distance-dependent (shielded) dielectric constant, epsilon = epsilon 0 R, to simulate solvent water. The structures of these polyelectrolyte polypeptides were obtained by the DPG-MC conformational search with epsilon 0 = 10, followed by calculation of solvation energies for the lowest energy conformers using the protein dipole-Langevin dipole method of Warshel. These calculations predict a correlation between amino acid sequence and global folded conformational minima: 1. Poly-L-Glu20, our structural benchmark, exhibited a preference for right-handed alpha-helix (47% helicity), which approximates experimental observations of 55-60% helicity in solution. 2. For Asp- and PSer-containing sequences, all conformers exhibited a low preference for right-handed alpha-helix formation (< or = 10%), but a significant percentage (approximately 20% or greater) of beta-strand and beta-turn dihedrals were found in all three sequence cases: (1) Aspn forms supercoil conformers, with a 2:1:1 ratio of beta-turn:beta-strand:alpha-helix dihedral angles; (2) PSer20 features a nearly 1:1 ratio of beta-turn:beta-sheet dihedral preferences, with very little preference for alpha-helical structure, and possesses short regions of strand and turn combinations that give rise to a collapsed bend or hairpin structure; (3) (PSer-Asp)10 features a 3:2:1 ratio of beta-sheet:beta-turn:alpha-helix and gives rise to a superturn or C-shaped structure.

Algorithms↗
PubMed2002

Occurrence, functions and biosynthesis of polyamides in microorganisms and biotechnological production.

Microorganisms are able to synthesize three different polyamides by enzymatic processes independently from ribosomal protein biosynthesis: poly(gamma-D-glutamic acid), poly(epsilon-L-lysine) and multi-L-arginyl-poly(L-aspartic acid) which is also referred to as cyanophycin. These polyamides, which occur mainly in Bacillus spp. (and only a few other eubacteria and the nematocysts of Cnidaria, in Streptomyces albulus or in cyanobacteria, respectively), have recently attracted considerable interest of the chemical industry and may be suitable for various applications. This review summarizes our current knowledge on the occurrence, biosynthesis, physiological functions, and biodegradation as well as on the properties and putative applications of these polyamides. Emphasis is placed on the enzymology of the polymerization and on the genes encoding the polymerizing enzymes, which have only recently become available for cyanophycin synthetases. Prospects for novel production processes. in particular for cyanophycin, are also presented.

Amino Acid Sequence↗
PubMed1998

A piece in the puzzle: an ion channel candidate gene for schizophrenia.

Mutations in ion channels have been found to cause a variety of mendelian genetic diseases, and polyglutamine repeat expansion is a newly recognized pathogenic mechanism that causes several rare, genetic, late-onset neurological syndromes. Polymorphic polyglutamine tracts are present in a recently described human, calcium-activated potassium channel, KCNN3 (also known as hKCa3), and alleles of this gene that contain longer repeats have been associated with schizophrenia. The physiological function of the channel is consistent with an etiological role in this disease; drugs designed to target this channel might therefore provide novel psychotherapeutics.

Alleles↗
PubMed1992

Polyglutamylated alpha-tubulin can enter the tyrosination/detyrosination cycle.

We have previously identified a major modification of neuronal alpha-tubulin which consists of the posttranslational addition of a varying number of glutamyl units on the gamma-carboxyl group of glutamate residue 445. This modification, called polyglutamylation, was initially found associated with detyrosinated alpha-tubulin [Eddé, B., Rossier, J., Le Caer, J.P., Desbruyères, E., Gros, F., & Denoulet, P. (1990) Science 247, 83-85]. In this report we show that a lateral chain of glutamyl units can also be present on tyrosinated alpha-tubulin. Incubation of cultured mouse brain neurons with radioactive tyrosine, in the presence of cycloheximide, resulted in a posttranslational labeling of six alpha-tubulin isoelectric variants. Because both tyrosination and polyglutamylation occur in the C-terminal region of alpha-tubulin, the structure of this region was investigated. [3H]tyrosinated tubulin was mixed with a large excess of unlabeled mouse brain tubulin and digested with thermolysin. Five peptides, detected by their radioactivity, were purified by high-performance liquid chromatography. Amino acid sequencing and mass spectrometry showed that one of these peptides corresponds to the native C-terminal part of alpha-tubulin 440VEGEGEEEGEEY451 and that the remainders bear a varying number of glutamyl units linked to glutamate residue 445, which explains the observed heterogeneity of tyrosinated alpha-tubulin. A quantitative analysis showed that the different tyrosinated forms of alpha-tubulin represent a minor (13%) fraction of the total alpha-tubulin present in the brain and that most (80%) of these tyrosinated forms are polyglutamylated.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1990

Poly(gamma-glutamic acid)s are the major constituents of nematocysts in Hydra (Hydrozoa, Cnidaria).

The 2.80 +/- 0.20 mumol of anions found/mg of isolated and purified dry nematocysts (capsular secretory products of stinging cells) from Hydra make up the majority of the soluble capsular content. They are, in cooperation with corresponding cations, responsible for the generation and regulation of an internal osmotic pressure that amounts up to 150 bar (Weber, J. (1989) Eur. J. Biochem. 184, 465-476). The anions are organized as linear homopolymers of L-glutamic acids which are linked by gamma-carboxyl-alpha-amino amide bonds; the degree of polymerization is heterogeneous and dependent on the particular type of nematocyst. In situ the intracapsular glutamic acid monomer concentration is as high as 2 M. This is the first time that poly(gamma-glutamic acid)s, which are known to occur in some selected bacteria, are reported for eucaryotes. It is suggested that they may also be present as predominant components in nematocysts of other cnidarian species and thus might represent a class of compounds which is characteristic for a whole phylum of the animal kingdom.

Amino Acids↗
PubMed2005

CapE, a 47-amino-acid peptide, is necessary for Bacillus anthracis polyglutamate capsule synthesis.

Polyglutamate is found in various bacteria, but displays different functions depending on the species and their environment. Here, we describe a minimal polyglutamate synthesis system in Bacillus anthracis. In addition to the three genes previously described as sufficient for polyglutamate synthesis, this system includes a small open reading frame, capE, belonging to the cap operon. The polyglutamate system's requirement for the five cap genes, for capsulation and anchoring, was assayed in nonpolar mutants. The capA, capB, capC, and capE genes are all necessary and are sufficient for polyglutamate synthesis by B. anthracis. capD is required for polyglutamate anchoring to the peptidoglycan. The 47-amino-acid peptide encoded by capE is localized in the B. anthracis membrane. It is not a regulator and it is required for polyglutamate synthesis, suggesting that it has a structural role in polyglutamate synthesis. CapE appears to interact with CapA. Bacillus subtilis ywtC is similar to capE and we named it pgsE. Genes similar to capE or pgsE were found in B. subtilis natto, Bacillus licheniformis, and Staphylococcus epidermidis, species that produce polyglutamate. All the bacterial polyglutamate synthesis systems analyzed show a similar genetic organization and, we suggest, the same protein requirements.

Amino Acid Sequence↗
PubMed1983

[Effect of folic acid deficiency on the synthesis of pteroylpolyglutamates].

In order to evaluate the effect of folate deficiency on pteroylpolyglutamate synthesis in rat liver, the hepatic and urinary content of reduced folates, the distribution of pteroylpolyglutamates and the incorporation of i.p. injected 3H folic acid in polyglutamates have been studied. In deficient rats the hepatic content of reduced folates and the urinary amounts of reduced metabolites are lower and do not increase after vitamin treatment. Longer chain pteroylpolyglutamates are severely depleted and their content is not significantly modified by folic acid treatment. The percentage of labelled folic acid incorporated into pteroylglutamates is markedly decreased. The inability of deficient rat liver to synthesize polyglutamates might be ascribed to the decrease of pteroylpolyglutamate synthetase activity, and/or to the lower availability of tetrahydrofolates, the preferred substrates for the enzyme.

Animals↗
PubMed1992

Effect of various polyamino acids and D- and L-amino acids on the blood fibrinolytic system.

1. Comparative additional effects of 24 commercially obtained amino acids and their derivatives were studied by the whole blood clot lysis time (WBCLT) method. D-Arg and L-Lys (greater than 50 micrograms/ml) activated the fibrinolytic system, and poly-L-Glu (mol. wt 6000-90,000) (less than 50 micrograms/ml) were less effective. 2. Poly-L-Arg, poly-L-Lys and poly-(Lys-Ala-Glu-Tyr) accelerated the TPA inhibition in the presence of human plasma. 3. For in vivo experiments, 5 mg of poly-L-Glu were given intravenously to 10 rats. 4. The shortening of WBCLT and elevation of EFA (P less than 0.01) were found after 1 hr administration. 5. The main enzymes which increased in plasma were proved to be the endogenous plasminogen activators with mol. wt higher than 70,000, by zymography.

Amino Acid Sequence↗
PubMed2002

Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis.

We determined the mechanisms of resistance of human CCRF-CEM leukemia cells to methotrexate (MTX) vs. those to six novel antifolates: the polyglutamatable thymidylate synthase (TS) inhibitors ZD1694, multitargeted antifolate, pemetrexed, ALIMTA (MTA) and GW1843U89, the non-polyglutamatable inhibitors of TS, ZD9331, and dihydrofolate reductase, PT523, as well as DDATHF, a polyglutamatable glycinamide ribonucleotide transformylase inhibitor. CEM cells were made resistant to these drugs by clinically relevant intermittent 24 hr exposures to 5-10 microM of MTX, ZD1694, GW1843U89, MTA and DDATHF, by intermittent 72 hr exposures to 5 microM of ZD9331 and by continuous exposure to stepwise increasing concentrations of ZD9331, GW1843U89 and PT523. Development of resistance required only 3 cycles of intermittent drug exposure to ZD1694 and MTA, but 5 cycles for MTX, DDATHF and GW1843U89 and 8 cycles for ZD9331. The predominant mechanism of resistance to ZD1694, MTA, MTX and DDATHF was impaired polyglutamylation due to approximately 10-fold decreased folylpolyglutamate synthetase activity. Resistance to intermittent exposures to GW1843U89 and ZD9331 was associated with a 2-fold decreased transport via the reduced folate carrier (RFC). The CEM cell lines resistant to intermittent exposures to MTX, ZD1694, MTA, DDATHF, GW1843U89 and ZD9331 displayed a depletion (up to 4-fold) of total intracellular reduced folate pools. Resistance to continuous exposure to ZD9331 was caused by a 14-fold increase in TS activity. CEM/GW70, selected by continuous exposure to GW1843U89 was 50-fold resistant to GW1843U89, whereas continuous exposure to PT523 generated CEM/PT523 cells that were highly resistant (1550-fold) to PT523. Both CEM/GW70 and CEM/PT523 displayed cross-resistance to several antifolates that depend on the RFC for cellular uptake, including MTX (95- and 530-fold). CEM/GW70 cells were characterized by a 12-fold decreased transport of [3H]MTX. Interestingly, however, CEM/GW70 cells displayed an enhanced transport of folic acid, consistent with the expression of a structurally altered RFC resulting in a 2.6-fold increase of intracellular folate pools. CEM/PT523 cells displayed a markedly impaired (100-fold) transport of [3H]MTX along with 12-fold decreased total folate pools. In conclusion, multifunctional mechanisms of resistance in CEM cells have a differential impact on cellular folate homeostasis: decreased polyglutamylation and transport defects lead to folate depletion, whereas a structurally altered RFC protein can provoke expanded intracellular folate pools.

Biological Transport↗
PubMed2005

Perturbation of nanoscale structure of polypeptide multilayer thin films.

Multilayer thin films formed by sequential deposition of oppositely charged polypeptides on a charged surface are known from previous studies to comprise a mixture of types of secondary structure. Here, study of the perturbation of polypeptide film structure by deposition of poly(allylamine hydrochloride) (PAH) and poly(styrenesulfonate) (PSS) on the film surface has revealed differences in behavior attributable to physical properties of the peptides. The methods of analysis were circular dichroism spectroscopy (CD), ultraviolet spectroscopy (UVS), and quartz crystal microbalance (QCM). Films made of poly(L-lysine) (PLL) and poly(L-glutamic acid) (PLGA) with an average charge per monomer of about 1 were substantially more susceptible to perturbation of structure than films made of designed polypeptides with an average charge per monomer of about 0.5, despite preparation under identical conditions. PLL-PLGA films showed loss or gain of material and change in secondary structure content on perturbation, whether made of high molecular mass (ca. 90 kDa) or low molecular mass (ca. 14 kDa) polymers. By contrast, films made of very low molecular mass (ca. 3.5 kDa) designed polypeptides showed little change in secondary structure content. The data suggest that the penetrability of PSS or PAH into a film and therefore film density can depend substantially on the polypeptides of which it is made and the character of intermolecular interactions.

Amino Acid Sequence↗
PubMed1988

Impaired polyglutamylation of methotrexate as a cause of resistance in CCRF-CEM cells after short-term, high-dose treatment with this drug.

Two methotrexate-resistant sublines, CCRF-CEM R3/7 and CCRF-CEM R30/6, were selected from the human leukemia T-lymphoblast cell line, CCRF-CEM, after repeated exposures (7 and 6 times, respectively) for 24 h to constant concentrations (3 and 30 microM) of the drug. Analysis of the mechanism of resistance revealed no differences in levels of dihydrofolate reductase activity, its binding affinity for methotrexate, or in methotrexate transport between the CCRF-CEM parent and methotrexate-resistant cell lines. The development of resistance to methotrexate was associated with a marked decrease in the intracellular level of methotrexate polyglutamates. Although the resistant sublines were able to form substantial amounts of folate polyglutamates when measured with [3H]folic acid, the level of polyglutamates formed was decreased to about 50% of that formed by the parent cell line. No qualitative differences in folate polyglutamates formed were noted between the parental and resistant sublines. This is the first example of a cell line which displays resistance which is solely attributable to defective methotrexate polyglutamate synthesis.

Drug Resistance↗
PubMed1987

The absence of gamma-glutamyltransferase activity in transport-dependent methotrexate-resistant hepatoma cells.

A cell line derived from H35 hepatoma cells resistant to methotrexate (MTX) as a result of a defective transport system for MTX has been examined to determine how closely the variant resembles the parent cells with regard to other biochemical properties. The capacity of extracts of resistant cells to catalyze the poly-gamma-glutamylation of MTX was approximately twice as great as that of wild-type cell extracts. Evidence of similarity between wild-type and H35 R0.3 cells was derived from the equitoxic activity to both cell lines of nonclassical antifolates and other miscellaneous antineoplastics which act by a variety of mechanisms. Two phenotypic markers of hepatic cell function, alpha-aminoisobutyric acid (AIB) transport and tyrosine aminotransferase (TAT) activity inducibility, were present in both cell types, demonstrating the maintenance of these phenotypic properties in the H35 R0.3 cells. gamma-Glutamyltransferase (GGT, EC 2.3.2.2) activity differed in that it was present in wild-type cells and barely detectable in H35 R0.3 cells. The GGT activity reappeared in the H35 cells when they regained MTX sensitivity after incubation for 14-20 weeks in MTX-free media. Although defective MTX transport appeared to be correlated with the disappearance of GGT activity in an H35 variant cell line, no functional relationship between them is apparent at this time. It is possible that a lack of GGT activity may be evidence of a more differentiated phenotype in the transport-resistant cell line.

Aminoisobutyric Acids↗
PubMed1992

European comparative clinical study of Inerpan: a new wound dressing in treatment of partial skin thickness burns.

Eleven European burns centres in five countries (Belgium, England, Germany, Italy, Switzerland) participated in a prospective, randomized clinical trial comparing a new wound dressing Inerpan with conventional dressings such as petroleum jelly gauze, petroleum jelly gauze with antibiotics and silver sulphadiazine cream. The indication was partial skin thickness burns and 62 patients were included. In each patient, two similar lesions (with respect to depth and surface area) were compared, one being treated with Inerpan, the other one with a control dressing. The following parameters were studied: healing time, quality of healing, intensity of pain, local tolerance and frequency of dressing changes. Analysis of the results showed that Inerpan-treated sites healed faster than conventional ones, and were associated with a highly significant reduction of pain. The frequency of dressing changes was greatly reduced and the local tolerance was good.

Adolescent↗