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PubMed1995

Molecular dynamics in sodium poly (L-glutamate) aqueous solutions analyzed by means of the stretched exponential decay of the Williams-Watts function.

The high-frequency dielectric dispersions of the sodium salt of poly(L-glutamic acid) aqueous solutions in the frequency range from 1 to 1,000 MHz have been analyzed by means of the Cole-Davidson relaxation function in the frequency domain and by means of the Williams-Watts relaxation function in the time domain. The analogies between the two descriptions are discussed on the basis of the analysis carried out by Lindsey and Patterson and the connections between the dipole-dipole correlation function based on the kinetic model for polyion dynamics proposed by Skinner and the Williams-Watts nonexponential decay function are briefly discussed.

Electrochemistry↗
PubMed1983

A synthetic approach to poly-gamma-glutamyl analogs of methotrexate.

Methotrexate poly-gamma-glutamates bearing two and three glutamate units above that present in methotrexate have been synthesized by extension of a previously described route by which the lower congener bearing one added glutamate unit was synthesized. Key steps in the sequence are the peptide coupling of N-[4-[[(benzyloxy)-carbonyl]methylamino]benzoyl]-L-glutamic acid alpha-benzyl ester (5) with oligo-gamma-L-glutamate benzyl esters, removal of blocking groups by catalytic hydrogenolysis, and introduction of the (2,4-diamino-6-pteridinyl)methyl grouping by alkylation with (6-bromomethyl)-2,4-pteridinediamine hydrobromide. Elaboration of the required oligo-gamma-L-glutamate chain was achieved one unit at a time beginning with the coupling of L-glutamic acid dibenzyl ester with t-butyloxycarbonyl-L-glutamic acid alpha-benzyl ester (7) followed by selective removal of the t-butyloxycarbonyl grouping and another coupling step with 5 or 7 as required. Diphenylphosphoryl azide was used as the coupling reagent in each conversion producing a peptide linkage. Intermediates were obtained in pure form according to thin-layer chromatography and elemental analysis results, and the final target compounds were obtained in high purity as judged by thin-layer chromatography, high-performance liquid chromatography, 1H NMR and mass spectral data, and elemental analysis results.

Animals↗
PubMed1991

Shear-wave detection of structural effects in aqueous solutions of bovine serum albumin and hemoglobin.

Using cylindrical quartz crystal torsional resonators operating at 39 and 75 kHz to generate shear waves in aqueous solutions of the proteins bovine serum albumin and hemoglobin and the polypeptide poly l-glutamic acid, it has been possible to determine the complex dynamic shear viscosities of the solutions. The effects of concentration, pH, and denaturation using various agents have been studied. It is possible to relate the viscosity and configurational elasticity of the solutions, to the intramolecular and intermolecular forces associated with the of the proteins at frequencies between 60 and 400 kHz and attributed to conformational changes of bovine serum albumin and the quaternary doublet interactions of hemoglobin have been confirmed and emphasized by the use of shear waves.

Animals↗
PubMed2000

Tumor irradiation enhances the tumor-specific distribution of poly(L-glutamic acid)-conjugated paclitaxel and its antitumor efficacy.

The poly(L-glutamic acid)-paclitaxel (PG-TXL) conjugate has been shown to exhibit significantly greater antitumor activity than conventionally formulated paclitaxel (TXL) against solid tumors (Li et al., Cancer Res., 58: 2404-2409, 1998). Here we report that local tumor irradiation enhanced the distribution of PG-TXL given 24 h later to ovarian OCa-1 carcinoma implanted i.m. in C3Hf/Kam mice. Radiation significantly increased tumor uptake of PG-TXL and tumor vascular permeability, caused elevation of the serum concentration of vascular endothelial growth factor, and arrested OCa-1 cells in the G1 phase of cell cycle. The enhancement factors, as measured by incremental tumor growth delay compared with PG-TXL alone, ranged from 1.36-4.44. Complete tumor regression was also observed at a higher radiation dose (>10 Gy) and a higher PG-TXL dose (>80 mg equivalentTXL/kg). Furthermore, combined radiation and PG-TXL produced a significantly greater tumor growth delay than treatment with radiation and TXL when both drugs were given at the same equivalent TXL dose of 60 mg/kg 24 h after tumor irradiation (enhancement factors, 4.44 versus 1.50). These data suggest that conjugation of TXL to poly(L-glutamic acid) is necessary for improved response and that the supra-additive effect of combined radiation and PG-TXL therapy is due in part to modulation of the enhanced permeability and retention effect of macromolecules by radiation. We propose a treatment strategy combining radiation and macromolecular chemotherapy that may have important clinical implications in terms of scheduling and optimization of the therapeutic ratio.

Animals↗
PubMed1994

The carboxy-terminal peptide of detyrosinated alpha tubulin provides a minimal system to study the substrate specificity of tubulin-tyrosine ligase.

The ATP-dependent tubulin-tyrosine ligase (TTL) restores the carboxy-terminal tyrosine of alpha tubulin in alpha beta tubulin that has been previously detyrosinated. Here we show that the carboxy-terminal tetradecapeptide of detyrosinated alpha tubulin is used by TTL as a substrate, albeit at 50-fold lower efficiency than alpha beta tubulin. The minimal system provided by the TTL/peptide combination mirrors the TTL/tubulin system in all aspects tested, and shows a pronounced substrate inhibition. Synthetic peptides varying in length and/or containing single amino acid replacements were used to analyze the TTL specificity for the carboxy-terminal sequence of detyrosinated alpha tubulin. Peptides ending like alpha tubulin with the sequence Gly-Glu-Glu are optimally tyrosinated once a peptide length of 12 residues is reached. Position -1 of this recognition sequence, to which the tyrosine is added, must be glutamic acid. Position -2 accepts only an acidic amino acid but glutamic acid is by far preferred over aspartic acid. These results explain why a subpopulation of brain alpha tubulin, which ends with the sequence Gly-Glu, is not tyrosinated by TTL. The carboxy-terminal dodecapeptide of brain alpha tubulin with its polyglutamyl side-chain on position -6 shows the same substrate activity as the corresponding synthetic peptide lacking the side-chain. We discuss the substrate specificity of TTL for different alpha tubulins and speculate why tubulin is a better substrate than the optimal peptide covering the carboxy-terminal of detyrosinated alpha tubulin.

Animals↗
PubMed1979

Plaque forming cell assay to measure responses in mice to the random copolymer (Glu60Phe40).

A plaque-forming cell (PFC) assay to measure the immune response of mice to the synthetic random copolymer of glutamic acid and phenylalanine (GPhe) is described here. GPhe can be coupled to sheep red blood cells (SRBC) using "aged" CrCl3. Both IgM and IgG plaques are detected in the murine GPhe response. Mice of H-2 haploytpes p and q are high responders, a and k are medium or low responders and b, d and s are nonresponders as detected by the PFC assay.

Animals↗
PubMed2004

Improving the toxicity profile of chemotherapy for advanced ovarian cancer: a potential role for CT-2103.

Significant progress has been made in the management of advanced ovarian cancer. Response rates to platinum-based chemotherapy are respectable; however, recurrence continues to be the rule rather than the exception. Chemotherapy is administered as initial treatment and for disease recurrence, often over a period of many years--thus ovarian cancer is considered a chronic disease by many oncologists. The importance of the taxanes in the treatment of ovarian cancer is well established. However, taxanes are associated with numerous toxicities, resulting in the need for alternative dosing strategies that produce fewer side effects, or the discovery of novel taxanes with equivalent anti-tumor activity, but a more favorable toxicity profile. Several taxanes are in development including CT-2103, a macromolecule consisting of paclitaxel conjugated to a biodegradable, water-soluble polymer of glutamic acid. Clinical data of CT-2103 as a single agent and in combination have demonstrated activity in previously treated ovarian cancer patients, both in platinum-sensitive and platinum-resistant disease. CT-2103 appears to be potentially associated with a more favorable toxicity profile relative to paclitaxel, and enhanced solubility allows for a 10-minute infusion. Ongoing trials employing this agent will focus on extending survival, optimizing quality of life, and defining a possible role for CT-2103 in the standard management of advanced ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

High yield of poly-gamma-glutamic acid from Bacillus subtilis by solid-state fermentation using swine manure as the basis of a solid substrate.

Solid-state fermentations (SSF), using swine manure as the basis of a solid substrate, were carried out for high yield of poly-gamma-glutamic acid (gamma-PGA) by Bacillus subtilis CCTCC202048. Fermentation medium and process parameters were optimized through three orthogonal array designs. The optimal medium consisted of 62.3% (w/w, dry weight basis) swine manure, 25.0% soybean cake, 5.0% wheat bran, 5.0% glutamic acid, 2.5% citric acid and 0.2% MnSO4.H2O. The optimal process parameters were 15.0 g medium with initial moisture content 60% and initial pH 9.0 in 250 ml flask, inoculation at mid-log phase with a 4% inoculum level and cultivation for 48 h at 37 degrees C. The average-PGA yield (6.0%) in triplicate under optimal conditions was obtained on the laboratory scale while it was 4.5% at compost experiment. These would lay a foundation for lessening the pollution of swine manure, increasing fertilizer efficiency and exploring a late-model organic fertilizer that retains water and nutrients.

Animals↗
PubMed1997

Artificial glycopolypeptide conjugates: simple synthesis of lactose- and N,N'-diacetylchitobiose-substituted poly(L-glutamic acid)s through N-beta-glycoside linkages and their interaction with lectins.

Poly(glutamic acid)s carrying lactose- and N,N'-diacetylchitobiose residues were synthesized via a simple two-step procedure. The oligosaccharides were treated with ammonium hydrogen carbonate and the resulting N-beta-glycosylamine was coupled with pendant carboxyl groups of poly(L-glutamic acid) in the presence of a mixture of benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and 1-hydroxybenzotriazole (HOBt) in dimethyl sulfoxide. The oligosaccharide incorporated as pendant N-glycosides was estimated by 1H-NMR spectroscopy to be 30 mol% (or 45 wt%) for lactose and 27 mol% (46 wt%) for chitobiose. The glycopolypeptide carrying N,N'-diacetyl-chitobiose inhibited hemagglutination activity of wheat germ agglutinin (WGA) much more strongly (about 10(6) times) than N,N'-diacetylchitobiose itself. The high activity is due to the cluster or high density effect of the glycopolypeptides.

Glycopeptides↗
PubMed2005

Biosynthesis of poly-gamma-glutamic acid in plants: transient expression of poly-gamma-glutamate synthetase complex in tobacco leaves.

Transient expression of genes coding for the poly-gamma-glutamate (gammaPGA) synthetase system (pgs) was investigated in tobacco plants. Three genes of the pgs, pgsA, pgsB and pgsC, were separately placed under the control of the CaMV 35S promoter and introduced into tobacco leaves via Agrobacterium infection. Synthesized gammaPGA in plant tissues was detected immunologically with mouse anti-gammaPGA antiserum which specifically reacts with gammaPGA on a nitrocellulose membrane. Confirmation of gammaPGA biosynthesis in the transient expression analysis in tobacco tissue indicates that subunits of pgs complex were expressed and reassembled in a functional form.

Genes, Plant↗
PubMed1989

The dual role of polyelectrolytes and proteins as mineralization promoters and inhibitors of calcium oxalate monohydrate.

Polyelectrolytes and protein molecules appear to be able to act not only as crystallization inhibitors when present in solution, but also as promoters of crystal growth when immobilized onto surfaces. Because this is especially relevant for systems in which heterogeneous nucleation can occur, the influence of poly-L-glutamic (PGlu) acid, poly-L-aspartic (PAsp) acid, and human serum albumin (HSA) on the nucleation and growth inhibition of calcium oxalate monohydrate (COM) was studied using the Constant Composition (CC) kinetics technique. The overgrowth of COM on hydroxyapatite (HAP) seed crystals pretreated with HSA was also investigated. Pronounced differences in inhibiting and nucleating potential were found for the various additives. HSA, a relatively poor growth inhibitor when present in solution, was found to nucleate very regular, hexagonal COM crystals when immobilized on a surface and to enhance the overgrowth of COM when adsorbed on HAP surfaces.

Calcium Oxalate↗
PubMed1989

The involvement of ionic interactions during asbestos-induced enzyme release from polymorphonuclear leukocytes.

Chrysotile asbestos permeabilizes the plasma membrane of rabbit polymorphonuclear leukocytes (PMNs) which is evident from the release of the cytoplasmic enzyme lactate dehydrogenase (LDH) from the cell. When Ca2+ is present in the medium exocytosis is observed, evident from the release of the granule associated enzyme lysozyme which is not liberated in the absence of Ca2+. Asbestos-induced enzyme release is inhibited by polyanions or by removal of positive charges on asbestos, and resembles enzyme release induced by synthetic polycations. Pretreatment of PMNs with neuraminidase does not affect the ability of asbestos to induce enzyme release from these cells. Asbestos induces release of glucose from glucose-loaded liposomes, and this effect can be inhibited by the polyanion poly-D-glutamic acid. The results are compatible with the view that positive charges play a decisive role in the interaction between PMNs and asbestos, and that the primary target of asbestos could be the lipid bilayer of the membrane. The interaction results in a permeabilized plasma membrane. When Ca2+ is present in the medium it moves into the cell and causes exocytosis of the granule enzyme lysozyme. Inhibition of cytotoxicity by polyanion may cause a diminished Ca2+-influx and hence inhibition of lysozyme release.

Animals↗
PubMed2003

Antifreeze activities of poly(gamma-glutamic acid) produced by Bacillus licheniformis.

Various enantiomeric isomers, metals salts and molecular sizes of poly(gamma-glutamic acid), gamma-PGA, produced by Bacillus licheniformis CCRC 12826, were prepared and their antifreeze activities were studied by differential scanning calorimetry. The antifreeze activity of gamma-PGA increased as its molecular weight decreased but was indifferent to its D/L-glutamate composition. The antifreeze activity was cation dependent decreasing in the order Mg2+ >> Ca2+ approximately Na+ >> K+ which follows that of inorganic chlorides in that high ionic charge leads to high antifreeze activity. The mechanism by which the cryoprotective effects of gamma-PGA can be explained is still yet to be determined.

Antifreeze Proteins↗
PubMed1992

Vibrational CD of the amide II band in some model polypeptides and proteins.

The amide II vibrational CD (VCD) spectra of poly (L-glutamic acid) and poly (L-lysine) in various conformational forms and those of several proteins in H2O have been measured. Characteristic VCD patterns have been observed in the amide II region due to helix, beta-sheet, and coil conformations in polypeptides. Based on their x-ray crystal structures, the proteins studied have been assigned to six categories. Proteins in the same category give rise to similar amide II VCD. While the protein conformational type is indicated using the amide II VCD, discrimination between types is less characteristic than with the previously studied amide I' VCD in D2O.

Amides↗
PubMed2006

Chain conformations of poly(gamma-benzyl-L-glutamate) pre and post an electrospinning process.

In order to reveal mechanisms for the electrospinning of proteins, this study focuses on the polymer chain conformation, which is considered to be a critical factor for successful electrospinning. Poly(gamma-benzyl-L-glutamate) (PBLG) is employed and the relationships between the chain conformations of the pre-spun PBLG molecules and the morphologies of the post-spun PBLG fibers are investigated. By combining viscosity measurements, and circular dichroism and FT-IR spectroscopies, chain conformations of the pre- and post-spun PBLG are characterized. The chain conformations of the pre-spun PBLG changes from an alpha-helix to a random coil upon changing the solvent ratios of dichloromethane (CH(2)Cl(2)) and trifluoroacetic acid (CF(3)COOH) from 100:0 to 0:100. In an alpha-helix conformation, the morphology of PBLG fibers is relatively thick, while that of the random coil is thin and homogenous. The mean fiber diameters decrease when the chain conformations change from an alpha-helix to a random coil. FT-IR spectroscopy and wide-angle X-ray diffraction measurements reveal that electrospinning predominantly induces an alpha-helical conformation in post-spun PBLG fibers, and more highly crystallized fibers are generated as the alpha-helical content in the pre-spun solution increases.

Electrochemistry↗
PubMed2004

Induction of opsonic antibodies to the gamma-D-glutamic acid capsule of Bacillus anthracis by immunization with a synthetic peptide-carrier protein conjugate.

The capsule of Bacillus anthracis, a polymer of gamma-D-glutamic acid, functions as a virulence determinant and is a poor immunogen. In this study we show that antibodies reactive with the B. anthracis capsule can be elicited in mice by immunization with a conjugate consisting of a synthetic gamma-D-glutamic acid nonamer peptide (gamma-D-glu9) covalently coupled to keyhole limpet hemocyanin. The serum response to gamma-D-glu9 was comprised primarily of IgG antibodies that recognized an epitope requiring a minimum of four gamma-linked D-glutamic acid residues. Antibodies to (gamma-D-glu9) bound to the surface of encapsulated B. anthracis cells and mediated opsonophagoctosis. These findings suggest that anti-capsular antibodies could mediate the clearance of vegetative B. anthracis cells in vivo. Thus, inclusion of an immunogenic capsular component as well as protective antigen in new anthrax vaccines would generate immune responses targeting both the bacteremic and toxigenic aspects of anthrax infection and thus may increase protective efficacy.

Animals↗
PubMed2005

Medium optimization by response surface methodology for poly-gamma-glutamic acid production using dairy manure as the basis of a solid substrate.

Dairy manure, supplemented with agro-industrial materials, was used as the solid substrate for high yield of poly-gamma-glutamic acid (gamma-PGA) by Bacillus subtilis CCTCC202048. The solid-state fermentation medium was optimized by response surface methodology. In the first optimization step, a Plackett-Burman design was used to evaluate the influence of related factors. Wheat bran, soybean cake and glutamic acid were found to be more compatible supplement with dairy manure and positively influenced on gamma-PGA production. In the second step, the concentrations of the three supplemental nutrients above were further optimized using a Box-Behnken design. The average gamma-PGA yield (4.70%) in triplicate under optimal conditions was obtained on the laboratory scale, whereas it was 3.58% at compost experiment. These would lay a foundation for lessening the pollution of dairy manure, increasing fertilizer efficiency and exploring a late-model organic fertilizer that retains water and nutrients.

Animals↗
PubMed2005

Natural and edible biopolymer poly-gamma-glutamic acid: synthesis, production, and applications.

Poly-gamma-glutamic acid (gamma-PGA) is a very promising biodegradable polymer that is produced by Bacillus subtilis. Gamma-PGA is water-soluble, anionic, biodegradable, and edible. This paper reviews the production of a strain of gamma-PGA and recent developments with respect to applications in terms of Ca absorption, moisturizing properties, gamma-PGA conjugation, super absorbent polymer, and so on. Our recent research shows that gamma-PGA can be used as an immune-stimulating and anti-tumor agent, especially at high molecular weight.

Adjuvants, Immunologic↗