Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00790 (PGA)
 2,475 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new type of double hydrophilic block copolymer, poly(ethylene oxide) (PEO)-block-poly(glycerol monoacrylate) (PGA) have been synthesized via atom transfer radical polymerization of solketal acrylate (SA) using PEO-Br as macro-initiator, and subsequent hydrolysis of the acetal-protecting group in 1N HCl solution in THF. The polymerization is of a "living" nature and the copolymers with controlled molecular weight and narrow polydispersity (M(w)/M(n) = 1.01-1.03) were obtained. The complete hydrolysis of the acetal-protecting group was verified by IR and NMR spectroscopies. A hydrophobic fluorescent compound, 1-pyrenecarboxaldehyde, was used as a model drug, which was covalently bound to the PEO-b-PGA block copolymer via a pH-sensitive acetal linkage. The kinetics of the pyrene release was studied in THF/aqueous buffers at pH 5.0 (close to pH in endosomes) and 7.4 (pH of blood plasma) by fluorescent spectroscopy. The pyrene was released much faster at pH 5.0 than that at pH 7.4. The micelle behavior in solutions at pH 5.0 and 7.4 was studied by dynamic light scattering. All results show that this double hydrophilic PEO-b-PGA is a promising candidate for potential application as drug carrier for those carbonyl-containing hydrophobic drugs.
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PMID:Double hydrophilic block copolymers PEO-b-PGA: synthesis, application as potential drug carrier and drug release via pH-sensitive linkage. 1797 19

ADP-glucose (Glc) pyrophosphorylase (AGPase), a key regulatory enzyme in starch biosynthesis, is highly regulated. Transgenic approaches in four plant species showed that alterations in either thermal stability or allosteric modulation increase starch synthesis. Here, we show that the classic regulators 3-phosphoglyceric acid (3-PGA) and inorganic phosphate (Pi) stabilize maize (Zea mays) endosperm AGPase to thermal inactivation. In addition, we show that glycerol phosphate and ribose-5-P increase the catalytic activity of maize AGPase to the same extent as the activator 3-PGA, albeit with higher K(a) (activation constant) values. Activation by fructose-6-P and Glc-6-P is comparable to that of 3-PGA. The reactants ATP and ADP-Glc, but not Glc-1-P and pyrophosphate, protect AGPase from thermal inactivation, a result consistent with the ordered kinetic mechanism reported for other AGPases. 3-PGA acts synergistically with both ATP and ADP-Glc in heat protection, decreasing the substrate concentration needed for protection and increasing the extent of protection. Characterization of a series of activators and inhibitors suggests that they all bind at the same site or at mutually exclusive sites. Pi, the classic "inhibitor" of AGPase, binds to the enzyme in the absence of other metabolites, as determined by thermal protections experiments, but does not inhibit activity. Rather, Pi acts by displacing bound activators and returning the enzyme to its activity in their absence. Finally, we show from thermal inactivation studies that the enzyme exists in two forms that have significantly different stabilities and do not interconvert rapidly.
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PMID:Heat stability and allosteric properties of the maize endosperm ADP-glucose pyrophosphorylase are intimately intertwined. 1802 61

We have previously demonstrated the ability of poly(glycerol adipate) backbone (PGA) and PGA polymer backbone substituted with varying amounts of pendant C(18) chain length acyl groups to yield Dexamethasone phosphate DXMP loaded nanoparticles. The aim of this study was to obtain a deeper understanding of the underlying principles responsible for good drug incorporation and controlled release of drugs from poly (glycerol adipate) (PGA) nanoparticles. We compared the incorporation of the water soluble drugs DXMP and Cytosine arabinoside (CYT-ARA) in both unmodified and substituted PGA polymers. We investigated the effect of change in acyl group chain length and the degree of substitution on the physicochemical properties, drug loading and release of DXMP and CYT-ARA. Nanoparticles were prepared by the interfacial deposition technique and the simultaneous emulsification method. Amongst the nanoparticles prepared using acylated polymers with varying chain lengths (C(2) to C(10)) for DXMP incorporation, polymers with acyl group chain lengths containing 8 carbon atoms (C(8)) showed maximum drug incorporation. Amongst the C(8) series, polymers with 100% acylation provided both good drug incorporation and a controlled release for DXMP while for CYT-ARA it was the unsubstituted polymer backbone that had maximum drug loading and slower release. A number of inter-related factors are responsible for producing particles with particular size, zeta potential, drug loading and release characteristics. Drug loading and release from nanoparticles are primarily influenced by the nature of interactions between the drug and polymers which in turn depend upon the type of drug used and the physical chemistry of the polymer.
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PMID:Drug incorporation and release of water soluble drugs from novel functionalized poly(glycerol adipate) nanoparticles. 1803 43

Polymer-based microparticles are increasingly becoming of interest for a variety of applications including drug delivery. Recently poly(glycerol adipate) (PGA) and poly(glycol adipate-co-omega-pentadecalactone) have shown promise for delivery of dexamethasone phosphate and ibuprofen. In this paper the copolyester poly(glycol adipate-co-omega-pentadecalactone) was evaluated as a colloidal delivery system for encapsulated therapeutic proteins. Enzyme containing microparticles were prepared via the double water-in-oil-in-water (w/o/w) emulsion-solvent evaporation methodology. alpha-Chymotrypsin was used as a model proteolytic enzyme and its transfer was monitored during the emulsification process, in addition to in vitro release from formed particles. On average, 22.1 microg protein per 1 mg polymer was encapsulated, although gradual loss of activity of the protein, once released, was recorded. The work presented shows the potential of this polyester as a delivery system for enzymes via microparticles, with improvements to the system achievable via polymer and process optimization. The pendant hydroxyl groups on the polymer backbone provide future capacity for tailored alteration of the physical and chemical properties of the polymer, in addition to covalent attachment of various compounds.
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PMID:Encapsulation and release of alpha-chymotrypsin from poly(glycerol adipate-co-omega-pentadecalactone) microparticles. 1838 25

Tween-80, dimethyl sulfoxide (DMSO), and glycerol could be used as novel materials to regulate the central carbon metabolic pathway and improve gamma-PGA biosynthesis by Bacillus subtilis CGMCC 0833. With glycerol in the medium, the activity of 2-oxoglutarate dehydrogenase complex at the key node of 2-oxoglutarate was depressed, more carbon flux distribution was directed to synthesize glutamate, the substrate of gamma-PGA, which led to overproducing of gamma-PGA, reached 31.7 g/l, compared to the original value of 26.7 g/l. When Tween-80 or DMSO was in the medium, the activity of isocitrate dehydrogenase was stimulated, the branch flux from 2-oxoglutarate to glutamate was also enhanced due to the increasing of total flux from iso-citrate to 2-oxoglutarate, then a large amount of glutamate was produced, and formation of gamma-PGA was also improved, which was a different process compared with that of glycerol. Moreover, with the addition of Tween-80 or DMSO, cell membrane permeability was increased, which facilitated the uptake of extracellular substrates and the secretion of gamma-PGA by this strain; therefore, gamma-PGA production was further stimulated, and 34.4 and 32.7 g/l gamma-PGA were obtained, respectively. This work firstly employed additives to improve the biosynthesis of gamma-PGA and would be helpful in understanding the biosynthesis mechanism of gamma-PGA by Bacillus species deeply.
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PMID:Improvement of poly(gamma-glutamic acid) biosynthesis and redistribution of metabolic flux with the presence of different additives in Bacillus subtilis CGMCC 0833. 1844 83

Ibuprofen was conjugated at different levels to a novel polyester, poly(glycerol-adipate-co-omega-pentadecalactone) (PGA-co-PL), via an ester linkage to form a prodrug. The conjugates were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), infrared (IR), gel permeation chromatography (GPC), ultraviolet (UV), and high-performance liquid chromatography (HPLC). The conjugates had a molecular weight between 18 and 24 kDa, and there was a suppression of the free hydroxyl groups within the conjugated polymer. DSC scans showed a lowering of the melting point (T(m)) when compared with the polyester alone and a difference in the number and area of T(m) peaks. Drug release studies showed an initial burst release (13-18%) followed thereafter by very slow release (maximum 35% after 18 days). Continuous work may produce ester-linked conjugates that are sufficiently labile to allow for complete release of ibuprofen over the time period studied.
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PMID:Synthesis and evaluation of novel polyester-ibuprofen conjugates for modified drug release. 1862 77

Bacillus licheniformis ATCC 9945A was grown on Medium E in batch fermentations in which the pH was maintained at 5.5., 6.5, 7.4, and 8.25. The effects of pH on cell growth, carbon source utilization, and gamma-polyglutamic acid (gamma-PGA) production, molecular weight, and polymer stereochemistry were determined. The gamma-PGA yield was highest (15 g/L, 96 h growth time) at pH 6.5. The increase in gamma-PGA formation at pH 6.5 corresponded with a relatively high specific production rate at high gamma-PGA concentration (0.09 h(-1), approximately 15 g/L gamma-PGA). In contrast, the specific gamma-PGA production rates at fermentor pH values of 5.5 and 7.4 decreased significantly for gamma-PGA fermentor yields > approximately 5 g/L. Interestingly, alteration of the medium pH had little to no significant effects on the product quality as measured by stereochemical composition and molecular weight. While glutamate and glycerol utilization were similar as a function of pH, citrate consumption increased at pH 6.5, indicating that the formation of gamma-PGA from citrate at pH 6.5 was of increased importance. The effect of aeration was evaluated by increasing the agitation speed (250 to 800 rpm) and aeration rate (0.5 to 2.0 L/min) at pH 6.5, the pH of maximal gamma-PGA production. Increased aeration resulted in doubling of the cell dry weights (2 to 4 g/L), increasing gamma-PGA yields (6.3 to 23 g/L by 48 h) and increasing in the maximum gamma-PGA-specific production rate (0.09 to 0.11 h(-1)). Other effects of increased agitation included a rapid depletion of glutamate and citrate (by 50 h) and a decrease in product molecular weight. Despite the increase in agitation and aeration, oxygen limitation of the culture was not avoided, because the partial pressure decreased to <1.0% by 29 h.
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PMID:Effects of pH and aeration on gamma-poly(glutamic acid) formation by Bacillus licheniformis in controlled batch fermentor cultures. 1862 40

Glycerol would stimulate the production of poly(gamma-glutamic acid) (gamma-PGA) and decrease its molecular weight in Bacillus subtilis NX-2. When 20 g/l glycerol was added in the medium, the yield of gamma-PGA increased from 26.7 +/- 1.0 to 31.7 +/- 1.3 g/l, and molecular weight of gamma-PGA decreased from 2.43 +/- 0.07 x 10(6) to 1.86 +/- 0.06 x 10(6) Da. In addition, it was found that the decrease of gamma-PGA chain length by glycerol would lead to the decrease of broth viscosity during the fermentation and enhanced the uptake of substrates, which could not only improve cell growth but also stimulate gamma-PGA production. Moreover, it was also found that glycerol could effectively regulate molecular weight between 2.43 +/- 0.07 x 10(6) and 1.42 +/- 0.05 x 10(6) Da with the concentration ranging from 0 to 60 g/l. This was the first time to discover such contribution of glycerol on gamma-PGA production in Bacillus genus. And the effects of glycerol on molecular weight of gamma-PGA would be developed to be an approach for the regulation of microbial gamma-PGA chain length, which is of practical importance for future commercial development of this polymer.
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PMID:Contribution of glycerol on production of poly(gamma-Glutamic Acid) in Bacillus subtilis NX-2. 1869 62

A novel polyester, poly(glycerol-adipate-co-omega-pentadecalactone) (PGA-co-PL), was conjugated with a model drug, ibuprofen, through the free hydroxyl groups of the former and the free carboxyl group of the latter at various levels of substitution. The conjugated material was processed into microspheres by both emulsion solvent evaporation and spray-drying methods. Samples of conjugated material were also blended with non-conjugated drug and the microspheres produced were evaluated by various methods. Morphologically, the microspheres produced were satisfactory. However, there was some initial burst drug release from all samples, probably due to the presence of non-conjugated drug. Subsequent drug release was very slow due to the relative stability of the covalent bonding of the drug-polyester conjugate. Stability tests showed that storage at high relative humidity resulted in increased burst release.
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PMID:Preparation and evaluation of microspheres prepared from novel polyester-ibuprofen conjugates blended with non-conjugated ibuprofen. 1988 76

Poly(glycerol adipate) (PGA) is a biodegradable polymer with promising features for nanoparticulate drug carrier systems. By acylation of PGA with fatty acids, composite systems with amphiphilic properties can be obtained. Variation of the fatty acid (laurate, stearate and behenate) and their substitution degrees lead to a wide range of different polymer structures. This strongly influences the aggregation of the polymer and thus the nature of the resulting colloidal system. Based on the modification of the interfacial deposition method, various self-stabilizing nanoparticles with defined sizes and narrow size distributions could be prepared. Non-spherical shapes (squares, pentagons) with an internal lamellar-like structure were observed for low substituted PGA-stearates. Higher substitution degrees lead to ellipsoidal or spherical particles. The size, charge, fluidity and polarity of the nanoparticles have been studied comprehensively by PCS, AF4, zeta potential measurements, DSC, NMR, TEM and fluorescence spectroscopy. The chain lengths of the attached fatty acids as well as their substitution degree substantially influence the physicochemical properties of the bulk polymers and the nanoparticles. With their diverse particle shapes and internal structures as well as their different thermal behavior, aggregate states and polarities, the systems offer promising possibilities as delivery systems for lipophilic, amphiphilic and water soluble drugs.
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PMID:Poly(glycerol adipate)-fatty acid esters as versatile nanocarriers: From nanocubes over ellipsoids to nanospheres. 2197 Dec 95


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