Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enzymatic degradation and polymerization using an enzyme were carried out with respect to the establishment of a sustainable chemical recycling system for poly(epsilon-caprolactone) (PCL) which is a typical biodegradable synthetic plastic. The enzymatic transformation of PCL having an Mn of 110,000 using Candida antarctica lipase (lipase CA) in water-containing toluene at 40 degrees C afforded the corresponding cyclic dicaprolactone (DCL, 1,8-dioxacyclotetradecane-2,9-dione) in a yield of up to 97%. Thus the obtained DCL readily polymerized again using both the fresh and recovered lipase CAs.
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PMID:Lipase-catalyzed transformation of poly(epsilon-caprolactone) into cyclic dicaprolactone. 1171 Jan 74

Chlorpyrifos oxon (CPO) activates extracellular signal-regulated kinase (ERK 44/42) in Chinese hamster ovary (CHOK1) cells but the mechanism is not defined. This study tests the hypothesis that diacylglycerol (DAG) is the secondary messenger responsible for CPO-induced ERK 44/42 activation. It is known that DAG is sequentially hydrolyzed by DAG lipase and monoacylglycerol (MAG) lipase, both of which are organophosphate sensitive. Inhibition of these enzymes might therefore lead to the accumulation of DAG and MAG, of which only DAG is a secondary messenger. The experiments show that treatment of CHOK1 cells with CPO significantly inhibits DAG/MAG lipase activity and elevates cellular DAG levels. Pretreatment of CHOK1 cells with CPO or a carbamate known to be a DAG lipase inhibitor, followed by treatment with a cell-permeable DAG (1,2-dihexanoyl-sn-glycerol), results in synergistic activation of ERK 44/42. CPO-potentiated DAG-induced ERK 44/42 activation is both time and concentration dependent. This activation is blocked by inhibitors of protein kinase C and mitogen-activated protein kinase kinase, suggesting that these enzymes are important in CPO/DAG cellular signaling. Activation by a stable DAG analogue (phorbol ester) was not altered by CPO, suggesting that DAG metabolism is the probable target for CPO-potentiated DAG-induced ERK 44/42 activation. These observations support the hypothesis that CPO potentiates DAG signaling in CHOK1 cells by inhibiting a CPO-sensitive DAG lipase, thereby providing a potential mechanism of toxicity not associated with acetylcholinesterase inhibition.
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PMID:Chlorpyrifos oxon potentiates diacylglycerol-induced extracellular signal-regulated kinase (ERK 44/42) activation, possibly by diacylglycerol lipase inhibition. 1178 Oct 77

A biodegradable block copolymer (PCL-b-PLLA, M(n) = 1.72 x 10(4), M(w)/M(n) = 1.37) of poly(epsilon-caprolactone) (PCL) and poly(L-lactide) (PLLA) with very low crystallinity was obtained by forming the inclusion complex between alpha-cyclodextrin molecules and PCL-b-PLLA followed by coalescence of the guest polymer chains. Films of the as-synthesized and coalesced copolymer samples, PCL and PLLA homopolymers of approximately the same chain lengths as the corresponding blocks of PCL-b-PLLA, and a physical blend of PCL/PLLA homopolymers with the same molar composition as PCL-b-PLLA were prepared by melt-compression molding between Teflon plates. Subsequently, the in vitro biodegradation behavior of these films was studied in phosphate buffer solution containing lipase from Rhizopus arrhizus, by means of ultraviolet spectra, attenuated total reflectance FTIR spectra, differential scanning calorimetry, wide-angle X-ray diffraction measurements, and weight loss analysis. PCL segments were found to degrade much faster than PLLA segments, both in the pure state and in copolymer or blend samples. Consistent with our expectation, suppression of the phase separation, as well as a decrease of crystallinity, in the coalesced copolymer sample led to a much faster enzymatic degradation than that of either as-synthesized copolymer or the PCL/PLLA physical blend sample, especially during the early stages of biodegradation. Thus the biodegradation behavior of biodegradable block copolymers, which is of decisive importance in drug delivery and controlled release systems, may be regulated by the novel and convenient means recently reported by us.(1)
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PMID:Formation of and coalescence from the inclusion complex of a biodegradable block copolymer and alpha-cyclodextrin. 2: A novel way to regulate the biodegradation behavior of biodegradable block copolymers. 1186 74

By using 4-C-hydroxymethyl-alpha-D-pentofuranose as the sugar core and lipase-catalyzed transformations, a macromer was constructed with exceptional control of substituent placement around the carbohydrate core. The key synthetic transformations performed were as follows: (1) selective lipase-catalyzed acrylation along with prochiral selection of 4-C-hydroxymethyl-1,2-O-isopropylidene-alpha-D-pentofuranose (diastereomeric excess up to 93%); (2) the ring-opening of epsilon-caprolactone, epsilon-CL, from the remaining primary hydroxyl group to give an acryl-sugar capped macromer (M(n) = 11 300, M(w)/M(n) = 1.36, initiator efficiency 50-55%, <5% water initiated PCL chains); (3) selective lipase-catalyzed esterification of the terminal hydroxyl of oligo(epsilon-CL) chains; (4) hydrolysis of the 1,2-O-isopropylidene group at the sugar core without any substantial loss in macromer molecular weight; and (5) homopolymerization of the corresponding macromer. In principle, the method developed is flexible so that it can be used to generate a wide array of unusual macromers and heteroarm stars. In the absence of biocatalytic transformation, such structural control would be extremely difficult or currently impossible to obtain.
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PMID:Biocatalytic route to well-defined macromers built around a sugar core. 1186 87

Block copolymers were prepared by ring-opening polymerization of epsilon-caprolactone in the presence of monohydroxyl or dihydroxyl poly(ethylene glycol) (PEG), using Zn powder as catalyst. The resulting poly(epsilon-caprolactone) (PCL)-PEG diblock and PCL-PEG-PCL triblock copolymers were characterized by various analytical techniques such as NMR, size-exclusion chromatography, differential scanning calorimetry, and X-ray diffraction. Both copolymers were semicrystalline polymers, the crystalline structure being of the PCL type. Films were prepared by casting dichloromethane solutions of the polymers on a glass plate. Square samples with dimensions of 10 x 10 mm were allowed to degrade in a pH = 7.0 phosphate buffer solution containing Pseudomonas lipase. Data showed that the introduction of PEG blocks did not decrease the degradation rate of poly(epsilon-caprolactone).
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PMID:Enzymatic degradation of block copolymers prepared from epsilon-caprolactone and poly(ethylene glycol). 1200 24

Triacylglycerol analogue p-nitrophenyl phosphonates specifically react with the active-site serine of lipolytic enzymes to give covalent lipase-inhibitor complexes, mimicking the first transition state which is involved in lipase-mediated ester hydrolysis. Here we report on a new type of phosphonate inhibitors containing a polarity-sensitive fluorophore to monitor micropolarity around the active site of the enzyme in different solvents. The respective compounds are hexyl and methyl dimethylamino-naphthalenecarbonylethylmercaptoethoxy-phosphonates. The hexyl phosphonate derivative was reacted with lipases from Rhizopus oryzae (ROL), Chromobacterium viscosum (CVL), and Pseudomonas cepacia (PCL). The resulting lipid-protein complexes were characterized in solution with respect to water penetration into the lipid binding site and the associated conformational changes of the proteins as a consequence of solvent polarity changes. We found that the accessibility of the lipid-binding site in all lipases studied was lowest in water. It was much higher when the protein was dissolved in aqueous ethanol. These biophysical effects may contribute to the previously observed dramatic changes of enzyme functions such as activity and stereoselectivity depending on the respective solvents.
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PMID:Fluorescent inhibitors reveal solvent-dependent micropolarity in the lipid binding sites of lipases. 1200 3

To increase the local concentration of tamoxifen in estrogen receptor (ER) positive breast cancer, we have developed and characterized nanoparticle formulation using poly(epsilon -caprolactone) (PCL). The nanoparticles were prepared by solvent displacement method using acetone-water system. Particle size analysis, scanning electron microscopy, zeta potential measurements, and differential scanning calorimetry (DSC) were used for nanoparticle characterization. Biodegradation studies were performed in the presence and absence of Pseudomonas lipase in phosphate-buffered saline (PBS, pH 7.4) at 37 degrees C. Tamoxifen loading over different concentrations was analyzed by high-performance liquid chromatography (HPLC) and the optimum loading concentration was determined. In vitro release studies were performed in 0.5% (w/v) sodium lauryl sulfate (SLS) containing PBS at 37 degrees C. Cellular uptake and distribution of fluorescent-labeled nanoparticles was examined in MCF-7 breast cancer cells. SEM micrographs and Coulter analysis showed nanoparticles with spherical shape and uniform size distribution (250-300 nm), respectively. Zeta potential analysis revealed a positive surface charge of +25 mV on the tamoxifen-loaded formulation. Being hydrophobic crystalline polyester, PCL did not degrade in PBS alone, but the degradation was enhanced by the presence of lipase. The maximum tamoxifen loading efficiency was 64%. Initial burst release of tamoxifen was observed, probably due to significant surface presence of the drug on the nanoparticles. A large fraction of the administered nanoparticle dose was taken up by MCF-7 cells through non-specific endocytosis. The nanoparticles were found in the perinuclear region after 1 h. Results of the study suggest that nanoparticle formulations of selective ER modulators, like tamoxifen, would provide increased therapeutic benefit by delivering the drug in the vicinity of the ER.
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PMID:Biodegradable poly(epsilon -caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen. 1243 41

Commercial lipases were examined for their degradation efficiency of aliphatic polyester films. In 100 days immersion of polyester films in lipase solutions at 37 degrees C at pH 7.0, Lipase Asahi derived from Chromobacterium viscosum degraded polybutylene succinate-co-adipate (PBSA), poly (e-caprolactone) (PCL) and polybutylene succinate (PBS), and Lipase F derived from Rhizopus niveus degraded PBSA and PCL during 4-17 days. Lipase F-AP15 derived from Rhizopus orizae could degrade PBSA in 22 days. In these cases, PBS and PBSA were mainly degraded to dimers, whereas PCL was mainly degraded to monomers. Only poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/V) and poly (L-lactide) (PLA) were not degraded in the experiments. However, PLA degraded completely at 55 degrees C, pH 8.5 with Lipase PL during 20 days. This result could be explained with the sequential reactions of the chemical hydrolysis of the polymer to oligomers at higher pH and temperature, and the succeeding enzymatic hydrolysis of oligomers to the monomers.
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PMID:Degradation of aliphatic polyester films by commercially available lipases with special reference to rapid and complete degradation of poly(L-lactide) film by lipase PL derived from Alcaligenes sp. 1244 16

Lipases SP525, AK, LIP, and PS were immobilized on three kinds of mesoporous silicates (FMS, PESO, and SBA) with diameters of 27 to 92 A. The amount of lipase activity adsorbed on these supports was related to the pore size of the silicate. Enantioselectivities of immobilized lipases were similar to those of free lipases, and recycling could be done in both aqueous and organic solvents.
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PMID:Catalytic properties of lipases immobilized on various mesoporous silicates. 1261 98

Nontypeable Haemophilus influenzae (NTHI) is an important etiological agent of otitis media (OM) and of exacerbated chronic obstructive pulmonary diseases (COPD). Inflammation is a hallmark of both diseases. Interleukin-8 (IL-8), one of the important inflammatory mediators, is induced by NTHI and may play a significant role in the pathogenesis of these diseases. Our studies demonstrated that a soluble cytoplasmic fraction (SCF) from NTHI induced much greater IL-8 expression by human epithelial cells than did NTHI lipooligosaccharides and envelope proteins. The IL-8-inducing activity was associated with molecules of < or =3 kDa from SCF and was peptidase and lipase sensitive, suggesting that small lipopeptides are responsible for the strong IL-8 induction. Moreover, multiple intracellular signaling pathways were activated in response to cytoplasmic molecules. The results indicated that the p38 mitogen-activated protein kinase (MAPK) and Src-dependent Raf-1-Mek1/2-extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) pathways are required for NTHI-induced IL-8 production. In contrast, the phosphatidylinositol 3-kinase (PI3K)-Akt pathway did not affect IL-8 expression, although this pathway was concomitantly activated upon exposure to NTHI SCF. The PI3K-Akt pathway was also directly activated by IL-8 and significantly inhibited by an antagonist of IL-8 receptors during NTHI stimulation. These results indicated that the PI3K-Akt pathway is activated in response to IL-8 that is induced by NTHI and may lead to other important epithelial cell responses. This work provides insight into essential molecular and cellular events that may impact on the pathogenesis of OM and COPD and identifies rational targets for anti-inflammatory intervention.
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PMID:Up-regulation of interleukin-8 by novel small cytoplasmic molecules of nontypeable Haemophilus influenzae via p38 and extracellular signal-regulated kinase pathways. 1450 Apr 70


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