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991.
Biochemical characterization and structural analysis of a highly proficient cocaine esterase 总被引:4,自引:0,他引:4
Turner JM Larsen NA Basran A Barbas CF Bruce NC Wilson IA Lerner RA 《Biochemistry》2002,41(41):12297-12307
The bacterial cocaine esterase, cocE, hydrolyzes cocaine faster than any other reported cocaine esterase. Hydrolysis of the cocaine benzoyl ester follows Michaelis-Menten kinetics with k(cat) = 7.8 s(-1) and K(M) = 640 nM. A similar rate is observed for hydrolysis of cocaethylene, a more potent cocaine metabolite that has been observed in patients who concurrently abuse cocaine and alcohol. The high catalytic proficiency, lack of observable product inhibition, and ability to hydrolyze both cocaine and cocaethylene make cocE an attractive candidate for rapid cocaine detoxification in an emergency setting. Recently, we determined the crystal structure of this enzyme, and showed that it is a serine carboxylesterase, with a catalytic triad formed by S117, H287, and D259 within a hydrophobic active site, and an oxyanion hole formed by the backbone amide of Y118 and the Y44 hydroxyl. The only enzyme previously known to use a Tyr side chain to form the oxyanion hole is prolyl oligopeptidase, but the Y44F mutation of cocE has a more deleterious effect on the specificity rate constant (k(cat)/K(M)) than the analogous Y473F mutation of prolyl oligopeptidase. Kinetic studies on a series of cocE mutants both validate the proposed mechanism, and reveal the relative contributions of active site residues toward substrate recognition and catalysis. Inspired by the anionic binding pocket of the cocaine binding antibody GNC92H2, we found that a Q55E mutation within the active site of cocE results in a modest (2-fold) improvement in K(M), but a 14-fold loss of k(cat). The pH rate profile of cocE was fit to the ionization of two groups (pK(a1) = 7.7; pK(a2) = 10.4) that likely represent titration of H287 and Y44, respectively. We also describe the crystal structures of both S117A and Y44F mutants of cocE. Finally, urea denaturation studies of cocE by fluorescence and circular dichroism show two unfolding transitions (0.5-0.6 M and 3.2-3.7 M urea), with the first transition likely representing pertubation of the active site. 相似文献
992.
cDNA corresponding to a flavonol synthase gene from Arabidopsis thaliana was cloned and expressed in Escherichia coli. The recombinant protein was purified to near-homogeneity and the catalytic properties of the enzyme were studied in vitro. Together with kaempferol and apigenin the recombinant protein synthesised the (2R,3S)-cis- and (2S,3S)-trans-isomers of dihydrokaempferol from the (2S)- and (2R)-isomers of naringenin, respectively. Flavanones and dihydroflavanols differing in degree of A- or B-ring hydroxylation were also accepted as substrates. 相似文献
993.
Two new coumarin glycosides (1 and 2) along with two known coumarin glucosides, daphnin (3) and daphnetin glucoside (4) were isolated from the aerial parts of Cruciata taurica. The structures of the new compounds were elucidated by spectral methods and chemical means as 7-O-(6' -acetoxy-beta-D-glucopyranosyl)-8-hydroxycoumarin (1) and 7-O-[6 '-O-(3',4'-dihydroxycinnamoyl)-beta-D-glucopyranosyl]-8-hydroxycoumarin (2). The phylogenetic significance of coumarins in C. taurica was discussed. 相似文献
994.
995.
Ahmad M Grancher N Heil M Black RC Giovani B Galland P Lardemer D 《Plant physiology》2002,129(2):774-785
Cryptochrome blue-light photoreceptors are found in both plants and animals and have been implicated in numerous developmental and circadian signaling pathways. Nevertheless, no action spectrum for a physiological response shown to be entirely under the control of cryptochrome has been reported. In this work, an action spectrum was determined in vivo for a cryptochrome-mediated high-irradiance response, the blue-light-dependent inhibition of hypocotyl elongation in Arabidopsis. Comparison of growth of wild-type, cry1cry2 cryptochrome-deficient double mutants, and cryptochrome-overexpressing seedlings demonstrated that responsivity to monochromatic light sources within the range of 390 to 530 nm results from the activity of cryptochrome with no other photoreceptor having a significant primary role at the fluence range tested. In both green- and norflurazon-treated (chlorophyll-deficient) seedlings, cryptochrome activity is fairly uniform throughout its range of maximal response (390-480 nm), with no sharply defined peak at 450 nm; however, activity at longer wavelengths was disproportionately enhanced in CRY1-overexpressing seedlings as compared with wild type. The action spectrum does not correlate well with the absorption spectra either of purified recombinant cryptochrome photoreceptor or to that of a second class of blue-light photoreceptor, phototropin (PHOT1 and PHOT2). Photoreceptor concentration as determined by western-blot analysis showed a greater stability of CRY2 protein under the monochromatic light conditions used in this study as compared with broad band blue light, suggesting a complex mechanism of photoreceptor activation. The possible role of additional photoreceptors (in particular phytochrome A) in cryptochrome responses is discussed. 相似文献
996.
Tu AH Girotto JA Singh N Dufresne CR Robertson BC Seyfer AE Manson PN Iliff N 《Plastic and reconstructive surgery》2002,109(4):1259-1265
Dog bites are commonly associated with soft-tissue injury to the face but rarely result in facial fractures. This article reports six new cases of facial fractures associated with dog bites and reviews additional cases reported in the literature. The demographics of the patients attacked, the location of facial fractures, and the characteristics of associated soft-tissue injuries or complications developing from the dog bite are described. With six new cases and 10 from the literature, this article reviewed a total of 16 cases involving 27 facial fractures. Eighty-seven percent of the cases involved children less than 16 years of age. The periorbital or nasal bones were involved in 69 percent of the cases. Lacerations were the most frequently associated soft-tissue injury. Additional injuries included facial nerve damage, lacrimal duct damage requiring stenting and reconstruction, ptosis from levator transection, and blood loss requiring transfusion. Although facial fractures are not commonly considered to be associated with dog bite injuries, the index of suspicion for a fracture should be raised when the injury occurs in a child, particularly when injury occurs near the orbit, nose, and cheek. 相似文献
997.
Chimpanzee research plays a central role in the discussions of conflict negotiation. Reconciliation, or the attraction and
affiliation of former opponents following conflict, has been proposed as a central element of conflict negotiation in chimpanzees
and various other taxa. In an attempt to expand the database of chimpanzee conflict resolution, conflict and post-conflict
behavior were recorded for a small group of socially housed chimpanzees at the Chimpanzee and Human Communication Institute,
at Central Washington University. Data were collected over six 6-week periods between 1997 and 2000, for a total of 840 hours
of observation, resulting in a substantial post-conflict (PC) and matched control (MC) data set. The data demonstrate this
group’s tendencies to maintain visual contact and closer proximity after conflicts. Dyadic corrected conciliatory tendencies
ranged between 0 – 37.5% and averaged 17.25% across all dyads. Individual corrected conciliatory tendencies ranged between
5.8 and 32%. The results of this study combined with recent publications on captive and free-ranging chimpanzee post-conflict
behavior suggest that variation in post-conflict behavior may be important to our understanding of chimpanzee conflict negotiation,
and may also have implications for the design and management of captive chimpanzee enclosures and social groups, respectively. 相似文献
998.
999.
Solinís MA de la Cruz Y Calvo B Hernández RM Gascón AR Goñi I Gurruchaga MD Pedraz JL 《Chirality》2002,14(10):806-813
We studied the release of salbutamol and ketoprofen enantiomers from HPMC K100M matrices containing two types of cellulose derivatives: cellulose tris (3,5-dimethylphenylcarbamate) and cellulose tris (2,3-dichlorophenylcarbamate), chiral excipients used as stationary phases for liquid chromatography. These matrices provided an extended release of both drugs. Ketoprofen release from formulations elaborated with cellulose tris (2,3-dichlorophenylcarbamate) was by anomalous transport, because the value of n (release exponent of the diffusion equation) ranged between 0.60-0.68, whereas for all other formulations the value of exponent n ranged from 0.50-0.54. The drug thus diffuses through the matrix and is released following a quasi-Fickian diffusion mechanism (stereoselective process). The matrices preferentially retained R-salbutamol and S-ketoprofen and cellulose tris (3,5-dimethylphenylcarbamate) showed more capacity of chiral discrimination for both drugs than cellulose tris (2,3-dichlorophenylcarbamate). Moreover, we observed that stereoselectivity is dependent on the amount of chiral excipient in the formulation. Diffusion tests confirmed the chiral interaction between drugs and cellulose derivatives observed in the dissolution assays except for matrices elaborated with ketoprofen and cellulose tris (2,3-dichlorophenylcarbamate), where the low stereoselectivity observed with the matrices is due to the presence of HPMC K100M. We conclude that the inclusion of these cellulose derivatives in HPMC matrices does not result in a relevant stereoselectivity with respect to the two drugs studied. 相似文献
1000.
Delporte C Muñoz O Rojas J Ferrándiz M Payá M Erazo S Negrete R Maldonado S San FA Backhouse N 《Zeitschrift für Naturforschung. C, Journal of biosciences》2002,57(1-2):100-108
The probable antipyretic, antiinflammatory, analgesic and antioxidant properties of Kageneckia oblonga, Rosaceae, were investigated and the major compounds of its active extracts were isolated. The study comprised the acute toxicity of the extracts of global methanol, hexane, dichloromethane and methanol. The cytotoxicity of global methanol extract was studied in three tumoral cell lines. All the extracts exhibited the pharmacological activities under study. Methanol and dichloromethane were the most toxic extracts. From the global methanol extract, isolations were performed of prunasin, 23,24- dihydro-cucurbitacin F, and a new cucurbitacin, 3beta-(beta-D-glucosyloxy)-16alpha,23alpha-epoxycucurbita-5,24-diene-11-one. The cytotoxicity of both cucurbitacins on human neutrophils at the assayed concentrations was not statistically significant. In-vitro assays showed that both cucurbitacins can be partly responsible for the analgesic, antipyretic, and anti-inflammatory activities. Evaluation was done of the cytotoxicity of global methanol extract, 23, 24-dihydrocucurbitacin F, aqueous extracts and prunasin against P-388 murine leukaemia, A-549 human lung carcinoma and HT-29 colon carcinoma. Since global methanol extract presented a strong cytotoxicity against P-388 murine leukaemia, A-549 human lung carcinoma, and HT-29 cell lines, it is highly probable that this extract contain one or more cytotoxic compounds that could be investigated for their potential use as an agent against cancer. 相似文献