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81.
Elliott JM Carling RW Chambers M Chicchi GG Hutson PH Jones AB MacLeod A Marwood R Meneses-Lorente G Mezzogori E Murray F Rigby M Royo I Russell MG Sohal B Tsao KL Williams B 《Bioorganic & medicinal chemistry letters》2006,16(22):5748-5751
A new class of potent NK3R antagonists based on the N',2-diphenylquinoline-4-carbohydrazide core is described. In an ex vivo assay in gerbil, the lead compound 2g occupies receptors within the CNS following oral dosing (Occ(90) 30 mg/kg po; plasma Occ(90) 0.95 microM) and has good selectivity and promising PK properties. 相似文献
82.
Combe JP Basran J Hothi P Leys D Rigby SE Munro AW Scrutton NS 《The Journal of biological chemistry》2006,281(26):17977-17988
Dihydroorotate dehydrogenase B (DHODB) catalyzes the oxidation of dihydroorotate (DHO) to orotate and is found in the pyrimidine biosynthetic pathway. The Lactococcus lactis enzyme is a dimer of heterodimers containing FMN, FAD, and a 2Fe-2S center. Lys-D48 is found in the catalytic subunit and its side-chain adopts different positions, influenced by ligand binding. Based on crystal structures of DHODB in the presence and absence of orotate, we hypothesized that Lys-D48 has a role in facilitating electron transfer in DHODB, specifically in stabilizing negative charge in the reduced FMN isoalloxazine ring. We show that mutagenesis of Lys-D48 to an alanine, arginine, glutamine, or glutamate residue (mutants K38A, K48R, K48Q, and K48E) impairs catalytic turnover substantially (approximately 50-500-fold reduction in turnover number). Stopped-flow studies demonstrate that loss of catalytic activity is attributed to poor rates of FMN reduction by substrate. Mutation also impairs electron transfer from the 2Fe-2S center to FMN. Addition of methylamine leads to partial rescue of flavin reduction activity. Nicotinamide coenzyme oxidation and reduction at the distal FAD site is unaffected by the mutations. Formation of the spin-interacting state between the FMN semiquinone-reduced 2Fe-2S centers observed in wild-type enzyme is retained in the mutant proteins, consistent with there being little perturbation of the superexchange paths that contribute to the efficiency of electron transfer between these cofactors. Our data suggest a key charge-stabilizing role for Lys-D48 during reduction of FMN by dihydroorotate, or by electron transfer from the 2Fe-2S center, and establish a common mechanism of FMN reduction in the single FMN-containing A-type and the complex multicenter B-type DHOD enzymes. 相似文献
83.
Heuts DP Gummadova JO Pang J Rigby SE Scrutton NS 《The Journal of biological chemistry》2011,286(34):29584-29593
Human vascular adhesion protein-1 (VAP-1) is an endothelial copper-dependent amine oxidase involved in the recruitment and extravasation of leukocytes at sites of inflammation. VAP-1 is an important therapeutic target for several pathological conditions. We expressed soluble VAP-1 in HEK293 EBNA1 cells at levels suitable for detailed mechanistic studies with model substrates. Using the model substrate benzylamine, we analyzed the steady-state kinetic parameters of VAP-1 as a function of solution pH. We found two macroscopic pK(a) values that defined a bell-shaped plot of turnover number k(cat,app) as a function of pH, representing ionizable groups in the enzyme-substrate complex. The dependence of (k(cat)/K(m))(app) on pH revealed a single pK(a) value (~9) that we assigned to ionization of the amine group in free benzylamine substrate. A kinetic isotope effect (KIE) of 6 to 7.6 on (k(cat)/K(m))(app) over the pH range of 6 to 10 was observed with d(2)-benzylamine. Over the same pH range, the KIE on k(cat) was found to be close to unity. The unusual KIE values on (k(cat)/K(m))(app) were rationalized using a mechanistic scheme that includes the possibility of multiple isotopically sensitive steps. We also report the analysis of quantitative structure-activity relationships (QSAR) using para-substituted protiated and deuterated phenylethylamines. With phenylethylamines we observed a large KIE on k(cat,app) (8.01 ± 0.28 with phenylethylamine), indicating that C-H bond breakage is limiting for 2,4,5-trihydroxyphenylalanine quinone reduction. Poor correlations were observed between steady-state rate constants and QSAR parameters. We show the importance of combining KIE, QSAR, and structural studies to gain insight into the complexity of the VAP-1 steady-state mechanism. 相似文献
84.
Why should parasite resistance be costly? 总被引:3,自引:0,他引:3
Parasite resistance is sometimes associated with fitness costs. Costs of resistance are fundamentally important in epidemiology, and in the ecology and evolution of host-parasite interactions. The cost of resistance is often envisioned as the cost of re-allocating limiting resources to resistance machinery from other traits. This popular paradigm has resulted in a spate of research that assumes a fitness cost to resistance. We comment on this trend and propose a working framework of various resistance means and mechanisms. Within these means and mechanisms, we suggest that many are not likely to incur significant fitness costs. 相似文献
85.
Adam Macierzanka Alan R. Mackie Balazs H. Bajka Neil M. Rigby Fran?oise Nau Didier Dupont 《PloS one》2014,9(4)
The final boundary between digested food and the cells that take up nutrients in the small intestine is a protective layer of mucus. In this work, the microstructural organization and permeability of the intestinal mucus have been determined under conditions simulating those of infant and adult human small intestines. As a model, we used the mucus from the proximal (jejunal) small intestines of piglets and adult pigs. Confocal microscopy of both unfixed and fixed mucosal tissue showed mucus lining the entire jejunal epithelium. The mucus contained DNA from shed epithelial cells at different stages of degradation, with higher amounts of DNA found in the adult pig. The pig mucus comprised a coherent network of mucin and DNA with higher viscosity than the more heterogeneous piglet mucus, which resulted in increased permeability of the latter to 500-nm and 1-µm latex beads. Multiple-particle tracking experiments revealed that diffusion of the probe particles was considerably enhanced after treating mucus with DNase. The fraction of diffusive 500-nm probe particles increased in the pig mucus from 0.6% to 64% and in the piglet mucus from ca. 30% to 77% after the treatment. This suggests that extracellular DNA can significantly contribute to the microrheology and barrier properties of the intestinal mucus layer. To our knowledge, this is the first time that the structure and permeability of the small intestinal mucus have been compared between different age groups and the contribution of extracellular DNA highlighted. The results help to define rules governing colloidal transport in the developing small intestine. These are required for engineering orally administered pharmaceutical preparations with improved delivery, as well as for fabricating novel foods with enhanced nutritional quality or for controlled calorie uptake. 相似文献
86.
Andrea LJ Marschall Frank N Single Katrin Schlarmann Andreas Bosio Nina Strebe Joop van den Heuvel André Frenzel Stefan Dübel 《MABS-AUSTIN》2014,6(6):1394-1401
Functional knockdowns mediated by endoplasmatic reticulum-retained antibodies (ER intrabodies) are a promising tool for research because they allow functional interference on the protein level. We demonstrate for the first time that ER intrabodies can induce a knock-down phenotype in mice. Surface VCAM1 was suppressed in bone marrow of heterozygous and homozygous ER intrabody mice (iER-VCAM1 mice). iER-VCAM1 mice did not have a lethal phenotype, in contrast to the constitutive knockout of VCAM1, but adult mice exhibited physiological effects in the form of aberrant distribution of immature B-cells in blood and bone marrow. The capability to regulate knock-down strength may spark a new approach for the functional study of membrane and plasma proteins, which may especially be valuable for generating mouse models that more closely resemble disease states than classic knockouts do. 相似文献
87.
Thomas H. Cribb Sylvie Pichelin Vincent Dufour Rodney A. Bray Claude Chauvet Elizabeth Faliex Ren Galzin Cdrik M. Lo Alain Lo-Yat Serge Morand Mark C. Rigby Pierre Sasal 《International journal for parasitology》2000,30(14):185-1451
Recruiting coral reef fish larvae from 38 species and 19 families from New Caledonia were examined for parasites. We found 13 parasite species (Platyhelminthes: Monogenea, Cestoda and Trematoda) but no acanthocephalan, crustacean or nematode parasites. Over 23% of individual fish were infected. Didymozoid metacercariae were the most abundant parasites. We conclude that most of the parasites are pelagic species that become ‘lost’ once the fish larvae have recruited to the reef. Larval coral reef fish probably contribute little to the dispersal of the parasites of the adult fish so that parasite dispersal is more difficult than that of the fish themselves. 相似文献
88.
Simon J. Moore Rebekka Biedendieck Andrew D. Lawrence Evelyne Deery Mark J. Howard Stephen E. J. Rigby Martin J. Warren 《The Journal of biological chemistry》2013,288(1):297-305
The anaerobic pathway for the biosynthesis of cobalamin (vitamin B12) has remained poorly characterized because of the sensitivity of the pathway intermediates to oxygen and the low activity of enzymes. One of the major bottlenecks in the anaerobic pathway is the ring contraction step, which has not been observed previously with a purified enzyme system. The Gram-positive aerobic bacterium Bacillus megaterium has a complete anaerobic pathway that contains an unusual ring contraction enzyme, CbiH60, that harbors a C-terminal extension with sequence similarity to the nitrite/sulfite reductase family. To improve solubility, the enzyme was homologously produced in the host B. megaterium DSM319. CbiH60 was characterized by electron paramagnetic resonance and shown to contain a [4Fe-4S] center. Assays with purified recombinant CbiH60 demonstrate that the enzyme converts both cobalt-precorrin-3 and cobalt factor III into the ring-contracted product cobalt-precorrin-4 in high yields, with the latter transformation dependent upon DTT and an intact Fe-S center. Furthermore, the ring contraction process was shown not to involve a change in the oxidation state of the central cobalt ion of the macrocycle. 相似文献
89.
Follicular fluid effects on progesterone secretion are not due to follicle-stimulating hormone or steroids 总被引:1,自引:0,他引:1
An antiserum raised against porcine follicle-stimulating hormone (FSH) was unable to eliminate the stimulatory action of fluid from large antral porcine follicles on progesterone secretion by granulosa cells from small antral porcine follicles. The same titers of the antiserum were completely effective at eliminating the effect of 2 micrograms of NIH-FSH-P12, whereas maximal stimulation of progesterone secretion was observed with 0.5 micrograms FSH/ml. The androgen and estrogen concentrations measured in charcoal-treated inhibitory follicular fluid from small porcine antral follicles and from stimulatory follicular fluid from large follicles were added separately and together to culture media supplemented with serum to determine if these low concentrations (5 X 10(-11) to 5 X 10(-10) M) of steroids could mimic the actions of follicular fluid on progesterone secretion. Neither the inhibitory nor the stimulatory actions of the follicular fluids could be mimicked by these low concentrations of steroids. Higher concentration of steroids (10(-8) to 10(-7) M range) did stimulate progesterone secretion as reported by others. Our data indicate that the actions of charcoal-treated follicular fluids on granulosa cell progesterone secretion cannot be explained by difference in FSH or steroid contents between the inhibitory and stimulatory fluids and serum. 相似文献
90.
Negative regulation of viral enhancers in undifferentiated embryonic stem cells 总被引:127,自引:0,他引:127