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81.
A mutant strain, KLAM59, of Pseudomonas aeruginosa has been isolated that synthesizes a catalytically inactive amidase. The mutation in the amidase gene has been identified
(Glu59Val) by direct sequencing of PCR-amplified mutant gene and confirmed by sequencing the cloned PCR-amplified gene. The
wild-type and altered amidase genes were cloned into an expression vector and both enzymes were purified by affinity chromatography
on epoxy-activated Sepharose 6B-acetamide followed by gel filtration chromatography. The mutant enzyme was catalytically inactive,
and it was detected in column fractions by monoclonal antibodies previously raised against the wild-type enzyme using an ELISA
sandwich method. The recombinant wild-type and mutant enzymes were purified with a final recovery of enzyme in the range of
70–80%. The wild-type and mutant enzymes behaved differently on the affinity column as shown by their elution profiles. The
molecular weights of the purified wild-type and mutant amidases were found to be 210,000 and 78,000 Dalton, respectively,
by gel filtration chromatography. On the other hand, the mutant enzyme ran as a single protein band on SDS-PAGE and native
PAGE with a M
r of 38,000 and 78,000 Dalton, respectively. These data suggest that the substitution Glu59Val was responsible for the dimeric
structure of the mutant enzyme as opposed to the hexameric form of the wild-type enzyme. Therefore, the Glu59 seems to be
a critical residue in the maintenance of the native quaternary structure of amidase. 相似文献
82.
Galli GL Skovgaard N Abe AS Taylor EW Wang T 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2005,175(3):201-208
The functional role of nitric oxide (NO) was investigated in the systemic and pulmonary circulations of the South American rattlesnake, Crotalus durissus terrificus. Bolus, intra-arterial injections of the NO donor, sodium nitroprusside (SNP) caused a significant systemic vasodilatation resulting in a reduction in systemic resistance (Rsys). This response was accompanied by a significant decrease in systemic pressure and a rise in systemic blood flow. Pulmonary resistance (Rpul) remained constant while pulmonary pressure (Ppul) and pulmonary blood flow (Qpul) decreased. Injection of L-Arginine (L-Arg) produced a similar response to SNP in the systemic circulation, inducing an immediate systemic vasodilatation, while Rpul was unaffected. Blockade of NO synthesis via the nitric oxide synthase inhibitor, L-NAME, did not affect haemodynamic variables in the systemic circulation, indicating a small contribution of NO to the basal regulation of systemic vascular resistance. Similarly, Rpul and Qpul remained unchanged, although there was a significant rise in Ppul. Via injection of SNP, this study clearly demonstrates that NO causes a systemic vasodilatation in the rattlesnake, indicating that NO may contribute in the regulation of systemic vascular resistance. In contrast, the pulmonary vasculature seems far less responsive to NO. 相似文献
83.
Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor 总被引:1,自引:0,他引:1
Duffy JL Kirk BA Konteatis Z Campbell EL Liang R Brady EJ Candelore MR Ding VD Jiang G Liu F Qureshi SA Saperstein R Szalkowski D Tong S Tota LM Xie D Yang X Zafian P Zheng S Chapman KT Zhang BB Tata JR 《Bioorganic & medicinal chemistry letters》2005,15(5):1401-1405
A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of 13, which exhibited good potency as an hGCGR functional antagonist (IC50 = 34 nM) and moderate bioavailability (36% in mice). 相似文献
84.
Discovery of novel, potent, and orally active spiro-urea human glucagon receptor antagonists 总被引:4,自引:0,他引:4
Shen DM Zhang F Brady EJ Candelore MR Dallas-Yang Q Ding VD Dragovic J Feeney WP Jiang G McCann PE Mock S Qureshi SA Saperstein R Shen X Tamvakopoulos C Tong X Tota LM Wright MJ Yang X Zheng S Chapman KT Zhang BB Tata JR Parmee ER 《Bioorganic & medicinal chemistry letters》2005,15(20):4564-4569
A novel class of spiro-ureas has been discovered as potent human glucagon receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound 15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30 mpk. Compound 15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP. 相似文献
85.
86.
Summary Hydroxyurea inhibited growth of Pseudomonas aeruginosa strain AI 3 on media containing either acetanilide (N-phenyl acetamide) or acetamide as sole carbon sources. Mutants resistant to hydroxyurea inhibition of growth on acetanilide (OUCH strains) and acetamide (AmOUCH strains) displayed altered growth properties on various amide media compared with the parent strain AI 3. AI 3 amidase, which catalyses the initial step in the metabolism of acetanilide and acetamide, was inhibited by hydroxyurea in a time-dependent reaction that was slowly reversible at pH 7.2 Compared with AI 3 amidase, amidases from the OUCH mutants were much less sensitive to inhibition by hydroxyurea and showed altered substrate specificities and pH/activity profiles; amidases from the AmOUCH mutants were more sensitive to hydroxyurea inhibition but showed increased activity towards acetamide. Association of resistance to hydroxyurea inhibition with a mutation in the amidase structural gene of strain OUCH 4 was confirmed by transduction. 相似文献
87.
88.
Fluorescamine (Fluram, Roche) has been used as a reagent for locating proteins after electrophoresis in starch gel and on paper. Attractive features of the method are speed, sensitity, and no destaining of gel or paper is required. The latex protein hevein, which is particularly difficult to stain by conventional methods, was detected very readily in starch gel and on paper with Fluorescamine. 相似文献
89.
R. Halliburton J. Tata 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》1988,75(3):468-473
Summary The relative net fitness of a compound chromosome strain of Drosophila melanogaster was about 0.05, compared with the chromosomally normal strain from which it was derived. Based on meiotic considerations alone, the expected relative fitness was about 0.25. There were no significant differences in fertility between the compound and normal strains; the compound strain produced about 28% as many offspring as the normal strain and developed faster than the normal strain in two replicates, and slower in one replicate. The low relative fitness of the compound strain was apparently due to assortative mating, in which normal females discriminated strongly against compound males. Implications for pest control projects are dicussed. 相似文献
90.
Brooke Tata Lukas Huijbregts Sandrine Jacquier Zsolt Csaba Emmanuelle Genin Vincent Meyer Sofia Leka Joelle Dupont Perrine Charles Didier Chevenne Jean-Claude Carel Juliane Léger Nicolas de Roux 《PLoS biology》2014,12(9)
Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3α as a key controller of neuronal and endocrine homeostatic processes. 相似文献