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51.
The capacity to monitor spatiotemporal activity of phospholipase C (PLC) isozymes with a PLC-selective sensor would dramatically enhance understanding of the physiological function and disease relevance of these signaling proteins. Previous structural and biochemical studies defined critical roles for several of the functional groups of the endogenous substrate of PLC isozymes, phosphatidylinositol 4,5-bisphosphate (PIP(2)), indicating that these sites cannot be readily modified without compromising interactions with the lipase active site. However, the role of the 6-hydroxy group of PIP(2) for interaction and hydrolysis by PLC has not been explored, possibly due to challenges in synthesizing 6-hydroxy derivatives. Here, we describe an efficient route for the synthesis of novel, fluorescent PIP(2) derivatives modified at the 6-hydroxy group. Two of these derivatives were used in assays of PLC activity in which the fluorescent PIP(2) substrates were separated from their diacylglycerol products and reaction rates quantified by fluorescence. Both PIP(2) analogues effectively function as substrates of PLC-δ1, and the K(M) and V(max) values obtained with one of these are similar to those observed with native PIP(2) substrate. These results indicate that the 6-hydroxy group can be modified to develop functional substrates for PLC isozymes, thereby serving as the foundation for further development of PLC-selective sensors. 相似文献
52.
Harden CJ Perez-Carrion K Babakordi Z Plummer SF Hepburn N Barker ME Wright PC Evans CA Corfe BM 《Journal of Proteomics》2012,75(10):2916-2923
Current measurement of appetite depends upon tools that are either subjective (visual analogue scales), or invasive (blood). Saliva is increasingly recognised as a valuable resource for biomarker analysis. Proteomics workflows may provide alternative means for the assessment of appetitive response. The study aimed to assess the potential value of the salivary proteome to detect novel biomarkers of appetite using an iTRAQ-based workflow. Diurnal variation of salivary protein concentrations was assessed. A randomised, controlled, crossover study examined the effects on the salivary proteome of isocaloric doses of various long chain fatty acid (LCFA) oil emulsions compared to no treatment (NT). Fasted males provided saliva samples before and following NT or dosing with LCFA emulsions. The oil component of the DHA emulsion contained predominantly docosahexaenoic acid and the oil component of OA contained predominantly oleic acid. Several proteins were present in significantly (p<0.05) different quantities in saliva samples taken following treatments compared to fasting samples. DHA caused alterations in thioredoxin and serpin B4 relative to OA and NT. A further study evaluated energy intake (EI) in response to LCFA in conjunction with subjective appetite scoring. DHA was associated with significantly lower EI relative to NT and OA (p=0.039). The collective data suggest investigation of salivary proteome may be of value in appetitive response. This article is part of a Special Issue entitled: Proteomics: The clinical link. 相似文献
53.
Williams JD Khan AR Harden EA Hartline CB Jefferson GM Keith KA Prichard MN Zemlicka J Peet NP Bowlin TL 《Bioorganic & medicinal chemistry》2012,20(12):3710-3718
A second-generation series of substituted methylenecyclopropane nucleosides (MCPNs) has been synthesized and evaluated for antiviral activity against a panel of human herpesviruses, and for cytotoxicity. Although alkylated 2,6-diaminopurine analogs showed little antiviral activity, the compounds containing ether and thioether substituents at the 6-position of the purine did demonstrate potent and selective antiviral activity against several different human herpesviruses. In the 6-alkoxy series, antiviral activity depended on the length of the ether carbon chain, with the optimum chain length being about four carbon units long. For the corresponding thioethers, compounds containing secondary thioethers were more potent than those with primary thioethers. 相似文献
54.
Karmella A Haynes Marian L Broderick Adam D Brown Trevor L Butner James O Dickson W Lance Harden Lane H Heard Eric L Jessen Kelly J Malloy Brad J Ogden Sabriya Rosemond Samantha Simpson Erin Zwack A Malcolm Campbell Todd T Eckdahl Laurie J Heyer Jeffrey L Poet 《Journal of biological engineering》2008,2(1):1-12
55.
Gentles RG Grant-Young K Hu S Huang Y Poss MA Andres C Fiedler T Knox R Lodge N Weaver CD Harden DG 《Bioorganic & medicinal chemistry letters》2008,18(19):5316-5319
An initial SAR study on a series of apamin-displacing 2-aminothiazole K(Ca)2 channel blockers is described. Potent inhibitors such as N-(4-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (13) are disclosed, and for select members of the series, the relationship between the observed activity in a thallium flux, a binding and a whole-cell electrophysiology assay is presented. 相似文献
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57.
B L Blake M R Wing J Y Zhou Q Lei J R Hillmann C I Behe R A Morris T K Harden D A Bayliss R J Miller D P Siderovski 《The Journal of biological chemistry》2001,276(52):49267-49274
G gamma(13) is a divergent member of the G gamma subunit family considered to be a component of the gustducin G-protein heterotrimer involved in bitter and sweet taste reception in taste bud cells. G gamma(13) contains a C-terminal asparagine-proline-tryptophan (NPW) tripeptide, a hallmark of RGS protein G gamma-like (GGL) domains which dimerize exclusively with G beta(5) subunits. In this study, we investigated the functional range of G gamma(13) assembly with G beta subunits using multiple assays of G beta association and G beta gamma effector modulation. G gamma(13) was observed to associate with all five G beta subunits (G beta(1-5)) upon co-translation in vitro, as well as function with all five G beta subunits in the modulation of Kir3.1/3.4 (GIRK1/4) potassium and N-type (alpha(1B)) calcium channels. Multiple G beta/G gamma(13) pairings were also functional in cellular assays of phospholipase C (PLC) beta 2 activation and inhibition of G alpha(q)-stimulated PLC beta 1 activity. However, upon cellular co-expression of G gamma(13) with different G beta subunits, only G beta(1)/G gamma(13), G beta(3)/G gamma(13), and G beta(4)/G gamma(13) pairings were found to form stable dimers detectable by co-immunoprecipitation under high-detergent cell lysis conditions. Collectively, these data indicate that G gamma(13) forms functional G beta gamma dimers with a range of G beta subunits. Coupled with our detection of G gamma(13) mRNA in mouse and human brain and retina, these results imply that this divergent G gamma subunit can act in signal transduction pathways other than that dedicated to taste reception in sensory lingual tissue. 相似文献
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59.
W. Harwood S. Ross S. Bulley S. Travella B. Busch J. Harden J. Snape 《Plant cell reports》2002,21(4):320-326
Transgenic lines of the spring barley variety Golden Promise containing the firefly luciferase gene were produced by particle bombardment of immature embryos. Non-destructive analysis of luciferase gene expression was used to monitor the transformation process. This revealed that transformation efficiency, in terms of the percentage of bombarded immature embryos giving rise to transformed callus lines, was very high, up to 40%. Following the expression of the luciferase gene provided a method for the sensitive, non-destructive, real-time monitoring of gene expression throughout the transformation process. Luciferase expression could also be used to easily identify transgenic plants and to identify homozygous transgenic plants at an early stage. The production of transgenic barley by selecting for luciferase-positive material, without an additional selection system, was possible but technically difficult. 相似文献
60.