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101.
Srinivasan Sundararaj Ajay K. Saxena Ruby Sharma Kapil Vashisht Supriya Sharma Anup Anvikar Rajnikant Dixit Philip J. Rosenthal Kailash C. Pandey 《PloS one》2014,9(4)
Cysteine proteases play a crucial role in the development of the human malaria parasites Plasmodium falciparum and Plasmodium vivax. Our earlier studies demonstrated that these enzymes are equipped with specific domains for defined functions and further suggested the mechanism of activation of cysteine proteases. The activities of these proteases are regulated by a new class of endogenous inhibitors of cysteine proteases (ICPs). Structural studies of the ICPs of Trypanosoma cruzi (chagasin) and Plasmodium berghei (PbICP) indicated that three loops (termed BC, DE, and FG) are crucial for binding to target proteases. Falstatin, an ICP of P. falciparum, appears to play a crucial role in invasion of erythrocytes and hepatocytes. However, the mechanism of inhibition of cysteine proteases by falstatin has not been established. Our study suggests that falstatin is the first known ICP to function as a multimeric protein. Using site-directed mutagenesis, hemoglobin hydrolysis assays and peptide inhibition studies, we demonstrate that the BC loop, but not the DE or FG loops, inhibits cysteine proteases of P. falciparum and P. vivax via hydrogen bonds. These results suggest that the BC loop of falstatin acts as a hot-spot target for inhibiting malarial cysteine proteases. This finding suggests new strategies for the development of anti-malarial agents based on protease-inhibitor interactions. 相似文献
102.
Origin recognition complex (ORC) is highly dynamic, with several ORC subunits getting posttranslationally modified by phosphorylation or ubiquitination in a cell cycle-dependent manner. We have previously demonstrated that a WD repeat containing protein ORC-associated (ORCA/LRWD1) stabilizes the ORC on chromatin and facilitates pre-RC assembly. Further, ORCA levels are cell cycle-regulated, with highest levels during G1, and progressively decreasing during S phase, but the mechanism remains to be elucidated. We now demonstrate that ORCA is polyubiquitinated in vivo, with elevated ubiquitination observed at the G1/S boundary. ORCA utilizes lysine-48 (K48) ubiquitin linkage, suggesting that ORCA ubiquitination mediates its regulated degradation. Ubiquitinated ORCA is re-localized in the form of nuclear aggregates and is predominantly associated with chromatin. We demonstrate that ORCA associates with the E3 ubiquitin ligase Cul4A-Ddb1. ORCA is ubiquitinated at the WD40 repeat domain, a region that is also recognized by Orc2. Furthermore, Orc2 associates only with the non-ubiquitinated form of ORCA, and Orc2 depletion results in the proteasome-mediated destabilization of ORCA. Based on the results, we suggest that Orc2 protects ORCA from ubiquitin-mediated degradation in vivo. 相似文献
103.
Total chlorophyll content and chlorophyllase (chlorophyll-chlorophyllido hydrolase EC 3.1.1.14) activity in fresh leaves of
Piper betle L. landrace KS was, respectively, twofold higher and eight fold lower than KV, showing negative correlation between chlorophyll
and chlorophyllase activity. Specific chlorophyllase activity was nearly eightfold more in KV than KS. ORF of 918 nt was found
in cloned putative chlorophyllase cDNAs from KV and KS. The gene was present as single copy in both the landraces. The encoded
polypeptide of 306 amino acids differed only at two positions between the KV and KS; 203 (cysteine to tyrosine) and 301 (glutamine
to glycine). Difference in chlorophyllase gene expression between KV and KS was evident in fresh and excised leaves. Up regulation
of chlorophyllase gene by ABA and down regulation by BAP was observed in both the landraces; however, there was quantitative
difference between KV and KS. Data suggests that chlorophyllase in P. betle is involved in chlorophyll homeostasis and chlorophyll loss during post harvest senescence. 相似文献
104.
Beedkar SD Khobragade CN Chobe SS Dawane BS Yemul OS 《International journal of biological macromolecules》2012,50(4):947-956
Xanthine oxidase (XO) is a complex metalloflavoprotein, overproduction of which usually leads to a pathological condition called Gout. XO inhibitors may prove to be promising antigout agents. Present investigation describes synthesis, characterization and evaluation of 26 thiazolo-pyrazolyl derivatives V(a-z) for XO inhibitory and free radical scavenging activities. Derivatives Vq, Vo and Vh showed most promising XO inhibitory and free radical scavenging activities on the basis of their IC(50) values ranging from (6.5-9 μM). Significant dock scores compared with Allopurinol have been figured out using molecular docking. Evaluation of Vq, Vo and Vh for both the activities for first time may provide a new approach for antigout research. 相似文献
105.
Xu G Yong KT Roy I Mahajan SD Ding H Schwartz SA Prasad PN 《Bioconjugate chemistry》2008,19(6):1179-1185
We report here, what we believe to be the first time, the successful transport of bioconjugated quantum rods (QRs) across an in vitro blood-brain barrier (BBB) model via a receptor-mediated transport, as well as the use of QR multiplexing technique to compare simultaneously the transmigration efficiency of different biomolecules across the BBB. The migration rate of bioconjugated QRs crossing the in vitro BBB was found to be concentration- and time-dependent. This work illustrates a nanoparticle-based platform that will not only allow a direct visualization of the transmigration ability of various kinds of biomolecules across the BBB, but also facilitate the development of novel diagnostic and therapeutic nanoprobes for early diagnosis and therapy of various disorders of the brain following systemic administration. 相似文献
106.
107.
Conklin BR Hsiao EC Claeysen S Dumuis A Srinivasan S Forsayeth JR Guettier JM Chang WC Pei Y McCarthy KD Nissenson RA Wess J Bockaert J Roth BL 《Nature methods》2008,5(8):673-678
We are creating families of designer G protein-coupled receptors (GPCRs) to allow for precise spatiotemporal control of GPCR signaling in vivo. These engineered GPCRs, called receptors activated solely by synthetic ligands (RASSLs), are unresponsive to endogenous ligands but can be activated by nanomolar concentrations of pharmacologically inert, drug-like small molecules. Currently, RASSLs exist for the three major GPCR signaling pathways (G(s), G(i) and G(q)). We review these advances here to facilitate the use of these powerful and diverse tools. 相似文献
108.
Srinivasan S Sadegh L Elle IC Christensen AG Faergeman NJ Ashrafi K 《Cell metabolism》2008,7(6):533-544
We investigated serotonin signaling in C. elegans as a paradigm for neural regulation of energy balance and found that serotonergic regulation of fat is molecularly distinct from feeding regulation. Serotonergic feeding regulation is mediated by receptors whose functions are not required for fat regulation. Serotonergic fat regulation is dependent on a neurally expressed channel and a G protein-coupled receptor that initiate signaling cascades that ultimately promote lipid breakdown at peripheral sites of fat storage. In turn, intermediates of lipid metabolism generated in the periphery modulate feeding behavior. These findings suggest that, as in mammals, C. elegans feeding behavior is regulated by extrinsic and intrinsic cues. Moreover, obesity and thinness are not solely determined by feeding behavior. Rather, feeding behavior and fat metabolism are coordinated but independent responses of the nervous system to the perception of nutrient availability. 相似文献
109.
Neill J. Horley Kenneth J.M. Beresford Supriya Kaduskar Prashant Joshi Glen J.P. McCann Ketan C. Ruparelia Ibidapo S. Williams Linda Gatchie Vinay R. Sonawane Sandip B. Bharate Bhabatosh Chaudhuri 《Bioorganic & medicinal chemistry letters》2017,27(24):5409-5414
The overexpression of CYP1 family of enzymes is reported to be associated with development of human carcinomas. It has been well reported that CYP1A1 specific inhibitors prevents carcinogenesis. Herein, thirteen pyridine-4-yl series of chalcones were synthesized and screened for inhibition of CYP1 isoforms 1A1, 1B1 and 1A2 in Sacchrosomes? and live human HEK293 cells. The structure-activity relationship analysis indicated that chalcones bearing tri-alkoxy groups (8a and 8k) on non-heterocyclic ring displayed selective inhibition of CYP1A1 enzyme, with IC50 values of 58 and 65?nM, respectively. The 3,4,5-trimethoxy substituted derivative 8a have shown >10-fold selectivity towards CYP1A1 with respect to other enzymes of the CYP1 sub-family and >100-fold selectivity with respect to CYP2 and CYP3 family of enzymes. The potent and selective CYP1A1 inhibitor 8a displayed antagonism of B[a]P mediated activation of aromatic hydrocarbon receptor (AhR) in yeast cells, and also protected human cells from CYP1A1-mediated B[a]P toxicity in human cells. This potent and selective inhibitor of CYP1A1 enzyme have a potential for development as cancer chemopreventive agent. 相似文献
110.
Nup358 binds to AGO proteins through its SUMO‐interacting motifs and promotes the association of target mRNA with miRISC
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