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101.
The relationship between the superadjacency topochemical index and the anti-HIV activity of HEPT analogs has been investigated in the present study. The values of superadjacency topochemical index of all the analogs involved in the data set were calculated using an in-house computer program. Resulting data were analyzed and a suitable model was developed after identification of the active range. Subsequently, a computed biological activity was assigned to each of the compounds involved in the dataset, which was then compared with the reported anti-HIV activity. Accuracy of prediction was found to be 88% using the said model. The predictive ability of the model indicates that this model can be used for predicting the anti-HIV activity of the compounds prior to synthesis and may prove to be highly beneficial for providing lead structures for development of potent anti-HIV agents. 相似文献
102.
Schmidt AE Padmanabhan K Underwood MC Bode W Mather T Bajaj SP 《The Journal of biological chemistry》2002,277(32):28987-28995
The serine protease domain of activated protein C (APC) contains a Na+ and a Ca2+ site. However, the number and identity of the APC residues that coordinate to Na+ is not precisely known. Further, the functional link between the Na+ and the Ca2+ site is insufficiently defined, and their linkage to the substrate S1 site has not been studied. Here, we systematically investigate the functional significance of these two cation sites and their thermodynamic links to the S1 site. Kinetic data reveal that Na+ binds to the substrate-occupied APC with K(d) values of approximately 24 mm in the absence and approximately 6 mm in the presence of Ca2+. Sodium-occupied APC has approximately 100-fold increased catalytic efficiency ( approximately 4-fold decrease in K(m) and approximately 25-fold increase in k(cat)) in hydrolyzing S-2288 (H-d-Ile-Pro-Arg-p-nitroanilide) and Ca2+ further increases this k(cat) slightly ( approximately 1.2-fold). Ca2+ binds to the protease domain of APC with K(d) values of approximately 438 microm in the absence and approximately 105 microm in the presence of Na+. Ca2+ binding to the protease domain of APC does not affect K(m) but increases the k(cat) approximately 10-fold, and Na+ further increases this k(cat) approximately 3-fold and decreases the K(m) value approximately 3.7-fold. In agreement with the K(m) data, sodium-occupied APC has approximately 4-fold increased affinity in binding to p-aminobenzamidine (S1 probe). Crystallographically, the Ca2+ site in APC is similar to that in trypsin, and the Na+ site is similar to that in factor Xa but not thrombin. Collectively, the Na+ site is thermodynamically linked to the S1 site as well as to the protease domain Ca2+ site, whereas the Ca2+ site is only linked to the Na+ site. The significance of these findings is that under physiologic conditions, most of the APC will exist in Na2+-APC-Ca2+ form, which has 110-fold increased proteolytic activity. 相似文献
103.
104.
Phytase from Nocardia sp. MB 36 was purified (9.65-fold) to homogeneity by acetone precipitation, ion exchange, and molecular sieve chromatography. Native polyacrylamide gel electrophoresis (PAGE) and zymogram analysis showed a single active protein in the purified enzyme preparation. Sodium dodecyl sulfate (SDS)-PAGE analysis showed that phytase was a monomeric protein with a molecular weight of approximately 43 kDa. Phytase exhibited activity and stability over a broad pH range (2–8) and elevated temperatures (50–80°C), and utilized several phosphate compounds as substrates. Phytase was extremely resistant to pepsin and trypsin. Various metal ions viz. Fe2+, Co2+, and Mn2+, and NH4+, ethylenediaminetetraacetic acid or EDTA and phenylmethylsulfonyl fluoride or PMSF had no influence on activity, while Ca2+ and Zn2+ enhanced activity by 15 % and 3.58 %, respectively. SDS caused significant reduction in enzyme activity (41.8 %), while 2,3-butanedione did so moderately (15.9 %). Features of Nocardia sp. MB 36 phytase suggest a potential for animal feed applications. 相似文献
105.
S. P. Bajaj S. I. Rapaport S. L. Maki S. F. Brown 《Preparative biochemistry & biotechnology》2013,43(3):191-214
Abstract A DEAE-Sephadex column chromatography step utilized to purify human Factor VII consistently yields a protein peak between the factor VII activity peak and prothrombin, factor X and factor IX activity peak (S.P. Bajaj, S.I. Rapaport, and S.F. Brown: J. Biol. Chem. 251., 253-259, 1981). We now report that this protein peak contains protein C and protein S. Preparative disc polyacryla-mide gel electrophoresis of the proteins in this peak 'permitted a complete separation of protein C from protein S. Protein C at this step usually contained approximately 5-10% of Factor X, which could be removed by a goat anti-human Factor X antibody column. For a typical preparation, starting with 10L of plasma, the yield of Protein C was 5 mg and of protein S was 4 mg. Both proteins 相似文献
106.
Alternative splicing of mRNAs is known to involve a major regulation of gene expression at RNA level in mammalian cells. The PTEN (Phosphatase and TENsin homologue deleted from the human chromosome 10), TPTE (Transmembrane Phosphatase with TEnsin homology) and TPIP (TPTE and PTEN homologous Inositol lipid Phosphatase) belong to a family of dual-specific lipid and protein phosphatases. PTEN is a well characterized tumor suppressor, which plays crucial role in cell survival, cell cycle regulation, cell proliferation as well as adhesion, motility and migration of cells. The C2-domain of PTEN is essential for PTEN-functions. We have isolated a novel 1019 bp human TPIP cDNA (TPIP-C2) from a human testis cDNA library. In silico analysis of the cDNA revealed that it is produced from the TPIP-locus on the human chromosome 13 by alternative RNA-splicing. It has a unique 5'-Alu sequence, a LINE sequence followed by a 582 bp Open Reading Frame (ORF) encoding a 193 aa polypeptide with a partial phosphatase domain and a C2-domain. TPIP-C2 mRNA is expressed in human testis and in mouse tissues. Mouse testis and brain showed higher levels of TPIP-C2 mRNA in comparison to the heart, liver and kidney under normal physiological conditions. TPIP-C2 mRNAs from human and mouse testes show extensive sequence identity. Over-expression of TPIP-C2 cDNA in HeLa cells strongly (up to 85%) inhibited cell growth/proliferation and caused apoptosis in a caspase 3-dependent manner. These findings suggest for the first time that a TPIP splice-variant mRNA with a partial phosphatase domain and a C2-domain is expressed in cells and tissues of human and murine origins under normal physiological conditions. Inhibition of cell growth/proliferation and induction of apoptosis by overexpression of TPIP-C2 mRNA in HeLa cells suggest that it may be involved in negative regulation of cell growth/proliferation. 相似文献
107.
108.
Komal Bajaj Sandeep Burudkar Pranay Shah Ashish Keche Usha Ghosh Prashant Tannu Smriti Khanna Ankita Srivastava Nitin J. Deshmukh Amol Dixit Yogesh Ahire Anagha Damre Kumar V.S. Nemmani Asha Kulkarni-Almeida Chandrika B-Rao Rajiv Sharma H. Sivaramakrishnan 《Bioorganic & medicinal chemistry letters》2013,23(3):834-838
We report our attempts at improving the oral efficacy of low-nanomolar inhibitors of xanthine oxidase from isocytosine series through chemical modifications. Our lead compound had earlier shown good in vivo efficacy when administered intraperitoneally but not orally. Several modifications are reported here which achieved more than twofold improvement in exposure. A compound with significant improvement in oral efficacy was also obtained. 相似文献
109.
Nicholas C. Vanderslice Amanda S. Messer Kanagasabai Vadivel S. Paul Bajaj Martin Phillips Mostafa Fatemi Weijie Xu William H. Velander 《Analytical biochemistry》2015
This study uses high-pressure size exclusion chromatography (HPSEC) to quantify divalent metal ion (X2+)-induced compaction found in vitamin K-dependent (VKD) proteins. Multiple X2+ binding sites formed by the presence of up to 12 γ-carboxyglutamic acid (Gla) residues are present in plasma-derived FIX (pd-FIX) and recombinant FIX (r-FIX). Analytical ultracentrifugation (AUC) was used to calibrate the Stokes radius (R) measured by HPSEC. A compaction of pd-FIX caused by the filling of Ca2+ and Mg2+ binding sites resulted in a 5 to 6% decrease in radius of hydration as observed by HPSEC. The filling of Ca2+ sites resulted in greater compaction than for Mg2+ alone where this effect was additive or greater when both ions were present at physiological levels. Less X2+-induced compaction was observed in r-FIX with lower Gla content populations, which enabled the separation of biologically active r-FIX species from inactive ones by HPSEC. HPSEC was sensitive to R changes of approximately 0.01 nm that enabled the detection of FIX compaction that was likely cooperative in nature between lower avidity X2+ sites of the Gla domain and higher avidity X2+ sites of the epidermal growth factor 1 (EGF1)-like domain. 相似文献
110.
Gaurav Bajaj Andrew M. Hau Peter Hsu Philip R. Gafken Michael I. Schimerlik Jane E. Ishmael 《Biochemical and biophysical research communications》2014
N-methyl-d-aspartate (NMDA) receptors are calcium-permeable ion channels assembled from four subunits that each have a common membrane topology. The intracellular carboxyl terminal domain (CTD) of each subunit varies in length, is least conserved between subunits, and binds multiple intracellular proteins. We defined a region of interest in the GluN2A CTD, downstream of well-characterized membrane-proximal motifs, that shares only 29% sequence similarity with the equivalent region of GluN2B. GluN2A (amino acids 875–1029) was fused to GST and used as a bait to identify proteins from mouse brain with the potential to bind GluN2A as a function of calcium. Using mass spectrometry we identified calmodulin as a calcium-dependent GluN2A binding partner. Equilibrium fluorescence spectroscopy experiments indicate that Ca2+/calmodulin binds GluN2A with high affinity (5.2 ± 2.4 nM) in vitro. Direct interaction of Ca2+/calmodulin with GluN2A was not affected by disruption of classic sequence motifs associated with Ca2+/calmodulin target recognition, but was critically dependent upon Trp-1014. These findings provide new insight into the potential of Ca2+/calmodulin, previously considered a GluN1-binding partner, to influence NMDA receptors by direct association. 相似文献