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151.
Sujit S Nair Binoj C Nair Valerie Cortez Dimple Chakravarty Eric Metzger Roland Schüle Darrell W Brann Rajeshwar R Tekmal Ratna K Vadlamudi 《EMBO reports》2010,11(6):438-444
Histone methylation has a key role in oestrogen receptor (ERα)‐mediated transactivation of genes. Proline glutamic acid and leucine‐rich protein 1 (PELP1) is a new proto‐oncogene that functions as an ERα co‐regulator. In this study, we identified histone lysine demethylase, KDM1, as a new PELP1‐interacting protein. These proteins, PELP1 and KDM1, were both recruited to ERα target genes, and PELP1 depletion affected the dimethyl histone modifications at ERα target genes. Dimethyl‐modified histones H3K4 and H3K9 are recognized by PELP1, and PELP1 alters the substrate specificity of KDM1 from H3K4 to H3K9. Effective demethylation of dimethyl H3K9 by KDM1 requires a KDM1–ERα–PELP1 functional complex. These results suggest that PELP1 is a reader of H3 methylation marks and has a crucial role in modulating the histone code at the ERα target genes. 相似文献
152.
Sourav RoyChoudhury Tushar H. More Ratna Chattopadhyay Indrani Lodh Chaitali Datta Ray Gunja Bose Himadri S. Sarkar Baidyanath Chakravarty Srikanth Rapole Koel Chaudhury 《Metabolomics : Official journal of the Metabolomic Society》2017,13(10):115
Introduction
Polycystic ovary syndrome (PCOS) is a complex, heterogeneous endocrinological disorder with uncertain pathogenesis and is very common in women of reproductive age. There are few reports of utilizing metabolomics approach to understand the complex pathophysiology of PCOS. However, excluding one previous NMR-based metabolomics study, none of the study was conducted in Indian population.Objective
The study aims to compare the serum metabolomic profile of PCOS women with controls from the Eastern region of India.Methods
PCOS women (n?=?35) and healthy control women (n?=?30) undergoing tubal ligation were recruited for this study. Serum metabolic profiles were generated using liquid chromatography–tandem mass spectrometry (LC-MS/MS) and gas chromatography–mass spectrometry (GC-MS). Multivariate statistical analysis was applied to spectral data obtained from both the LC-MS/MS and GC/MS.Results
Nine metabolites were identified to be most significantly dysregulated in sera of PCOS women; however, few other identified metabolites were also altered but with lesser significance. Amongst these metabolites, riboflavin, sucrose, adenine and N-acetyl glycine, phosphoric acid and cortisol were down-regulated, whereas, thymine, cystathionine, and phenylalanine were up-regulated in PCOS when compared with controls. The observed changes in metabolite expression suggested alterations in aminoacyl-tRNA biosynthesis, metabolism of nitrogen, alanine-aspartate-glutamate, galactose, glycine-serine-threonine, and pyrimidine-purine among several metabolic pathways possibly implicated in these PCOS women.Conclusion
The altered metabolites identified in PCOS women of Eastern Indian population, provide insight into current perceptive of the disease pathology, metabolic involvements, and may be considered as putative markers of PCOS.153.
154.
Mavunkel BJ Chakravarty S Perumattam JJ Luedtke GR Liang X Lim D Xu YJ Laney M Liu DY Schreiner GF Lewicki JA Dugar S 《Bioorganic & medicinal chemistry letters》2003,13(18):3087-3090
p38alpha Mitogen Activated Protein Kinase (MAP kinase) is an intracellular soluble serine threonine kinase. p38alpha kinase is activated in response to cellular stresses, growth factors and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). The central role of p38alpha activation in settings of both chronic and acute inflammation has led efforts to find inhibitors of this enzyme as possible therapies for diseases such as rheumatoid arthritis, where p38alpha activation is thought to play a causal role. Herein, we report structure-activity relationship studies on a series of indole-based heterocyclic inhibitors that led to the design and identification of a new class of p38alpha inhibitors. 相似文献
155.
Accurate identification of cavities is important in the study of protein structure, stability, design, and ligand binding. Identification and quantitation of cavities is a nontrivial problem because most cavities are connected to the protein exterior. We describe a computational procedure for quantitating cavity volumes and apply this to derive an estimate of the hydrophobic driving force in protein folding. A grid-based Monte Carlo procedure is used to position water molecules on the surface of a protein. A Voronoi procedure is used to identify and quantitate empty space within the solvated protein. Additional cavities not detected by other existing procedures can be identified. Most of these are close to surface concavities. Residue volumes for both the interior and the surface residues as well as cavity volumes are in good agreement with volumes calculated from fully hydrated protein structures obtained from molecular dynamic simulations. We show that the loss of stability because of cavity-creating mutations correlates better with cavity volumes determined by this procedure than with cavity volumes determined by other methods. Available structural and thermodynamic data for a number of cavity-containing mutants were analyzed to obtain estimates of 26.1 cal x mol(-1) x A(-3) and 18.5 cal x mol(-1) x A(-2) for the relative contributions of cavity formation and the hydrophobic effect to the observed stability changes. The present estimate for the hydrophobic driving force is at the lower end of estimates derived from model compound studies and considerably lower than previous estimates of approximately 50 cal x mol(-1) x A(-2) derived from protein mutational data. In the absence of structural rearrangement, on average, deletion of a single methylene group is expected to result in losses in stability of 0.41 and 0.70 kcal x mol(-1) resulting from decrease in hydrophobicity and packing, respectively. 相似文献
156.
Elucidation of factors responsible for enhanced thermal stability of proteins: a structural genomics based study 总被引:11,自引:0,他引:11
Understanding the molecular basis for the enhanced stability of proteins from thermophiles has been hindered by a lack of structural data for homologous pairs of proteins from thermophiles and mesophiles. To overcome this difficulty, complete genome sequences from 9 thermophilic and 21 mesophilic bacterial genomes were aligned with protein sequences with known structures from the protein data bank. Sequences with high homology to proteins with known structures were chosen for further analysis. High quality models of these chosen sequences were obtained using homology modeling. The current study is based on a data set of models of 900 mesophilic and 300 thermophilic protein single chains and also includes 178 templates of known structure. Structural comparisons of models of homologous proteins allowed several factors responsible for enhanced thermostability to be identified. Several statistically significant, specific amino acid substitutions that occur going from mesophiles to thermophiles are identified. Most of these are at solvent-exposed sites. Salt bridges occur significantly more often in thermophiles. The additional salt bridges in thermophiles are almost exclusively in solvent-exposed regions, and 35% are in the same element of secondary structure. Helices in thermophiles are stabilized by intrahelical salt bridges and by an increase in negative charge at the N-terminus. There is an approximate decrease of 1% in the overall loop content and a corresponding increase in helical content in thermophiles. Previously overlooked cation-pi interactions, estimated to be twice as strong as ion-pairs, are significantly enriched in thermophiles. At buried sites, statistically significant hydrophobic amino acid substitutions are typically consistent with decreased side chain conformational entropy. 相似文献
157.
Two new dammarane-type jujubogenin bisdesmosides, bacopasaponins E and F of biological interest have been isolated from the reputed Indian medicinal plant Bacopa monniera and defined as 3-O-[beta-D-glucopyranosyl(1 --> 3)[alpha-L-arabinofuranosyl(1 --> 2)]alpha-L-arabinopyranosyl]-20-O-(alpha-L-arabinopyranosyl) jujubogenin and 3-O-[beta-D-glucopyranosyl(1 --> 3)[alpha-L-arabinofuranosyl(1 --> 2)]beta-D-glucopyranosyl]-20-O-alpha-L-arabinopyranosyl) jujubogenin respectively by spectroscopic methods and some chemical transformations. 相似文献
158.
Crosstalk between the p190-B RhoGAP and IGF signaling pathways is required for embryonic mammary bud development 总被引:2,自引:0,他引:2
Heckman BM Chakravarty G Vargo-Gogola T Gonzales-Rimbau M Hadsell DL Lee AV Settleman J Rosen JM 《Developmental biology》2007,309(1):137-149
P190-B RhoGAP (p190-B, also known as ARHGAP5) has been shown to play an essential role in invasion of the terminal end buds (TEBs) into the surrounding fat pad during mammary gland ductal morphogenesis. Here we report that embryos with a homozygous p190-B gene deletion exhibit major defects in embryonic mammary bud development. Overall, p190-B-deficient buds were smaller in size, contained fewer cells, and displayed characteristics of impaired mesenchymal proliferation and differentiation. Consistent with the reported effects of p190-B deletion on IGF-1R signaling, IGF-1R-deficient embryos also displayed a similar small mammary bud phenotype. However, unlike the p190-B-deficient embryos, the IGF-1R-deficient embryos exhibited decreased epithelial proliferation and did not display mesenchymal defects. Because both IGF and p190-B signaling affect IRS-1/2, we examined IRS-1/2 double knockout embryonic mammary buds. These embryos displayed major defects similar to the p190-B-deficient embryos including smaller bud size. Importantly, like the p190-B-deficient buds, proliferation of the IRS-1/2-deficient mesenchyme was impaired. These results indicate that IGF signaling through p190-B and IRS proteins is critical for mammary bud formation and ensuing epithelial-mesenchymal interactions necessary to sustain mammary bud morphogenesis. 相似文献
159.
160.
Ternary S-methyl-L-cysteine (SMe-l-cys) copper(II) complexes [Cu(SMe-L-cys)(B)(H(2)O)](X) (1-4), where the heterocyclic base B is 2,2'-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), dipyridoquinoxaline (dpq, 3) and dipyridophenazine (dppz, 4), and X is ClO(4)(-) (1-3) or NO(3)(-) (4), are prepared and their DNA binding and cleavage properties studied. Complexes 2 and 4 are structurally characterized by X-ray crystallography. Both the crystal structures show distorted square-pyramidal (4+1) CuN(3)O(2) coordination geometry of the complexes in which the N,O-donor S-methyl-L-cysteine and N,N-donor heterocyclic base bind at the basal plane with a water molecule as the axial ligand. In addition, the dppz structure shows the presence of a 1D-chain formed due to covalent linkage of the carboxylate oxygen atom belonging to another molecule at the elongated axial site. The crystal structures show chemically significant non-covalent interactions like hydrogen bonding involving the axial aqua ligand and pi-pi interactions between dppz ligands. The complexes display a d-d band in the range of 605-654 nm in aqueous dimethylformamide (DMF) solution (9:1 v/v). The redox active complexes show quasireversible cyclic voltammetric response near 0.1 V in DMF assignable to the Cu(II)/Cu(I) couple. The complexes show good binding affinity to calf thymus (CT) DNA giving the order: 4 (dppz)>3 (dpq)>2 (phen)>1 (bpy). The intrinsic binding constants, obtained from UV-visible spectroscopic studies, are 1.3x10(4) and 2.15 x 10(4) M(-1) for 3 and 4, respectively. Control DNA cleavage experiments using pUC19 supercoiled (SC) DNA and minor groove binder distamycin suggest major groove binding propensity for the dppz complex, while the phen and dpq complexes bind at the minor groove of DNA. Complexes 2-4 show DNA cleavage activity in dark in the presence of a reducing agent 3-mercaptopropionic acid (MPA) via a mechanistic pathway involving formation of hydroxyl radical as the reactive species. The complexes also show efficient photo-induced DNA cleavage activity on irradiation with a monochromatic UV light of 365 nm in absence of any external reagent. The cleavage efficiency follows the order: 3>4>2. The complexes exhibit significant DNA cleavage activity on irradiation with visible light of 633 nm. Control experiments show inhibition of cleavage in presence of singlet oxygen quenchers like sodium azide, histidine and enhancement of cleavage in D(2)O, suggesting formation of singlet oxygen as a reactive species in a type-II process. The photosensitizing effect of the thiomethyl group of the amino acid is evidenced from the observation of significant DNA photocleavage activity of the phen complex 2 as the phen ligand itself is not a photosensitizer. 相似文献