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2,012 results for “Kinase”
Data from: Identification of glucose kinase dependent and independent pathways for carbon control of primary metabolism, development and antibiotic production in Streptomyces coelicolor by quantitative proteomics
Members of the soil-dwelling prokaryotic genus Streptomyces are indispensable for the recycling of complex polysaccharides, and produce a wide range of natural products. Nutrient availability is a major determinant for the switch to development and antibiotic production in streptomycetes. Carbon catabolite repression (CCR), a main signaling pathway underlying this phenomenon, was so far considered fully dependent on the glycolytic enzyme glucose kinase (Glk). Here we provide evidence of a novel Glk-independent pathway in Streptomyces coelicolor, using advanced proteomics that allowed the comparison of the expression of some 2,000 proteins, including virtually all enzymes for central metabolism. While CCR and inducer exclusion of enzymes for primary and secondary metabolism and precursor supply for natural products is mostly mediated via Glk, enzymes for the urea cycle, as well as for biosynthesis of the γ-butyrolactone Scb1 and the responsive cryptic polyketide Cpk are subject to Glk-independent CCR. Deletion of glkA led to strong downregulation of biosynthetic proteins for prodigionin and calcium-dependent antibiotic (CDA) in mannitol-grown cultures. Repression of bldB, bldN, and its target bldM explains the poor development of S. coelicolor on solid-grown cultures containing glucose. A new model for carbon catabolite repression in streptomycetes is presented.
Data from: A highly sensitive LC-MS/MS method to determine novel Bruton's tyrosine kinase inhibitor spebrutinib: application to metabolic stability evaluation
Spebrutinib (SBT) is a Bruton's tyrosine kinase inhibitor. SBT is currently in phase II and phase I clinical trials for the management of rheumatoid arthritis and chronic lymphocytic leukaemia, respectively. We developed and validated a liquid chromatography tandem mass spectrometry analytical method to quantify SBT and investigate its metabolic stability. SBT and the naquotinib as internal standard were isocratically eluted on a C18 column. The linearity of the developed method is 5-500 ng/mL (r2≥ 0.9999) in the human liver microsomes (HLMs) matrix. Good sensitivity was approved by the very low limit of detection (0.39 ng/mL). Inter- and intra- assay accuracy values of -1.41 to 12.44 and precision values of 0.71 to 4.78%, were obtained. SBT was found to have an in vitro half-life (82.52 min) and intrinsic clearance (8.4 µL/min/mg) as computed following its incubation with HLMs. The latter finding, hypothesize that SBT could be deliberately expelled from the body unlike other related tyrosine kinase inhibitors. So, drug plasma level and kidney function should be monitored because of potential bioaccumulation. To the best of our knowledge, this is considered the first analytical method for SBT quantification using LC-MS/MS with application to metabolic stability evaluation.
Data from: Investigation of discriminant metabolites in tamoxifen-resistant and choline kinase-alpha-downregulated breast cancer cells using 1H-nuclear magnetic resonance spectroscopy
Metabolites linked to changes in choline kinase-α (CK-α) expression and drug resistance, which contribute to survival and autophagy mechanisms, are attractive targets for breast cancer therapies. We previously reported that autophagy played a causative role in driving tamoxifen (TAM) resistance of breast cancer cells (BCCs) and was also promoted by CK-α knockdown, resulting in the survival of TAM-resistant BCCs. There is no comparative study yet about the metabolites resulting from BCCs with TAM-resistance and CK-α knockdown. Therefore, the aim of this study was to explore the discriminant metabolic biomarkers responsible for TAM resistance as well as CK-α expression, which might be linked with autophagy through a protective role. A total of 33 intracellular metabolites, including a range of amino acids, energy metabolism-related molecules and others from cell extracts of the parental cells (MCF-7), TAM-resistant cells (MCF-7/TAM) and CK-α knockdown cells (MCF-7/shCK-α, MCF-7/TAM/shCK-α) were analyzed by proton nuclear magnetic resonance spectroscopy (1H-NMRS). Principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA) revealed the existence of differences in the intracellular metabolites to separate the 4 groups: MCF-7 cells, MCF-7/TAM cells, MCF-7-shCK-α cells, and MCF-7/TAM/shCK-α cells. The metabolites with VIP>1 contributed most to the differentiation of the cell groups, and they included fumarate, UA (unknown A), lactate, myo-inositol, glycine, phosphocholine, UE (unknown E), glutamine, formate, and AXP (AMP/ADP/ATP). Our results suggest that these altered metabolites would be promising metabolic biomarkers for a targeted therapeutic strategy in BCCs that exhibit TAM-resistance and aberrant CK-α expression, which triggers a survival and drug resistance mechanism.
Data from: Structure-based network analysis of activation mechanisms in the ErbB family of receptor tyrosine kinases: the regulatory spine residues are global mediators of structural stability and allosteric interactions
The ErbB protein tyrosine kinases are among the most important cell signaling families and mutation-induced modulation of their activity is associated with diverse functions in biological networks and human disease. We have combined molecular dynamics simulations of the ErbB kinases with the protein structure network modeling to characterize the reorganization of the residue interaction networks during conformational equilibrium changes in the normal and oncogenic forms. Structural stability and network analyses have identified local communities integrated around high centrality sites that correspond to the regulatory spine residues. This analysis has provided a quantitative insight to the mechanism of mutation-induced "superacceptor" activity in oncogenic EGFR dimers. We have found that kinase activation may be determined by allosteric interactions between modules of structurally stable residues that synchronize the dynamics in the nucleotide binding site and the αC-helix with the collective motions of the integrating αF-helix and the substrate binding site. The results of this study have pointed to a central role of the conserved His-Arg-Asp (HRD) motif in the catalytic loop and the Asp-Phe-Gly (DFG) motif as key mediators of structural stability and allosteric communications in the ErbB kinases. We have determined that residues that are indispensable for kinase regulation and catalysis often corresponded to the high centrality nodes within the protein structure network and could be distinguished by their unique network signatures. The optimal communication pathways are also controlled by these nodes and may ensure efficient allosteric signaling in the functional kinase state. Structure-based network analysis has quantified subtle effects of ATP binding on conformational dynamics and stability of the EGFR structures. Consistent with the NMR studies, we have found that nucleotide-induced modulation of the residue interaction networks is not limited to the ATP site, and may enhance allosteric cooperativity with the substrate binding region by increasing communication capabilities of mediating residues.
Data from: Evolution of the leucine-rich repeat receptor-like protein kinase gene family: Ancestral copy number and functional divergence of BAM1 and BAM2 in Brassicaceae
Gene duplication allows for functional divergence and innovation that provide selective advantages. However, in flowering plants genetic studies have revealed that single-gene mutations affecting one of two or more closely related paralogs often fail to cause detectable morphological defects, suggesting functional redundancy. Flowering plants have hundreds of genes encoding leucine-rich repeat receptor-like protein kinases (LRR-RLKs), several of which play important roles in anther development but little is known about their evolutionary history and possible functional divergence. We investigated the evolutionary relationship of the LRR-RLK gene family by phylogenetic analysis and found that these closely related paralogs resulted from multiple duplication events, such as the one resulting in BAM1 and BAM2. We further used qRT-PCR to verify gene expression changes in immature anthers from the bam1/bam2 single and double mutants compared with wild type providing strong evidence that the BAM1 and BAM2 genes have evolved different functions, with differential effects on anther gene expression. Moreover, careful examination of anther development in bam1 and bam2 single mutants revealed previously unrecognized extra cell division in tapetum cell layers. Thus our results from phylogenetic, molecular and morphological analyses uncover sequence and functional differences between paralogs whose single mutants lack obvious fertility defects, effectively revealing functional divergence of duplicate genes.
Data from: High cell density upregulates calcium oscillation by increasing calcium store content via basal mitogen-activated protein kinase activity
Calcium releases of non-excitable cells are generally a combination of oscillatory and non-oscillatory patterns, and factors affecting the calcium dynamics are still to be determined. Here we report the influence of cell density on calcium increase patterns of clonal cell lines. The majority of HeLa cells seeded at 1.5 x 104/cm2 showed calcium oscillations in response to histamine and ATP, whereas cells seeded at 0.5 x 104/cm2 largely showed transient and sustained calcium increases. Cell density also affected the response of HEK293 cells to ATP in a similar manner. High cell density increased the basal activity of the mitogen-activated protein (MAP) kinase and calcium store content, and both calcium oscillation and calcium store content were down-regulated by a MAP kinase inhibitor, U0126. Thus, MAP kinase-mediated regulation of calcium store likely underlie the effect of cell density on calcium oscillation. Calcium increase patterns of HeLa cells were conserved at any histamine concentrations tested, whereas the overexpression of histamine H1 receptor, which robustly increased histamine-induced inositol phospholipid hydrolysis, converted calcium oscillations to sustained calcium increases only at high histamine concentrations. Thus, the consequence of modulating inositol phospholipid metabolism was distinct from that of changing cell density, suggesting the effect of cell density is not attributed to inositol phospholipid metabolism. Collectively, our results propose that calcium increase patterns of non-excitable cells reflect calcium store, which is regulated by the basal MAP kinase activity under the influence of cell density.
KinAce web portal and dataset of kinase-substrate interactions
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Figure 7 from: Sivakumar B, Kaliappan I (2023) Lead drug discovery from imidazolinone derivatives with Aurora kinase inhibitors. Pharmacia 70(4): 1529-1540. https://doi.org/10.3897/pharmacia.70.e114935
Figure 7 Two-dimensional diagram of Compounds 1, 7, 9, 13, 19 interactions (top) during 100 ns MD simulation and hit molecule compound 19_1MQ4 interaction (bottom).
Figure 5 from: Sivakumar B, Kaliappan I (2023) Lead drug discovery from imidazolinone derivatives with Aurora kinase inhibitors. Pharmacia 70(4): 1529-1540. https://doi.org/10.3897/pharmacia.70.e114935
Figure 5 The root mean square fluctuation (RMSF) of 1MQ4 protein during 100 ns MD, representing local changes along the protein chain for Compounds 1, 7, 9, 13, 19.
Figure 4 from: Sivakumar B, Kaliappan I (2023) Lead drug discovery from imidazolinone derivatives with Aurora kinase inhibitors. Pharmacia 70(4): 1529-1540. https://doi.org/10.3897/pharmacia.70.e114935
Figure 4 The root mean square deviation (RMSD) of 1MQ4 protein during 100 ns MD, Compounds 1, 7, 9, 13, 19.
Figure 6 from: Sivakumar B, Kaliappan I (2023) Lead drug discovery from imidazolinone derivatives with Aurora kinase inhibitors. Pharmacia 70(4): 1529-1540. https://doi.org/10.3897/pharmacia.70.e114935
Figure 6 The plot represents the hydrogen bonding interactions of compounds 1, 7, 9, 13, 19 with esteem to deposits of 1MQ4 throughout 100 ns MD simulation.
Figure 3 from: Sivakumar B, Kaliappan I (2023) Lead drug discovery from imidazolinone derivatives with Aurora kinase inhibitors. Pharmacia 70(4): 1529-1540. https://doi.org/10.3897/pharmacia.70.e114935
Figure 3 Leads generated from QSAR and docking studies (compounds 1, 7, 9, 13, 19) structural stability analysis upon ligand docking.
Supplementary material 1 from: Sivakumar B, Kaliappan I (2023) Lead drug discovery from imidazolinone derivatives with Aurora kinase inhibitors. Pharmacia 70(4): 1529-1540. https://doi.org/10.3897/pharmacia.70.e114935
Supplementary data
Fig. 7. Predicted Boiled-Egg plot from Swiss ADME online web tool for compounds 1–3 in Characterization of undescribed melanoma inhibitors from Euphorbia mauritanica L. cultivated in Egypt targeting BRAF and MEK 1 kinases via in-silico study and ADME prediction
Fig. 7. Predicted Boiled-Egg plot from Swiss ADME online web tool for compounds 1–3.
Fig. 1 in Characterization of undescribed melanoma inhibitors from Euphorbia mauritanica L. cultivated in Egypt targeting BRAF and MEK 1 kinases via in-silico study and ADME prediction
Fig. 1. Chemical structures of isolated compounds (1–11).
Fig. 3 in Characterization of undescribed melanoma inhibitors from Euphorbia mauritanica L. cultivated in Egypt targeting BRAF and MEK 1 kinases via in-silico study and ADME prediction
Fig. 3. Significant NOESY correlations of diterpenoids 1–3.
Fig. 2. Significant 1H 1H in Characterization of undescribed melanoma inhibitors from Euphorbia mauritanica L. cultivated in Egypt targeting BRAF and MEK 1 kinases via in-silico study and ADME prediction
Fig. 2. Significant 1H 1H COSY and HMBC correlations of diterpenoids 1–3.
Data for LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology spread
<p>Data that was analyzed and used to create figures in the paper.</p>
raw data - In classical Hodgkin lymphoma, the activity of Thymidine kinase-1 is not related to the tumor size.
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ATP-responsive biomolecular condensates tune bacterial kinase signaling
<p>Imaging and biochemical analyses data from the manuscript.</p>
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