Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracellular signaling pathways regulating vascular smooth muscle (VSM) cell growth and hypertrophy can be initiated by activation of receptor tyrosine kinases and/or protein kinase C (PKC). Mitogen-activated protein kinases (MAP kinases) are cytosolic serine/threonine kinases, proposed to act as a point of convergence for diverse growth factors utilizing these signaling pathways. The goals of this study were (1) to determine whether MAP kinase is expressed in cultured rat aortic VSM, (2) to assess the activation of MAP kinase by known proliferative and hypertrophic stimuli, and (3) to determine if stimulation of a PKC-dependent signaling pathway in these cells results in MAP kinase activation. MAP kinase activity was measured in cytosolic extracts of aortic VSM by quantifying myelin basic protein phosphorylation. Three peaks of activity were resolved chromatographically and identified as MAP kinase isoforms (MW 42, 44, and 46 kDa) by immunoblotting with antipeptide antibodies specific for MAP kinase. MAP kinase activity in quiescent growth-arrested cells (157 +/- 19 pmole 32P/min/mg) was markedly stimulated within 15 min by known mitogens (10% serum, 731 +/- 40 pmole 32P/min/mg; 40 ng/ml PDGF, 670 +/- 105 pmole 32P/min/mg; P < 0.01) and partially sustained for at least 90 min (serum, 606 +/- 34 pmole 32P/min/mg; PDGF, 323 +/- 59 pmole 32P/min/mg P < 0.05). Angiotensin II (AII, 0.1 microM) and a pharmacological PKC activator, phorbol 12,13-dibutyrate (PDB, 0.1 microM), are reported to be nonmitogenic hypertrophic stimuli in these cells. These stimuli transiently increased MAP kinase activity with a peak at 5 min (AII, 328 +/- 15 pmole 32P/min/mg; PDB, 592 +/- 41 pmole 32P/min/mg; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of MAP kinase activity by growth stimuli in vascular smooth muscle. 804 Nov 41

Metal ion binding domains are found in proteins that mediate transport, buffering or detoxification of metal ions. The objective of the study is to design and analyze metal binding motifs against the genes involved in phytoremediation. This is being done on the basis of certain pre-requisite amino-acid residues known to bind metal ions/metal complexes in medicinal and aromatic plants (MAP's). Earlier work on MAP's have shown that heavy metals accumulated by aromatic and medicinal plants do not appear in the essential oil and that some of these species are able to grow in metal contaminated sites. A pattern search against the UniProtKB/Swiss-Prot and UniProtKB/TrEMBL databases yielded true positives in each case showing the high specificity of the motifs designed for the ions of nickel, lead, molybdenum, manganese, cadmium, zinc, iron, cobalt and xenobiotic compounds. Motifs were also studied against PDB structures. Results of the study suggested the presence of binding sites on the surface of protein molecules involved. PDB structures of proteins were finally predicted for the binding sites functionality in their respective phytoremediation usage. This was further validated through CASTp server to study its physico-chemical properties. Bioinformatics implications would help in designing strategy for developing transgenic plants with increased metal binding capacity. These metal binding factors can be used to restrict metal update by plants. This helps in reducing the possibility of metal movement into the food chain.
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PMID:Predicted metal binding sites for phytoremediation. 2019 71

MAP kinases act as an integration point for multiple biochemical signals and are involved in a wide variety of cellular processes such as proliferation, differentiation, regulation of transcription and development. As a member of the MAP kinase family, ERK5 (MAPK7) is involved in the downstream signalling pathways of various cell-surface receptors, including receptor tyrosine kinases and G protein-coupled receptors. In the current study, five structures of the ERK5 kinase domain co-crystallized with ERK5 inhibitors are reported. Interestingly, three of the compounds bind at a novel allosteric binding site in ERK5, while the other two bind at the typical ATP-binding site. Binding of inhibitors at the allosteric site is accompanied by displacement of the P-loop into the ATP-binding site and is shown to be ATP-competitive in an enzymatic assay of ERK5 kinase activity. Kinase selectivity data show that the most potent allosteric inhibitor exhibits superior kinase selectivity compared with the two inhibitors that bind at the canonical ATP-binding site. An analysis of these structures and comparison with both a previously published ERK5-inhibitor complex structure (PDB entry 4b99) and the structures of three other kinases (CDK2, ITK and MEK) in complex with allosteric inhibitors are presented.
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PMID:Discovery of a novel allosteric inhibitor-binding site in ERK5: comparison with the canonical kinase hinge ATP-binding site. 2713 31

Betulin derivatives have been proven effective in vitro against Leishmania donovani amastigotes, which cause visceral leishmaniasis. Identifying the molecular targets and molecular mechanisms underlying their action is a currently an unmet challenge. In the present study, we tackle this problem using computational methods to establish properties essential for activity as well as to screen betulin derivatives against potential targets. Recursive partitioning classification methods were explored to develop predictive models for 58 diverse betulin derivatives inhibitors of L. donovani amastigotes. The established models were validated on a testing set, showing excellent performance. Molecular fingerprints FCFP_6 and ALogP were extracted as the physicochemical properties most extensively involved in separating inhibitors from non-inhibitors. The potential targets of betulin derivatives inhibitors were predicted by in silico target fishing using structure-based pharmacophore searching and compound-pharmacophore-target-pathway network analysis, first on PDB and then among L. donovani homologs using a PSI-BLAST search. The essential identified proteins are all related to protein kinase family. Previous research already suggested members of the cyclin-dependent kinase family and MAP kinases as Leishmania potential drug targets. The PSI-BLAST search suggests two L. donovani proteins to be especially attractive as putative betulin target, heat shock protein 83 and membrane transporter D1.
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PMID:Predictive classification models and targets identification for betulin derivatives as Leishmania donovani inhibitors. 3012 Jun 1

In epididymis, cimetidine induces androgenic failure due to reduced sex hormone-binding globulin stromal levels and blockade of androgen receptor (AR) nuclear import. UCHL1, a hydrolase of ubiquitin-proteasome system (UPS), seems to play a role in autophagy and apoptotic pathway. However, the role of UPS and autophagy in epididymis has not been clarified. We evaluated UCHL1 and autophagy in epididymal cauda epithelium under androgenic deficiency induced by cimetidine, focusing on the interplay among these processes and apoptosis. The integrity of epididymal muscular layer was also evaluated. Male rats received cimetidine (CMTG) or saline (CG). Seminal vesicles were weighed, the expression of androgen-responsive genes Crisp1 and connexin 43 (Cx43) in cauda epididymis was evaluated, and cauda fragments were processed for light and transmission electron microscopy. The epithelium height and muscular thickness were measured. TUNEL, immunohistochemistry for caspase-3 and Cx43, and immunofluorescence for AR, Bcl-2, UCHL1, MAP LC3A, and p62/SQSTM1 (autophagic markers) were performed. Bcl-2, UCHL1, and Cx43 were detected by Western blot. In CMTG, the reduction in seminal vesicles weight accompanied by downregulation of Crisp1 and Cx43 confirmed epididymal androgenic failure. These results were associated with muscular atrophy, apoptosis and weak Cx43 and AR immunoexpression, supporting the androgenic dependence of muscular integrity. The high UCHL1 levels and reduction in Bcl-2 reinforce UCHL1 role in epithelial cells death. The intense immunoexpression of LC3A and p62/SQSTM1 indicates autophagic disturb, which in association with high UCHL1 levels, points to a role of UPS and autophagy in the regulation of epididymal epithelial cells viability under androgenic control.
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PMID:Muscular atrophy, impaired epithelial autophagy and UCHL1 increase in androgen-deficient cauda epididymis. 3219 15