Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.2.1.1 (ACS)
 78,556 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported two novel serine/threonine kinases, Aie1 (mouse) and AIE2 (human), both later referred to as aurora-C, a newly recognized member of the mitotic aurora kinase family. In the present study, we analyzed the phosphorylation sites of mouse Aie1 by site-directed mutagenesis. Our results showed that protein kinase A (PKA) phosphorylates Aie1 at a threonine residue located at amino acid position 171. The T171A and T175A mutants, in which threonines located at residues 171 and 175 were replaced by alanines, revealed a significant increase in their kinase activities to phosphorylate ACS-1 (Aurora-C substrate 1). In contrast, the double mutant T171A-T175A showed impaired kinase activity. In addition, we had previously identified a PEST-like motif located at the N terminus of Aie1. Mutation analysis in the present study revealed that the quadruple mutant in which the PEST-like motif was mutated significantly abrogated Aie1 kinase activity. This is the first report of the analysis of potential phosphorylation sites of mouse aurora-C in vitro.
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PMID:Mutational analysis of the phosphorylation sites of the Aie1 (Aurora-C) kinase in vitro. 1187 79

Pathogenic Yersinia spp. secrete the effector YopJ (YopP) into host cells to counteract cytokine production and to induce programmed cell death (apoptosis). YopJ achieves these aims by inactivating mitogen-activated protein kinase (MAPK) and nuclear factor kappaB signaling pathways. YopJ was shown to bind to members of the MAPK kinase (MKK) family and was predicted to have protease activity toward ubiquitin (Ub)-like proteins. In a recent report, YopJ was demonstrated to inactivate MKKs via acetylation of critical serine or threonine residues. The ramifications of these exciting results are discussed in the context of other studies implicating YopJ as a Ub-like protease.
ACS Chem Biol 2006 Jul 21
PMID:Yersinia inhibits host signaling by acetylating MAPK kinases. 1716 70

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase implicated in cancer. Three new crystal structures of PP2A show how it interacts with inhibitory toxins and with one of its regulatory subunits. The structures also explain how specific site mutations may lead to cancer and suggest a novel role for PP2A methylation in the formation of PP2A holoenzymes.
ACS Chem Biol 2007 Feb 20
PMID:The 3D structure of protein phosphatase 2A: new insights into a ubiquitous regulator of cell signaling. 1731 79

O-linked N-acetylglucosamine (O-GlcNAc), a monosaccharide N-acetylglucosamine on the serine and threonine residues of nucleocytoplasmic proteins, is a novel protein modification that is ubiquitous among eukaryotes and implicated in cell regulation. Recent evidence indicates that O-GlcNAc regulates protein-protein interactions. Here we provide evidence that O-GlcNAc interrupts a known interaction between Sp1 and sterol regulatory element binding protein 2 (SREBP2), thereby inhibiting expression of the gene encoding acetyl-CoA synthetase 1, which is involved in lipid synthesis. This study suggests a novel mechanism in which lipid biosynthesis may be regulated by O-GlcNAc.
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PMID:O-GlcNAc inhibits interaction between Sp1 and sterol regulatory element binding protein 2. 2013 38

Bioconjugates of quantum dot nanocrystals possess unique optical properties that allow them to serve as exceptional biological imaging and sensing reagents. Protein kinases are an important family of enzymes that phosphorylate serine, threonine, or tyrosine side chains and are critical in cell signaling and cancer biology, but despite their biomedical and pharmaceutical significance, their activity has been little explored using quantum dot technology. We demonstrate that self-assembled peptide-quantum dot conjugates can serve as surrogate substrates in a simple homogeneous assay for protein kinase activity. Enzymatic phosphorylation of the peptide-conjugates is detected by means of a complementary FRET-acceptor labeled antiphosphotyrosine antibody, with formation of the immunocomplex resulting in energy transfer between the quantum dot and FRET acceptor molecules. This approach should facilitate the development of new assays for protein kinases and other enzymes based on quantum dot FRET donors.
ACS Nano 2010 Aug 24
PMID:Protein kinase-actuated resonance energy transfer in quantum dot--peptide conjugates. 2073 64

Protein kinase D (PKD) is a member of a novel family of serine/threonine kinases that regulate fundamental cellular processes. PKD is implicated in the pathogenesis of several diseases, including cancer. Progress in understanding the biological functions and therapeutic potential of PKD has been hampered by the lack of specific inhibitors. The benzoxoloazepinolone CID755673 was recently identified as the first potent and selective PKD inhibitor. The study of structure-activity relationships (SAR) of this lead structure led to further improvements in PKD1 potency. We describe herein the synthesis and biological evaluation of novel benzothienothiazepinone analogs. We achieved a ten-fold increase in the in vitro PKD1 inhibitory potency for the second generation lead kb-NB142-70 and accomplished a transition to an almost equally potent novel pyrimidine scaffold, while maintaining excellent target selectivity. These promising results will guide the design of pharmacological tools to dissect PKD function and pave the way for the development of potential anti-cancer agents.
ACS Med Chem Lett 2011 Feb 14
PMID:Synthesis and Structure-Activity Relationships of Benzothienothiazepinone Inhibitors of Protein Kinase D. 2161 63

The best characterized examples of crosstalk between two or more different post-translational modifications (PTMs) occur with respect to histones. These examples demonstrate the critical roles that crosstalk plays in regulating cell signaling pathways. Recently, however, non-histone crosstalk has been observed between serine/threonine phosphorylation and the modification of arginine and lysine residues within kinase consensus sequences. Interestingly, many kinase consensus sequences contain critical arginine/lysine residues surrounding the substrate serine/threonine residue. Therefore, we hypothesize that non-histone crosstalk between serine/threonine phosphorylation and arginine/lysine modifications is a global mechanism for the modulation of cellular signaling. In this review, we discuss several recent examples of non-histone kinase consensus sequence crosstalk, as well as provide the biophysical basis for these observations. In addition, we predict likely examples of crosstalk between protein arginine methyltransferase 1 (PRMT1) and Akt and discuss the future implications of these findings.
ACS Chem Biol 2011 Sep 16
PMID:Kinase consensus sequences: a breeding ground for crosstalk. 2172 11

DNA damage induced by ionizing radiation activates the ataxia telangiectasia mutated pathway, resulting in apoptosis or DNA repair. The serine/threonine checkpoint kinase (Chk2) is an important transducer of this DNA damage signaling pathway and mediates the ultimate fate of the cell. Chk2 is an advantageous target for the development of adjuvant drugs for cancer therapy, because inhibition of Chk2 allows normal cells to enter cell cycle arrest and DNA repair, whereas many tumors bypass cell cycle checkpoints. Chk2 inhibitors may thus have a radioprotective effect on normal cells. We report herein a class of natural product derived Chk2 inhibitors, exemplified by indoloazepine 1, that elicit a strong ATM-dependent Chk2-mediated radioprotection effect in normal cells and p53 wt cells, but not p53 mutant cells (>50% of all cancers). This study represents the first example of a radioprotective effect in human cells other than T-cells and implicates a functional ATM pathway as a requirement for IR-induced radioprotection by this class of Chk2 inhibitors. Several of the hymenialdisine-derived analogues inhibit Chk2 at nanomolar concentrations, inhibit autophosphorylation of Chk2 at Ser516 in cells, and increase the survival of normal cells following ionizing radiation.
ACS Chem Biol 2012 Jan 20
PMID:Radioprotection by hymenialdisine-derived checkpoint kinase 2 inhibitors. 2200 65

Nitrogen heterocycles are the key functional and structural elements in both RNA and DNA, in half a dozen of the most important coenzymes, and in many synthetic drug scaffolds. On the other hand, only 3 of 20 proteinogenic amino acids have nitrogen heterocycles: proline, histidine, and tryptophan. This inventory can be augmented in microbial proteins by posttranslational modifications downstream of leader peptide regions that convert up to 10 serine, threonine, and cysteine residues, side chains and peptide backbones, into oxazoles, thiazoles, and pyridine rings. Subsequent proteolysis releases these heterocyclic scaffolds in both linear and macrocyclic frameworks as bioactive small molecules.
ACS Chem Biol 2012 Mar 16
PMID:Three ring posttranslational circuses: insertion of oxazoles, thiazoles, and pyridines into protein-derived frameworks. 2220 79

Mucin glycoproteins present a complex structural landscape arising from the multiplicity of glycosylation patterns afforded by their numerous serine and threonine glycosylation sites, often in clusters, and with variations in respective glycans. To explore the structural complexities in such glycoconjugates, we used NMR to systematically analyze the conformational effects of glycosylation density within a cluster of sites. This allows correlation with molecular recognition through analysis of interactions between these and other glycopeptides, with antibodies, lectins, and sera, using a glycopeptide microarray. Selective antibody interactions with discrete conformational elements, reflecting aspects of the peptide and disposition of GalNAc residues, are observed. Our results help bridge the gap between conformational properties and molecular recognition of these molecules, with implications for their physiological roles. Features of the native mucin motifs impact their relative immunogenicity and are accurately encoded in the antibody binding site, with the conformational integrity being preserved in isolated glycopeptides, as reflected in the antibody binding profile to array components.
ACS Chem Biol 2012 Jun 15
PMID:Deciphering structural elements of mucin glycoprotein recognition. 2244 68


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