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  1 / 9213 MEDLINE  
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PMID:29191553
Autor:Holien JK; Seibt B; Roberts V; Salvaris E; Parker MW; Cowan PJ; Dwyer KM
Endereço:ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. Electronic address: jholien@svi.edu.au.
Título:AMP and adenosine are both ligands for adenosine 2B receptor signaling.
Fonte:Bioorg Med Chem Lett; 28(2):202-206, 2018 01 15.
ISSN:1464-3405
País de publicação:England
Idioma:eng
Resumo:Adenosine is considered the canonical ligand for the adenosine 2B receptor (A R). A R is upregulated following kidney ischemia augmenting post ischemic blood flow and limiting tubular injury. In this context the beneficial effect of A R signaling has been attributed to an increase in the pericellular concentration of adenosine. However, following renal ischemia both kidney adenosine monophosphate (AMP) and adenosine levels are substantially increased. Using computational modeling and calcium mobilization assays, we investigated whether AMP could also be a ligand for A R. The computational modeling suggested that AMP interacts with more favorable energy to A R compared with adenosine. Furthermore, AMPαS, a non-hydrolyzable form of AMP, increased calcium uptake by Chinese hamster ovary (CHO) cells expressing the human A R, indicating preferential signaling via the G pathway. Therefore, a putative AMP-A R interaction is supported by the computational modeling data and the biological results suggest this interaction involves preferential G activation. These data provide further insights into the role of purinergic signaling in the pathophysiology of renal IRI.
Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Nome de substância:0 (Ligands); 0 (Receptor, Adenosine A2B); 415SHH325A (Adenosine Monophosphate); K72T3FS567 (Adenosine)


  2 / 9213 MEDLINE  
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PMID:29240815
Autor:Vobruba S; Kadlcik S; Gazak R; Janata J
Endereço:Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic.
Título:Evolution-guided adaptation of an adenylation domain substrate specificity to an unusual amino acid.
Fonte:PLoS One; 12(12):e0189684, 2017.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:Adenylation domains CcbC and LmbC control the specific incorporation of amino acid precursors in the biosynthesis of lincosamide antibiotics celesticetin and lincomycin. Both proteins originate from a common L-proline-specific ancestor, but LmbC was evolutionary adapted to use an unusual substrate, (2S,4R)-4-propyl-proline (PPL). Using site-directed mutagenesis of the LmbC substrate binding pocket and an ATP-[32P]PPi exchange assay, three residues, G308, A207 and L246, were identified as crucial for the PPL activation, presumably forming together a channel of a proper size, shape and hydrophobicity to accommodate the propyl side chain of PPL. Subsequently, we experimentally simulated the molecular evolution leading from L-proline-specific substrate binding pocket to the PPL-specific LmbC. The mere change of three amino acid residues in originally strictly L-proline-specific CcbC switched its substrate specificity to prefer PPL and even synthetic alkyl-L-proline derivatives with prolonged side chain. This is the first time that such a comparative study provided an evidence of the evolutionary relevant adaptation of the adenylation domain substrate binding pocket to a new sterically different substrate by a few point mutations. The herein experimentally simulated rearrangement of the substrate binding pocket seems to be the general principle of the de novo genesis of adenylation domains' unusual substrate specificities. However, to keep the overall natural catalytic efficiency of the enzyme, a more comprehensive rearrangement of the whole protein would probably be employed within natural evolution process.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Amino Acids); 0 (Proteins); 415SHH325A (Adenosine Monophosphate)


  3 / 9213 MEDLINE  
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PMID:28972974
Autor:Theron A; Roth RL; Hoppe H; Parkinson C; van der Westhuyzen CW; Stoychev S; Wiid I; Pietersen RD; Baker B; Kenyon CP
Endereço:CSIR Biosciences, Pretoria, South Africa.
Título:Differential inhibition of adenylylated and deadenylylated forms of M. tuberculosis glutamine synthetase as a drug discovery platform.
Fonte:PLoS One; 12(10):e0185068, 2017.
ISSN:1932-6203
País de publicação:United States
Idioma:eng
Resumo:Glutamine synthetase is a ubiquitous central enzyme in nitrogen metabolism that is controlled by up to four regulatory mechanisms, including adenylylation of some or all of the twelve subunits by adenylyl transferase. It is considered a potential therapeutic target for the treatment of tuberculosis, being essential for the growth of Mycobacterium tuberculosis, and is found extracellularly only in the pathogenic Mycobacterium strains. Human glutamine synthetase is not regulated by the adenylylation mechanism, so the adenylylated form of bacterial glutamine synthetase is of particular interest. Previously published reports show that, when M. tuberculosis glutamine synthetase is expressed in Escherichia coli, the E. coli adenylyl transferase does not optimally adenylylate the M. tuberculosis glutamine synthetase. Here, we demonstrate the production of soluble adenylylated M. tuberulosis glutamine synthetase in E. coli by the co-expression of M. tuberculosis glutamine synthetase and M. tuberculosis adenylyl transferase. The differential inhibition of adenylylated M. tuberulosis glutamine synthetase and deadenylylated M. tuberulosis glutamine synthetase by ATP based scaffold inhibitors are reported. Compounds selected on the basis of their enzyme inhibition were also shown to inhibit M. tuberculosis in the BACTEC 460TB™ assay as well as the intracellular inhibition of M. tuberculosis in a mouse bone-marrow derived macrophage assay.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Antitubercular Agents); 415SHH325A (Adenosine Monophosphate); EC 6.3.1.2 (Glutamate-Ammonia Ligase)


  4 / 9213 MEDLINE  
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PMID:28893424
Autor:Appling FD; Lucius AL; Schneider DA
Endereço:Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
Título:Quantifying the influence of 5'-RNA modifications on RNA polymerase I activity.
Fonte:Biophys Chem; 230:84-88, 2017 Nov.
ISSN:1873-4200
País de publicação:Netherlands
Idioma:eng
Resumo:For ensemble and single-molecule analyses of transcription, the use of synthetic transcription elongation complexes has been a versatile and powerful tool. However, structural analyses demonstrate that short RNA substrates, often employed in these assays, would occupy space within the RNA polymerase. Most commercial RNA oligonucleotides do not carry a 5'-triphosphate as would be present on a natural, de novo synthesized RNA. To examine the effects of 5'-moities on transcription kinetics, we measured nucleotide addition and 3'-dinucleotide cleavage by eukaryotic RNA polymerase I using 5'-hydroxyl and 5'-triphosphate RNA substrates. We found that 5' modifications had no discernable effect on the kinetics of nucleotide addition; however, we observed clear, but modest, effects on the rate of backtracking and/or dinucleotide cleavage. These data suggest that the 5'-end may influence RNA polymerase translocation, consistent with previous prokaryotic studies, and these findings may have implications on kinetic barriers that confront RNA polymerases during the transition from initiation to elongation.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Oligoribonucleotides); 415SHH325A (Adenosine Monophosphate); 63231-63-0 (RNA); EC 2.7.7.6 (RNA Polymerase I)


  5 / 9213 MEDLINE  
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PMID:28882541
Autor:Yuan M; Vásquez-Valdivieso MG; McNae IW; Michels PAM; Fothergill-Gilmore LA; Walkinshaw MD
Endereço:Centre for Translational and Chemical Biology, School of Biological Sciences, University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3BF, UK.
Título:Structures of Leishmania Fructose-1,6-Bisphosphatase Reveal Species-Specific Differences in the Mechanism of Allosteric Inhibition.
Fonte:J Mol Biol; 429(20):3075-3089, 2017 Oct 13.
ISSN:1089-8638
País de publicação:England
Idioma:eng
Resumo:The gluconeogenic enzyme fructose-1,6-bisphosphatase has been proposed as a potential drug target against Leishmania parasites that cause up to 20,000-30,000 deaths annually. A comparison of three crystal structures of Leishmania major fructose-1,6-bisphosphatase (LmFBPase) along with enzyme kinetic data show how AMP acts as an allosteric inhibitor and provides insight into its metal-dependent reaction mechanism. The crystal structure of the apoenzyme form of LmFBPase is a homotetramer in which the dimer of dimers adopts a planar conformation with disordered "dynamic loops". The structure of LmFBPase, complexed with manganese and its catalytic product phosphate, shows the dynamic loops locked into the active sites. A third crystal structure of LmFBPase complexed with its allosteric inhibitor AMP shows an inactive form of the tetramer, in which the dimer pairs are rotated by 18° relative to each other. The three structures suggest an allosteric mechanism in which AMP binding triggers a rearrangement of hydrogen bonds across the large and small interfaces. Retraction of the "effector loop" required for AMP binding releases the side chain of His23 from the dimer-dimer interface. This is coupled with a flip of the side chain of Arg48 which ties down the key catalytic dynamic loop in a disengaged conformation and also locks the tetramer in an inactive rotated T-state. The structure of the effector site of LmFBPase shows different structural features compared with human FBPases, thereby offering a potential and species-specific drug target.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Coenzymes); 0 (Enzyme Inhibitors); 415SHH325A (Adenosine Monophosphate); 42Z2K6ZL8P (Manganese); EC 3.1.3.11 (Fructose-Bisphosphatase)


  6 / 9213 MEDLINE  
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PMID:28802512
Autor:Vaduganathan M; Harrington RA; Stone GW; Steg PG; Gibson CM; Hamm CW; Price MJ; Deliargyris EN; Prats J; Mahaffey KW; White HD; Bhatt DL; CHAMPION PHOENIX Investigators
Endereço:Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts.
Título:Cangrelor Versus Clopidogrel on a Background of Unfractionated Heparin (from CHAMPION PHOENIX).
Fonte:Am J Cardiol; 120(7):1043-1048, 2017 Oct 01.
ISSN:1879-1913
País de publicação:United States
Idioma:eng
Resumo:Cangrelor is approved for use during percutaneous coronary intervention (PCI) and is administered with different parenteral anticoagulants. We examined the efficacy and safety of cangrelor in the subgroup of patients who received unfractionated heparin (UFH) during PCI in the modified intention-to-treat population of the randomized CHAMPION PHOENIX trial (cangrelor vs clopidogrel; n = 10,939). The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis (ST) at 48 hours. The key secondary efficacy end point was ST. UFH was used in 69.2% (7,569/10,939) of patients. In the UFH subgroup, cangrelor reduced the primary composite efficacy end point at 48 hours compared with clopidogrel (4.8% vs 5.9%; odds ratio [OR] 0.80 [0.65 to 0.98]; p = 0.03). Cangrelor consistently reduced ST at 2 hours (0.7% vs 1.3%; OR 0.56 [0.35 to 0.90]; p = 0.01) and 48 hours (0.9% vs 1.4%; OR 0.70 [0.45 to 1.07]; p = 0.10). There was no difference in GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries)-defined severe or life-threatening bleeding (0.1% vs 0.1%; OR 1.24 [0.33 to 4.61]; p = 0.75) or blood transfusion requirement at 48 hours (0.4% vs 0.2%; OR 1.87 [0.83 to 4.21]; p = 0.12). In conclusion, cangrelor reduces early ischemic periprocedural complications without increasing severe bleeding compared with clopidogrel in patients undergoing PCI with UFH.
Tipo de publicação: JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
Nome de substância:0 (Anticoagulants); 0 (Platelet Aggregation Inhibitors); 415SHH325A (Adenosine Monophosphate); 6AQ1Y404U7 (cangrelor); 9005-49-6 (Heparin); A74586SNO7 (clopidogrel); OM90ZUW7M1 (Ticlopidine)


  7 / 9213 MEDLINE  
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PMID:28751376
Autor:McNally JR; O'Brien PJ
Endereço:From the Department of Biological Chemistry, Michigan Medicine, University of Michigan, Ann Arbor, Michigan 48109.
Título:Kinetic analyses of single-stranded break repair by human DNA ligase III isoforms reveal biochemical differences from DNA ligase I.
Fonte:J Biol Chem; 292(38):15870-15879, 2017 Sep 22.
ISSN:1083-351X
País de publicação:United States
Idioma:eng
Resumo:Humans have three genes encoding DNA ligases with conserved structural features and activities, but they also have notable differences. The gene encodes a ubiquitous isoform in all tissues (LIG3α) and a germ line-specific splicing isoform (LIG3ß) that differs in the C-terminal domain. Both isoforms are found in the nucleus and the mitochondria. Here, we determined the kinetics and thermodynamics of single-stranded break ligation by LIG3α and LIG3ß and compared this framework to that of LIG1, the nuclear replicative ligase. The kinetic parameters of the LIG3 isoforms are nearly identical under all tested conditions, indicating that the BRCA1 C terminal (BRCT) domain specific to LIG3α does not alter ligation kinetics. Although LIG3 is only 22% identical to LIG1 across their conserved domains, the two enzymes had very similar maximal ligation rates. Comparison of the rate and equilibrium constants for LIG3 and LIG1 nevertheless revealed important differences. The LIG3 isoforms were seven times more efficient than LIG1 at ligating nicked DNA under optimal conditions, mainly because of their lower value for the DNA substrate. This could explain why LIG3 is less prone to abortive ligation than LIG1. Surprisingly, the affinity of LIG3 for Mg was ten times weaker than that of LIG1, suggesting that Mg availability regulates DNA ligation , because Mg levels are higher in the mitochondria than in the nucleus. The biochemical differences between the LIG3 isoforms and LIG1 identified here will guide the understanding of both unique and overlapping biological roles of these critical enzymes.
Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE
Nome de substância:0 (Isoenzymes); 415SHH325A (Adenosine Monophosphate); EC 6.5.1.1 (DNA Ligase ATP); I38ZP9992A (Magnesium)


  8 / 9213 MEDLINE  
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PMID:28718281
Autor:Wang J; Custer G; Beckett D; Matysiak S
Endereço:Fischell Department of Bioengineering and ‡Department of Chemistry & Biochemistry, University of Maryland , College Park, Maryland 20742, United States.
Título:Long Distance Modulation of Disorder-to-Order Transitions in Protein Allostery.
Fonte:Biochemistry; 56(34):4478-4488, 2017 Aug 29.
ISSN:1520-4995
País de publicação:United States
Idioma:eng
Resumo:Elucidation of the molecular details of allosteric communication between distant sites in a protein is key to understanding and manipulating many biological regulatory processes. Although protein disorder is acknowledged to play an important thermodynamic role in allostery, the molecular mechanisms by which this disorder is harnessed for long distance communication are known for a limited number of systems. Transcription repression by the Escherichia coli biotin repressor, BirA, is allosterically activated by binding of the small molecule effector biotinoyl-5'-AMP. The effector acts by promoting BirA dimerization, which is a prerequisite for sequence-specific binding to the biotin biosynthetic operon operator sequence. A 30 Å distance separates the effector binding and dimerization surfaces in BirA, and previous studies indicate that allostery is mediated, in part, by disorder-to-order transitions on the two coupled sites. In this work, combined experimental and computational methods have been applied to investigate the molecular basis of allosteric communication in BirA. Double-mutant cycle analysis coupled with thermodynamic measurements indicates functional coupling between residues in disordered loops on the two distant surfaces. All atom molecular dynamics simulations reveal that this coupling occurs through long distance reciprocal modulation of the structure and dynamics of disorder-to-order transitions on the two surfaces.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (5'-AMP-biotin); 0 (Escherichia coli Proteins); 0 (Repressor Proteins); 415SHH325A (Adenosine Monophosphate); 6SO6U10H04 (Biotin); EC 6.3.- (Carbon-Nitrogen Ligases); EC 6.3.4.15 (birA protein, E coli)


  9 / 9213 MEDLINE  
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PMID:28700987
Autor:Droppa M; Borst O; Rath D; Müller K; Gawaz M; Bhatt DL; Geisler T
Endereço:Department of Cardiology and Cardiovascular Medicine, University Hospital of Tuebingen, Tuebingen, Germany.
Título:Impact of Intravenous P2Y12-Receptor Inhibition with Cangrelor in Patients Presenting with Acute Coronary Syndrome and Cardiogenic Shock - a Case Series.
Fonte:Cell Physiol Biochem; 42(4):1336-1341, 2017.
ISSN:1421-9778
País de publicação:Switzerland
Idioma:eng
Resumo:BACKGROUND/AIMS: Patients with acute coronary syndromes (ACS) presenting with cardiogenic shock (CS) are at particular risk for death and adverse cardiac events. Impaired effects and absorption of oral P2Y12-receptor inhibitors due to decreased organ hypoperfusion or hypothermia and challenges regarding oral administration contribute to this risk. We report a single center experience regarding the use of intravenous P2Y12-receptor inhibitor cangrelor in patients with CS treated with percutaneous coronary intervention (PCI). METHODS: Twelve patients with ACS and CS undergoing PCI, not pretreated with oral P2Y12-receptor inhibitors, were treated with cangrelor. Platelet inhibition was assessed by multiple electrode aggregometry (MEA) before and after PCI, immediately and 2 hours after stopping the cangrelor infusion. RESULTS: Nine patients recovered from their cardiogenic shock, 3 patients died. Platelet reactivity decreased from 65.9 (SD 41.0) U before PCI to 15.8 (SD 10.8) U after PCI, 13.4 (SD 7.7) U at the end of infusion and 33.8 (SD 19.9) 2 hours after stopping the cangrelor infusion. There was no non-responder under cangrelor infusion (MEA < 46 U). CONCLUSIONS: Due to its favorable PK/PD profile, cangrelor overcomes problems with reduced absorption and effects of oral P2Y12-receptor inhibitors and should be considered for periprocedural treatment of patients with CS.
Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE
Nome de substância:0 (Cardiotonic Agents); 0 (Platelet Aggregation Inhibitors); 0 (Purinergic P2Y Receptor Antagonists); 0 (Receptors, Purinergic P2Y); 415SHH325A (Adenosine Monophosphate); 6AQ1Y404U7 (cangrelor)


  10 / 9213 MEDLINE  
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PMID:28675237
Autor:Chen J; Wong HS; Leong PK; Leung HY; Chan WM; Ko KM
Endereço:Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China. bcrko@ust.hk.
Título:Ursolic acid induces mitochondrial biogenesis through the activation of AMPK and PGC-1 in C2C12 myotubes: a possible mechanism underlying its beneficial effect on exercise endurance.
Fonte:Food Funct; 8(7):2425-2436, 2017 Jul 19.
ISSN:2042-650X
País de publicação:England
Idioma:eng
Resumo:Mitochondrial biogenesis, which involves an increase in mitochondrial number and the overall capacity of oxidative phosphorylation, is a critical determinant of skeletal muscle function. Recent findings have shown that some natural products can enhance mitochondrial adaptation to aerobic exercise, which in turn improves exercise performance, presumably by delaying muscle fatigue. Ursolic acid (UA), a natural triterpene, is commonly found in various vegetables and fruits. In the current study, UA was shown to increase mitochondrial mass and ATP generation capacity, with a concomitant production of a low level of mitochondrial reactive oxygen species (ROS) in C2C12 myotubes. Mitochondrial ROS, in turn, activated the redox sensitive adenosine monophosphate-dependent protein kinase (AMPK)/peroxisome proliferator-activated receptor γ coactivator-1(PGC-1) pathway. The activation of AMPK/PGC-1 further increased the expression of cytochrome c oxidase (COX) and uncoupling protein 3. Animal studies showed that UA can also dose-dependently increase the endurance exercise capacity in mice, as assessed by a weight-loaded swimming test and a hanging wire test. Our findings suggest that UA may induce mitochondrial biogenesis through the activation of AMPK and PGC-1 pathways in skeletal muscle, thereby offering a promising prospect for its use to enhance exercise endurance and alleviating fatigue in humans.
Tipo de publicação: JOURNAL ARTICLE
Nome de substância:0 (Reactive Oxygen Species); 0 (Transcription Factors); 0 (Triterpenes); 0 (peroxisome-proliferator-activated receptor-gamma coactivator-1); 415SHH325A (Adenosine Monophosphate); EC 2.7.11.31 (AMP-Activated Protein Kinases); P3M2575F3F (ursolic acid)



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