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https://www.readbyqxmd.com/read/28343356/development-of-a-novel-strategy-to-target-cd39-antithrombotic-activity-to-the-endothelial-platelet-microenvironment-in-kidney-ischemia-reperfusion-injury
#1
Maithili Sashindranath, Karen M Dwyer, Shala Dezfouli, Carly Selan, Sandra Crikis, Bo Lu, Yuping Yuan, Michael J Hickey, Karlheinz Peter, Simon C Robson, Peter J Cowan, Harshal H Nandurkar
Kidney ischemia-reperfusion injury (IRI) is common during transplantation. IRI is characterised by inflammation and thrombosis and associated with acute and chronic graft dysfunction. P-selectin and its ligand PSGL-1 are cell adhesion molecules that control leukocyte-endothelial and leukocyte-platelet interactions under inflammatory conditions. CD39 is the dominant vascular nucleotidase that facilitates adenosine generation via extracellular ATP/ADP-phosphohydrolysis. Adenosine signalling is protective in renal IRI, but CD39 catalytic activity is lost with exposure to oxidant stress...
March 25, 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/28343137/synthesis-of-novel-muramic-acid-derivatives-and-their-interaction-with-lysozyme-action-of-lysozyme-revisited
#2
Manas Jana, Anirban Ghosh, Abhishek Santra, Rajiv Kumar Kar, Anup Kumar Misra, Anirban Bhunia
HYPOTHESIS: The interaction of lysozyme with the N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) unit of peptidoglycan (PGN) polymer of the bacterial cell wall is of immense importance to understand the mechanism of lysozyme on PGN. EXPERIMENTS: The synthesis of three novel NAM derivatives containing fused oxazinone ring to the NAM moiety has been achieved. The synthesized compounds were evaluated for their potential as a glycomimetic acceptor of lysozyme using different biophysical and computational methods such as (1)H NMR, STD NMR, DOSY and Molecular docking...
March 16, 2017: Journal of Colloid and Interface Science
https://www.readbyqxmd.com/read/28342900/critical-roles-of-ctp-synthase-n-terminal-in-cytoophidium-assembly
#3
Yong Huang, Jin-Jun Wang, Sanjay Ghosh, Ji-Long Liu
Several metabolic enzymes assemble into distinct intracellular structures in prokaryotes and eukaryotes suggesting an important functional role in cell physiology. The CTP-generating enzyme CTP synthase forms long filamentous structures termed cytoophidia in bacteria, yeast, fruit flies and human cells independent of its catalytic activity. However, the amino acid determinants for protein-protein interaction necessary for polymerisation remained unknown. In this study, we systematically analysed the role of the conserved N-terminal of Drosophila CTP synthase in cytoophidium assembly...
March 22, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28339071/direct-interaction-between-caffeic-acid-phenethyl-ester-and-human-neutrophil-elastase-inhibits-the-growth-and-migration-of-panc-1-cells
#4
Jianhui Duan, Yilixiati Xiaokaiti, Shengjun Fan, Yan Pan, Xin Li, Xuejun Li
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumors of the digestive system, but the mechanisms of its development and progression are unclear. Inflammation is thought to be fundamental to pancreatic cancer development and caffeic acid phenethyl ester (CAPE) is an active component of honey bee resin or propolis with anti-inflammatory and anticancer activities. We investigated the inhibitory effects of CAPE on cell growth and migration induced by human neutrophil elastase (HNE) and report that HNE induced cancer cell migration at low doses and growth at higher doses...
March 21, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28336574/switching-head-group-selectivity-in-mammalian-sphingolipid-biosynthesis-by-active-site-engineering-of-sphingomyelin-synthases
#5
Matthijs Kol, Radhakrishnan Panatala, Mirjana Nordmann, Leoni Swart, Leonie Van Suijlekom, Birol Cabukusta, Angelika Hilderink, Tanja Gabrietz, John G M Mina, Pentti Somerharju, Sergei Korneev, Fikadu G Tafesse, Joost C M Holthuis
Sphingomyelin (SM) is a fundamental component of mammalian cell membranes that contributes to mechanical stability, signaling and sorting. Its production involves the transfer of phosphocholine from phosphatidylcholine onto ceramide, a reaction catalyzed by SM synthase SMS1 in the Golgi and SMS2 at the plasma membrane. Mammalian cells also synthesize trace amounts of the SM analog ceramide phosphoethanolamine (CPE), but the physiological relevance of CPE production is unclear. Previous work revealed that SMS2 is a bifunctional enzyme producing both SM and CPE whereas a closely related enzyme, SMSr/SAMD8, acts as a monofunctional CPE synthase in the ER...
March 23, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28336405/photoactivation-mechanism-of-a-bacterial-light-regulated-adenylyl-cyclase
#6
Robert Lindner, Elisabeth Hartmann, Miroslaw Tarnawski, Andreas Winkler, Daniel Frey, Jochen Reinstein, Anton Meinhart, Ilme Schlichting
Light-regulated enzymes enable organisms to quickly respond to changing light conditions. We characterize a photoactivatable adenylyl cyclase from Beggiatoa sp. (bPAC) that translates a blue light signal into production of the second messenger cyclic AMP. bPAC contains a BLUF photoreceptor domain that senses blue light using a flavin chromophore, linked to an adenylyl cyclase (AC) domain. We present a dark state crystal structure of bPAC that closely resembles the recently published structure of the homologous OaPAC from Oscillatoria acuminata...
March 20, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28336403/broad-analysis-of-vicinal-disulfides-occurrences-conformations-with-cis-or-with-trans-peptides-and-functional-roles-including-sugar-binding
#7
Jane S Richardson, Lizbeth L Videau, Christopher J Williams, David C Richardson
Vicinal disulfides between sequence-adjacent cysteine residues are very rare and rather startling structural features which play a variety of functional roles. Typically discussed as an isolated curiosity, they have never received a general treatment covering both cis and trans forms. Enabled by the growing database of high-resolution structures, required deposition of diffraction data, and improved methods for discriminating reliable from dubious cases, we here identify and describe distinct protein families with reliably genuine examples of cis or trans vicinal disulfides and discuss their conformations, conservation, and functions...
March 20, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28335716/human-mfap1-is-a-cryptic-ortholog-of-the-saccharomyces-cerevisiae-spp381-splicing-factor
#8
Alexander K C Ulrich, Markus C Wahl
BACKGROUND: Pre-mRNA splicing involves the stepwise assembly of a pre-catalytic spliceosome, followed by its catalytic activation, splicing catalysis and disassembly. Formation of the pre-catalytic spliceosomal B complex involves the incorporation of the U4/U6.U5 tri-snRNP and of a group of non-snRNP B-specific proteins. While in Saccharomyces cerevisiae the Prp38 and Snu23 proteins are recruited as components of the tri-snRNP, metazoan orthologs of Prp38 and Snu23 associate independently of the tri-snRNP as members of the B-specific proteins...
March 24, 2017: BMC Evolutionary Biology
https://www.readbyqxmd.com/read/28335516/marine-diterpenes-molecular-modeling-of-thrombin-inhibitors-with-potential-biotechnological-application-as-an-antithrombotic
#9
Rebeca Cristina Costa Pereira, André Luiz Lourenço, Luciana Terra, Paula Alvarez Abreu, Valéria Laneuville Teixeira, Helena Carla Castro
Thrombosis related diseases are among the main causes of death and incapacity in the world. Despite the existence of antithrombotic agents available for therapy, they still present adverse effects like hemorrhagic risks which justify the search for new options. Recently, pachydictyol A, isopachydictyol A, and dichotomanol, three diterpenes isolated from Brazilian marine brown alga Dictyota menstrualis were identified as potent antithrombotic molecules through inhibition of thrombin, a key enzyme of coagulation cascade and a platelet agonist...
March 20, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28335001/fastkd1-and-fastkd4-have-opposite-effects-on-expression-of-specific-mitochondrial-rnas-depending-upon-their-endonuclease-like-rap-domain
#10
Erik Boehm, Sofia Zaganelli, Kinsey Maundrell, Alexis A Jourdain, Stéphane Thore, Jean-Claude Martinou
FASTK family proteins have been identified as regulators of mitochondrial RNA homeostasis linked to mitochondrial diseases, but much remains unknown about these proteins. We show that CRISPR-mediated disruption of FASTKD1 increases ND3 mRNA level, while disruption of FASTKD4 reduces the level of ND3 and of other mature mRNAs including ND5 and CYB, and causes accumulation of ND5-CYB precursor RNA. Disrupting both FASTKD1 and FASTKD4 in the same cell results in decreased ND3 mRNA similar to the effect of depleting FASTKD4 alone, indicating that FASTKD4 loss is epistatic...
March 10, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334966/structural-and-mechanistic-insights-into-regulation-of-hbo1-histone-acetyltransferase-activity-by-brpf2
#11
Ye Tao, Chen Zhong, Junjun Zhu, Shutong Xu, Jianping Ding
HBO1, a member of the MYST family of histone acetyltransferases (HATs), is required for global acetylation of histone H3K14 and embryonic development. It functions as a catalytic subunit in multisubunit complexes comprising a BRPF1/2/3 or JADE1/2/3 scaffold protein, and two accessory proteins. BRPF2 has been shown to be important for the HAT activity of HBO1 toward H3K14. Here we demonstrated that BRPF2 can regulate the HAT activity of HBO1 toward free H3 and H4, and nucleosomal H3. Particularly, a short N-terminal region of BRPF2 is sufficient for binding to HBO1 and can potentiate its activity toward H3K14...
February 24, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334932/ribosome-dependent-vibrio-cholerae-mrnase-higb2-is-regulated-by-a-%C3%AE-strand-sliding-mechanism
#12
San Hadži, Abel Garcia-Pino, Sarah Haesaerts, Dukas Jurenas, Kenn Gerdes, Jurij Lah, Remy Loris
Toxin-antitoxin (TA) modules are small operons involved in bacterial stress response and persistence. higBA operons form a family of TA modules with an inverted gene organization and a toxin belonging to the RelE/ParE superfamily. Here, we present the crystal structures of chromosomally encoded Vibrio cholerae antitoxin (VcHigA2), toxin (VcHigB2) and their complex, which show significant differences in structure and mechanisms of function compared to the higBA module from plasmid Rts1, the defining member of the family...
February 28, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28331945/from-a-metagenomic-source-to-a-high-resolution-structure-of-a-novel-alkaline-esterase
#13
Mariana Rangel Pereira, Thaís Carvalho Maester, Gustavo Fernando Mercaldi, Eliana Gertrudes de Macedo Lemos, Marko Hyvönen, Andrea Balan
Esterases catalyze the cleavage and formation of ester bonds and are members of the diverse family of α/β hydrolase fold. They are useful in industries from different sectors, such as food, detergent, fine chemicals, and biofuel production. In a previous work, 30 positive clones for lipolytic activity were identified from a metagenomic library of a microbial consortium specialized in diesel oil degradation. In this study, a putative gene encoding an esterase/lipase, denominated est8, has been cloned and the corresponding protein expressed recombinantly, purified to homogeneity and characterized functional and structurally...
March 22, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28330869/molecular-mechanisms-of-isocitrate-dehydrogenase-1-idh1-mutations-identified-in-tumors-the-role-of-size-and-hydrophobicity-at-residue-132-on-catalytic-efficiency
#14
Diego Avellaneda Matteo, Adam J Grunseth, Eric R Gonzalez, Stacy L Anselmo, Madison A Kennedy, Precious Moman, David A Scott, An Hoang, Christal D Sohl
Isocitrate dehydrogenase 1 (IDH1) catalyzes the reversible NADP+-dependent conversion of isocitrate (ICT) to α-ketoglutarate (αKG) in the cytosol and peroxisomes. Mutations in IDH1 have been implicated in > 80% of lower grade gliomas and secondary glioblastomas and primarily affect residue 132, which helps coordinate substrate binding. However, other mutations found in the active site have also been identified in tumors. IDH1 mutations typically result in a loss of catalytic activity, but many also can catalyze a new reaction, the NADPH-dependent reduction of αKG to D-2-hydroxyglutarate (D2HG)...
March 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28330208/purification-and-characterization-of-%C3%AE-mannanase-from-aspergillus-terreus-and-its-applicability-in-depolymerization-of-mannans-and-saccharification-of-lignocellulosic-biomass
#15
Hemant Soni, Hemant Kumar Rawat, Brett I Pletschke, Naveen Kango
Aspergillus terreus FBCC 1369 was grown in solid-state culture under statistically optimized conditions. β-Mannanase was purified to apparent homogeneity by ultrafiltration, anion exchange and gel filtration chromatography. A purification factor of 10.3-fold was achieved, with the purified enzyme exhibiting specific activity of 53 U/mg protein. The purified β-mannanase was optimally active at pH 7.0 and 70 °C and displayed stability over a broad pH range of 4.0-8.0 and a 30 min half-life at 80 °C. The molecular weight of β-mannanase was calculated as ~49 kDa by SDS-PAGE...
December 2016: 3 Biotech
https://www.readbyqxmd.com/read/28329765/structural-insights-into-adiponectin-receptors-suggest-ceramidase-activity
#16
Ieva Vasiliauskaité-Brooks, Remy Sounier, Pascal Rochaix, Gaëtan Bellot, Mathieu Fortier, François Hoh, Luigi De Colibus, Chérine Bechara, Essa M Saied, Christoph Arenz, Cédric Leyrat, Sébastien Granier
Adiponectin receptors (ADIPORs) are integral membrane proteins that control glucose and lipid metabolism by mediating, at least in part, a cellular ceramidase activity that catalyses the hydrolysis of ceramide to produce sphingosine and a free fatty acid (FFA). The crystal structures of the two receptor subtypes, ADIPOR1 and ADIPOR2, show a similar overall seven-transmembrane-domain architecture with large unoccupied cavities and a zinc binding site within the seven transmembrane domain. However, the molecular mechanisms by which ADIPORs function are not known...
March 22, 2017: Nature
https://www.readbyqxmd.com/read/28323400/stepwise-loop-insertion-strategy-for-active-site-remodeling-to-generate-novel-enzyme-functions
#17
Md Anarul Hoque, Yong Zhang, Liuqing Chen, Guang-Yu Yang, Mst Afroza Khatun, Hai-Feng Chen, Liu Hao, Yan Feng
The remodeling of active sites to generate novel biocatalysts is an attractive and challenging task. We developed a stepwise loop insertion strategy (StLois), in which randomized residue pairs are inserted into active site loops. The phosphotriesterase-like lactonase from Geobacillus kaustophilus (GkaP-PLL) was used to investigate StLois's potential for changing enzyme function. By inserting 6 residues into active site loop7, the best variant ML7-B6 demonstrated a 16 fold further increase in catalytic efficiency toward ethyl-paraoxon compared with its initial template, that is a 609-fold higher, >107 fold substrate specificity shift relative to that of wild-type lactonase...
March 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28322784/flaviviridae-viruses-use-a-common-molecular-mechanism-to-escape-nucleoside-analogue-inhibitors
#18
James J Valdés, Philip T Butterill, Daniel Růžek
The RNA-dependent RNA polymerases of Flaviviridae viruses are crucial for replication. The Flaviviridae polymerase is organized into structural motifs (A-G), with motifs F, A, C and E containing interrogating, priming and catalytic substrate-interacting sites. Modified nucleoside analogues act as antiviral drugs by targeting Flaviviridae polymerases and integrating into the synthesized product causing premature termination. A threonine mutation of a conserved serine residue in motif B of Flaviviridae polymerases renders resistance to 2'-C-methylated nucleoside analogues...
March 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28321576/two-distinct-cinnamoyl-coa-reductases-in-selaginella-moellendorffii-offer-insight-into-the-divergence-of-ccrs-in-plants
#19
Nan Chao, Shuang Li, Ning Li, Qi Qi, Wen-Ting Jiang, Xiang-Ning Jiang, Ying Gai
Two distinct cinnamoyl-coenzyme A reductases (CCRs) from Selaginella moellendorffii were evaluated, and of these, SmCCR2-1, which has both distinct sequence motifs and catalytic properties, was clustered into a new CCR subgroup. Cinnamoyl-coenzyme A reductases (CCRs) have been reported in many land plants to have critical functions in monolignol biosynthesis. In this study, we performed a genome-wide screen and obtained two distinct SmCCRs from S. moellendorffii. Phylogenetic analysis indicated that SmCCR2 (both SmCCR2-1 and 2-2) and SmCCR3 together with PpaCCR belong to a distinct subgroup of genuine CCRs with variations in the NAD(P)H-binding motif...
March 20, 2017: Planta
https://www.readbyqxmd.com/read/28320728/mutations-at-arg220-and-thr237-in-per-2-%C3%AE-lactamase-impact-on-conformation-activity-and-susceptibility-to-inhibitors
#20
Melina Ruggiero, Lucrecia Curto, Florencia Brunetti, Eric Sauvage, Moreno Galleni, Pablo Power, Gabriel Gutkind
PER-2 accounts for up to 10% of oxyimino-cephalosporin resistance in Klebsiella pneumoniae and Escherichia coli in Argentina, and hydrolyzes both cefotaxime and ceftazidime with high catalytic efficiencies (kcat/Km). Through crystallographic analyses, we recently proposed the existence of a hydrogen-bond network connecting Ser70-Gln69-oxyanion water-Thr237-Arg220 that might be important for the activity and inhibition of the enzyme. Mutations at Arg244 in most class A β-lactamases (as TEM and SHV) reduce susceptibility to mechanism-based inactivators, and Arg220 in PER β-lactamases is equivalent to Arg244...
March 20, 2017: Antimicrobial Agents and Chemotherapy
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