Browsing by Subject "Molecular Structure"

Now showing 1 - 4 of 4
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    Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes
    (American Diabetes Association, 2017-11) Hernandez-Perez, Marimar; Chopra, Gaurav; Fine, Jonathan; Conteh, Abass M.; Anderson, Ryan M.; Linnemann, Amelia K.; Benjamin, Chanelle; Nelson, Jennifer B.; Benninger, Kara S.; Nadler, Jerry L.; Maloney, David J.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Pediatrics, School of Medicine
    Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in β-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.
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    Photoinduced oxidative cyclopropanation of ene-ynamides: synthesis of 3-aza[n.1.0]bicycles via vinyl radicals
    (Royal Society of Chemistry, 2021-05) Deng, Yongming; Zhang, Jason; Bankhead, Bradley; Markham, Jonathan P.; Zeller, Matthias; Chemistry and Chemical Biology, School of Science
    The first photoinduced synthesis of polyfunctionalized 3-aza[n.1.0]bicycles from readily available ene-ynamides and 2,6-lutidine N-oxide using an organic acridinium photocatalyst is reported. Applying a photocatalytic strategy to the reactive distonic cation vinyl radical intermediate from ynamide, a series of bio-valuable 3-azabicycles, including diverse 3-azabicyclio[4.1.0]heptanes and 3-azabicyclo[5.1.0]octanes that are challenging to accomplish using traditional methods, have been successfully synthesized in good to high yields under mild and metal-free conditions. Mechanistic studies are consistent with the photocatalyzed single-electron oxidation of ene-ynamide and the intermediacy of a putative cationic vinyl radical in this transformation. Importantly, this strategy provides new access to the development of photocatalytic vinyl radical cascades for the synthesis of structurally sophisticated substrates.
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    SPOT-Seq-RNA: Predicting protein-RNA complex structure and RNA-binding function by fold recognition and binding affinity prediction
    (Springer, 2014) Yang, Yuedong; Zhao, Huiying; Wang, Jihua; Zhou, Yaoqi; Department of BioHealth Informatics
    RNA-binding proteins (RBPs) play key roles in RNA metabolism and post-transcriptional regulation. Computational methods have been developed separately for prediction of RBPs and RNA-binding residues by machine-learning techniques and prediction of protein-RNA complex structures by rigid or semiflexible structure-to-structure docking. Here, we describe a template-based technique called SPOT-Seq-RNA that integrates prediction of RBPs, RNA-binding residues, and protein-RNA complex structures into a single package. This integration is achieved by combining template-based structure-prediction software, SPARKS X, with binding affinity prediction software, DRNA. This tool yields reasonable sensitivity (46 %) and high precision (84 %) for an independent test set of 215 RBPs and 5,766 non-RBPs. SPOT-Seq-RNA is computationally efficient for genome-scale prediction of RBPs and protein-RNA complex structures. Its application to human genome study has revealed a similar sensitivity and ability to uncover hundreds of novel RBPs beyond simple homology. The online server and downloadable version of SPOT-Seq-RNA are available at http://sparks-lab.org/server/SPOT-Seq-RNA/.
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    Structural interpretation of the effects of threo-nucleotides on nonenzymatic template-directed polymerization
    (Oxford, 2021-01-25) Zhang, Wen; Kim, Seohyun Chris; Tam, Chun Pong; Lelyveld, Victor S.; Bala, Saikat; Chaput, John C.; Szostak, Jack W.; Biochemistry and Molecular Biology, School of Medicine
    The prebiotic synthesis of ribonucleotides is likely to have been accompanied by the synthesis of noncanonical nucleotides including the threo-nucleotide building blocks of TNA. Here, we examine the ability of activated threo-nucleotides to participate in nonenzymatic template-directed polymerization. We find that primer extension by multiple sequential threo-nucleotide monomers is strongly disfavored relative to ribo-nucleotides. Kinetic, NMR and crystallographic studies suggest that this is due in part to the slow formation of the imidazolium-bridged TNA dinucleotide intermediate in primer extension, and in part because of the greater distance between the attacking RNA primer 3'-hydroxyl and the phosphate of the incoming threo-nucleotide intermediate. Even a single activated threo-nucleotide in the presence of an activated downstream RNA oligonucleotide is added to the primer 10-fold more slowly than an activated ribonucleotide. In contrast, a single activated threo-nucleotide at the end of an RNA primer or in an RNA template results in only a modest decrease in the rate of primer extension, consistent with the minor and local structural distortions revealed by crystal structures. Our results are consistent with a model in which heterogeneous primordial oligonucleotides would, through cycles of replication, have given rise to increasingly homogeneous RNA strands.