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ACS chemical biology 37건

  1. [해외논문]   Structure and Function of a C–C Bond Cleaving Oxygenase in Atypical Angucycline Biosynthesis   SCIE

    Pan, Guohui (State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, ) , Gao, Xiaoqin (National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, ) , Fan, Keqiang (State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, ) , Liu, Junlin (iHuman Institute, ShanghaiTech University, Shanghai 201210, ) , Meng, Bing (iHuman Institute, ShanghaiTech University, Shanghai 201210, ) , Gao, Jinmin (State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, ) , Wang, Bin (State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, ) , Zhang, Chaobo (State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, ) , Han, Hui (State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, ) , Ai, Guomin (State Key Laboratory of Microbial Resources, Ins) , Chen, Yihua , Wu, Dong , Liu, Zhi-Jie , Yang, Keqian
    ACS chemical biology v.12 no.1 ,pp. 142 - 152 , 2017 , 1554-8929 ,

    초록

    C–C bond ring cleaving oxygenases represent a unique family of enzymes involved in the B ring cleavage reaction only observed in atypical angucycline biosynthesis. B ring cleavage is the key reaction leading to dramatic divergence in the final structures of atypical angucyclines. Here, we present the crystal structure of AlpJ, the first structure of this family of enzymes. AlpJ has been verified as the enzyme catalyzing C–C bond cleavage in kinamycin biosynthesis. The crystal structure of the AlpJ monomer resembles the dimeric structure of ferredoxin-like proteins. The N- and C-terminal halves of AlpJ are homologous, and both contain a putative hydrophobic substrate binding pocket in the “closed” and “open” conformations, respectively. Structural comparison of AlpJ with ActVA-Orf6 and protein–ligand docking analysis suggest that the residues including Asn60, Trp64, and Trp181 are possibly involved in substrate recognition. Site-directed mutagenesis results supported our hypothesis, as mutation of these residues led to nearly a complete loss of the activity of AlpJ. Structural analysis also revealed that AlpJ possesses an intramolecular domain–domain interface, where the residues His50 and Tyr178 form a hydrogen bond that probably stabilizes the three-dimensional structure of AlpJ. Site-directed mutagenesis showed that the two residues, His50 and Tyr178, were vital for the activity of AlpJ. Our findings shed light on the structure and catalytic mechanism of the AlpJ family of oxygenases, which presumably involves two active sites that might function in a cooperative manner. Graphic Abstract ACS Electronic Supporting Info

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  2. [해외논문]   Mapping the Phosphorylation Pattern of Drosophila melanogaster RNA Polymerase II Carboxyl-Terminal Domain Using Ultraviolet Photodissociation Mass Spectrometry   SCIE

    Mayfield, Joshua E. (Department of Biochemistry and Molecular Biology, Penn State University, University Park, Pennsylvania 16802,) , Robinson, Michelle R. , Cotham, Victoria C. , Irani, Seema , Matthews, Wendy L. , Ram, Anjana , Gilmour, David S. , Cannon, Joe R. , Zhang, Yan Jessie , Brodbelt, Jennifer S.
    ACS chemical biology v.12 no.1 ,pp. 153 - 162 , 2017 , 1554-8929 ,

    초록

    Phosphorylation of the C-terminal domain of RNA polymerase II (CTD) plays an essential role in eukaryotic transcription by recruiting transcriptional regulatory factors to the active polymerase. However, the scarcity of basic residues and repetitive nature of the CTD sequence impose a huge challenge for site-specific characterization of phosphorylation, hindering our understanding of this crucial biological process. Herein, we apply LC-UVPD-MS methods to analyze post-translational modification along native sequence CTDs. Application of our method to the Drosophila melanogaster CTD reveals the phosphorylation pattern of this model organism for the first time. The divergent nature of fly CTD allows us to derive rules defining how flanking residues affect phosphorylation choice by CTD kinases. Our data support the use of LC-UVPD-MS to decipher the CTD code and determine rules that program its function. Graphic Abstract ACS Electronic Supporting Info

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  3. [해외논문]   Sudemycin K: A Synthetic Antitumor Splicing Inhibitor Variant with Improved Activity and Versatile Chemistry   SCIE

    Makowski, Kamil (Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, ) , Vigevani, Luisa (Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, ) , Albericio, Fernando (Institute for Research in Biomedicine (IRB-Barcelona), Baldiri i Reixac 10, 08028, Barcelona, ) , Valcá (Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, ) , rcel, Juan (Institute for Research in Biomedicine (IRB-Barcelona), Baldiri i Reixac 10, 08028, Barcelona,) , Á , lvarez, Mercedes
    ACS chemical biology v.12 no.1 ,pp. 163 - 173 , 2017 , 1554-8929 ,

    초록

    Important links exist between the process of pre-mRNA splicing and cancer, as illustrated by the frequent mutation of splicing factors in tumors and the emergence of various families of antitumor drugs that target components of the splicing machinery, notably SF3B1, a protein subunit of spliceosomal U2 small nuclear ribonucleoprotein particle (snRNP). Sudemycins are synthetic compounds that harbor a pharmacophore common to various classes of splicing inhibitors. Here, we describe the synthesis and functional characterization of novel sudemycin analogues that functionally probe key chemical groups within this pharmacophore. Our results confirm the importance of a conjugated diene group and in addition reveal significant spatial flexibility in this region of the molecule. Sudemycin K, a derivative that replaces the pharmacophore’s oxycarbonyl by an amide group, displays improved potency as an inhibitor of cancer cell proliferation, as a regulator of alternative splicing in cultured cells and as an inhibitor of in vitro spliceosome assembly. Sudemycin K displays higher stability, likely related to the replacement of the oxycarbonyl group, which can be a substrate of esterases, by an amide group. The activity and special reactivity of sudemycin K can pave the way to the synthesis and evaluation of a variety of novel sudemycin derivatives. Graphic Abstract ACS Electronic Supporting Info

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  4. [해외논문]   Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis   SCIE

    Head, Sarah A. (Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, ) , Shi, Wei Q. (Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, ) , Yang, Eun Ju (Faculty of Health Sciences, University of Macau, Taipa, Macau SAR ) , Nacev, Benjamin A. (Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, ) , Hong, Sam Y. (Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, ) , Pasunooti, Kalyan K. (Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, ) , Li, Ruo-Jing (Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, ) , Shim, Joong Sup (Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, ) , Liu, Jun O. (Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205,)
    ACS chemical biology v.12 no.1 ,pp. 174 - 182 , 2017 , 1554-8929 ,

    초록

    The antifungal drug itraconazole was recently found to exhibit potent antiangiogenic activity and has since been repurposed as an investigational anticancer agent. Itraconazole has been shown to exert its antiangiogenic activity through inhibition of the mTOR signaling pathway, but the molecular mechanism of action was unknown. We recently identified the mitochondrial protein VDAC1 as a target of itraconazole and a mediator of its activation of AMPK, an upstream regulator of mTOR. However, VDAC1 could not account for the previously reported inhibition of cholesterol trafficking by itraconazole, which was also demonstrated to lead to mTOR inhibition. In this study, we demonstrate that cholesterol trafficking inhibition by itraconazole is due to direct inhibition of the lysosomal protein NPC1. We further map the binding site of itraconazole to the sterol-sensing domain of NPC1 using mutagenesis, competition with U18666A, and molecular docking. Finally, we demonstrate that simultaneous AMPK activation and cholesterol trafficking inhibition leads to synergistic inhibition of mTOR, endothelial cell proliferation, and angiogenesis. Graphic Abstract ACS Electronic Supporting Info

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  5. [해외논문]   Disruption of Mycobacterial AftB Results in Complete Loss of Terminal β(1 → 2) Arabinofuranose Residues of Lipoarabinomannan   SCIE

    Jankute, Monika (School of Biosciences, Institute of Microbiology and Infection, University of Birmingham, Edgbaston, B15 2TT Birmingham, ) , Alderwick, Luke J. (School of Biosciences, Institute of Microbiology and Infection, University of Birmingham, Edgbaston, B15 2TT Birmingham, ) , Noack, Stephan (Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich GmbH, Jülich D-52425, ) , Veerapen, Natacha (School of Biosciences, Institute of Microbiology and Infection, University of Birmingham, Edgbaston, B15 2TT Birmingham, ) , Nigou, Jé (Institut de Pharmacologie et de Biologie Structurale, Université) , rô (de Toulouse, CNRS, UPS, 31077 Toulouse, ) , me (School of Biosciences, Institute of Microbiology and Infection, University of Birmingham, Edgbaston, B15 2TT Birmingham,) , Besra, Gurdyal S.
    ACS chemical biology v.12 no.1 ,pp. 183 - 190 , 2017 , 1554-8929 ,

    초록

    Lipoarabinomannan (LAM) and arabinogalactan (AG) are the two major mycobacterial cell wall (lipo)polysaccharides, which contain a structurally similar arabinan domain that is highly branched and assembled in a stepwise fashion by variety of arabinofuranosyltransferases (Ara f T). In addition to playing an essential role in mycobacterial physiology, LAM and its biochemical precursor lipomannan possess potent immunomodulatory activities that affect the host immune response. In the search of additional mycobacterial Ara f Ts that participate in the synthesis of the arabinan segment of LAM, we disrupted aftB ( MSMEG_6400 ) in Mycobacterium smegmatis . The deletion of chromosomal aftB locus could only be achieved in the presence of a rescue plasmid carrying a functional copy of aftB , strongly suggesting that it is essential for the viability of M. smegmatis . Isolation and detailed structural characterization of a LAM molecule derived from the conditional mutant deficient in AftB revealed the absence of terminal β(1 → 2)-linked arabinofuranosyl residues. Furthermore, we demonstrated that truncated LAM displays proinflammatory activity, which is due to its ability to activate Toll-like receptor 2. All together, our results indicate that AftB is an essential mycobacterial Ara f T that plays a role in the synthesis of the arabinan domain of LAM. Graphic Abstract ACS Electronic Supporting Info

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  6. [해외논문]   Observing Biosynthetic Activity Utilizing Next Generation Sequencing and the DNA Linked Enzyme Coupled Assay   SCIE

    Raad, Markus de , Modavi, Cyrus , Sukovich, David J. , Anderson, J. Christopher
    ACS chemical biology v.12 no.1 ,pp. 191 - 199 , 2017 , 1554-8929 ,

    초록

    Currently, the identification of new genes drastically outpaces current experimental methods for determining their enzymatic function. This disparity necessitates the development of high-throughput techniques that operate with the same scalability as modern gene synthesis and sequencing technologies. In this paper, we demonstrate the versatility of the recently reported DNA-Linked Enzyme-Coupled Assay (DLEnCA) and its ability to support high-throughput data acquisition through next-generation sequencing (NGS). Utilizing methyltransferases, we highlight DLEnCA’s ability to rapidly profile an enzyme’s substrate specificity, determine relative enzyme kinetics, detect biosynthetic formation of a target molecule, and its potential to benefit from the scales and standardization afforded by NGS. This improved methodology minimizes the effort in acquiring biosynthetic knowledge by tying biochemical techniques to the rapidly evolving abilities in sequencing and synthesizing DNA. Graphic Abstract ACS Electronic Supporting Info

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  7. [해외논문]   Live Cell Imaging of Endogenous mRNA Using RNA-Based Fluorescence “Turn-On” Probe   SCIE

    Ong, Wei Qiang (Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94143, ) , Citron, Y. Rose (Graduate Program of Biophysics, University of California, San Francisco, San Francisco, California 94143, ) , Sekine, Sayaka (Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94143, ) , Huang, Bo (Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94143,)
    ACS chemical biology v.12 no.1 ,pp. 200 - 205 , 2017 , 1554-8929 ,

    초록

    Messenger RNA (mRNA) plays a critical role in cellular growth and development. However, there have been limited methods available to visualize endogenous mRNA in living cells with ease. We have designed RNA-based fluorescence “turn-on” probes that target mRNA by fusing an unstable form of Spinach with target-complementary sequences. These probes have been demonstrated to be selective, stable, and capable of targeting various mRNAs for live E. coli imaging. Graphic Abstract ACS Electronic Supporting Info

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  8. [해외논문]   Catalytic Promiscuity of O-GlcNAc Transferase Enables Unexpected Metabolic Engineering of Cytoplasmic Proteins with 2-Azido-2-deoxy-glucose   SCIE

    Shen, David L. (Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ) , Liu, Ta-Wei (Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ) , Zandberg, Wesley (Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ) , Clark, Tom (Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ) , Eskandari, Razieh (Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ) , Alteen, Matthew G. (Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ) , Tan, Hong Yee (Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ) , Zhu, Yanping (Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ) , Cecioni, Samy (Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, ) , Vocadlo, David (Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6,)
    ACS chemical biology v.12 no.1 ,pp. 206 - 213 , 2017 , 1554-8929 ,

    초록

    O -GlcNAc transferase (OGT) catalyzes the installation of N -acetylglucosamine (GlcNAc) O -linked to nucleocytoplasmic proteins ( O -GlcNAc) within multicellular eukaryotes. OGT shows surprising tolerance for structural changes in the sugar component of its nucleotide sugar donor substrate, uridine diphosphate N -acetylglucosamine (UDP-GlcNAc). Here, we find that OGT uses UDP-glucose to install O -linked glucose ( O -Glc) onto proteins only 25-fold less efficiently than O -GlcNAc. Spurred by this observation, we show that OGT transfers 2-azido-2-deoxy- d -glucose (GlcAz) in vitro from UDP-GlcAz to proteins. Further, feeding cells with per- O -acetyl GlcAz (AcGlcAz), in combination with inhibition or inducible knockout of OGT, shows OGT-dependent modification of nuclear and cytoplasmic proteins with O -GlcAz as detected using microscopy, immunoblot, and proteomics. We find that O -GlcAz is reversible within cells, and an unidentified cellular enzyme exists to cleave O -Glc that can also process O -GlcAz. We anticipate that AcGlcAz will prove to be a useful tool to study the O -GlcNAc modification. We also speculate that, given the high concentration of UDP-Glc within certain mammalian tissues, O -Glc may exist within mammals and serve as a physiologically relevant modification. Graphic Abstract ACS Electronic Supporting Info

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  9. [해외논문]   A Chemical Biology Solution to Problems with Studying Biologically Important but Unstable 9-O-Acetyl Sialic Acids   SCIE

    Khedri, Zahra (Glycobiology Research and Training Center, University of California, San Diego, California 92093, ) , Xiao, An (Department of Chemistry, University of California, Davis, California 95616, ) , Yu, Hai (Department of Chemistry, University of California, Davis, California 95616, ) , Landig, Corinna Susanne (Glycobiology Research and Training Center, University of California, San Diego, California 92093, ) , Li, Wanqing (Department of Chemistry, University of California, Davis, California 95616, ) , Diaz, Sandra (Glycobiology Research and Training Center, University of California, San Diego, California 92093, ) , Wasik, Brian R. (Department of Microbiology and Immunology, Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, ) , Parrish, Colin R. (Department of Microbiology and Immunology, Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, ) , Wang, Lee-Ping (Department of Chemistry, University of California, Davis, California 95616, ) , Varki, Ajit (Glycobiology Research and Training Center, University of California, San Die) , Chen, Xi
    ACS chemical biology v.12 no.1 ,pp. 214 - 224 , 2017 , 1554-8929 ,

    초록

    9-O-Acetylation is a common natural modification on sialic acids (Sias) that terminate many vertebrate glycan chains. This ester group has striking effects on many biological phenomena, including microbe-host interactions, complement action, regulation of immune responses, sialidase action, cellular apoptosis, and tumor immunology. Despite such findings, 9-O-acetyl sialoglycoconjugates have remained largely understudied, primarily because of marked lability of the 9-O-acetyl group to even small pH variations and/or the action of mammalian or microbial esterases. Our current studies involving 9-O-acetylated sialoglycans on glycan microarrays revealed that even the most careful precautions cannot ensure complete stability of the 9-O-acetyl group. We now demonstrate a simple chemical biology solution to many of these problems by substituting the oxygen atom in the ester with a nitrogen atom, resulting in sialic acids with a chemically and biologically stable 9-N-acetyl group. We present an efficient one-pot multienzyme method to synthesize a sialoglycan containing 9-acetamido-9-deoxy- N -acetylneuraminic acid (Neu5Ac9NAc) and compare it to the one with naturally occurring 9- O -acetyl- N -acetylneuraminic acid (Neu5,9Ac 2 ). Conformational resemblance of the two molecules was confirmed by computational molecular dynamics simulations. Microarray studies showed that the Neu5Ac9NAc-sialoglycan is a ligand for viruses naturally recognizing Neu5,9Ac 2 , with a similar affinity but with much improved stability in handling and study. Feeding of Neu5Ac9NAc or Neu5,9Ac 2 to mammalian cells resulted in comparable incorporation and surface expression as well as binding to 9-O-acetyl-Sia-specific viruses. However, cells fed with Neu5Ac9NAc remained resistant to viral esterases and showed a slower turnover. This simple approach opens numerous research opportunities that have heretofore proved intractable. Graphic Abstract ACS Electronic Supporting Info

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  10. [해외논문]   Elucidating the Origin of Long Residence Time Binding for Inhibitors of the Metalloprotease Thermolysin   SCIE

    Cramer, Jonathan (Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, 35032 Marburg, ) , Krimmer, Stefan G. (Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, 35032 Marburg, ) , Fridh, Veronica (GE Healthcare Bio-Sciences AB, SE-751 84 Uppsala, ) , Wulsdorf, Tobias (Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, 35032 Marburg, ) , Karlsson, Robert (GE Healthcare Bio-Sciences AB, SE-751 84 Uppsala, ) , Heine, Andreas (Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, 35032 Marburg, ) , Klebe, Gerhard (Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, 35032 Marburg,)
    ACS chemical biology v.12 no.1 ,pp. 225 - 233 , 2017 , 1554-8929 ,

    초록

    Kinetic parameters of protein–ligand interactions are progressively acknowledged as valuable information for rational drug discovery. However, a targeted optimization of binding kinetics is not easy to achieve, and further systematic studies are necessary to increase the understanding about molecular mechanisms involved. We determined association and dissociation rate constants for 17 inhibitors of the metalloprotease thermolysin by surface plasmon resonance spectroscopy and correlated kinetic data with high-resolution crystal structures in complex with the protein. From the structure–kinetics relationship, we conclude that the strength of interaction with Asn112 correlates with the rate-limiting step of dissociation. This residue is located at the beginning of a β-strand motif that lines the binding cleft and is commonly believed to align a substrate for catalysis. A reduced mobility of the Asn112 side chain owing to an enhanced engagement in charge-assisted hydrogen bonds prevents the conformational adjustment associated with ligand release and transformation of the enzyme to its open state. This hypothesis is supported by kinetic data of ZF P LA, a known pseudopeptidic inhibitor of thermolysin, which blocks the conformational transition of Asn112. Interference with this retrograde induced-fit mechanism results in variation of the residence time of thermolysin inhibitors by a factor of 74 000. The high conservation of this structural motif within the M4 and M13 metalloprotease families underpins the importance of this feature and has significant implications for drug discovery. Graphic Abstract ACS Electronic Supporting Info

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