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ACS chemical biology 37건

  1. [해외논문]   High-throughput Identification of DNA-Encoded IgG Ligands that Distinguish Active and Latent Mycobacterium tuberculosis Infections   SCIE

    Mendes, Kimberly R. (Opko Health, Inc., 5353 Parkside Drive Jupiter, Florida 33458, ) , Malone, Marie Lynne (Opko Health, Inc., 5353 Parkside Drive Jupiter, Florida 33458, ) , Ndungu, John Maina (Opko Health, Inc., 5353 Parkside Drive Jupiter, Florida 33458, ) , Suponitsky-Kroyter, Irena (Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical TB Research/Medical Research Council Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, ) , Cavett, Valerie J. (Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical TB Research/Medical Research Council Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, ) , McEnaney, Patrick J. (Opko Health, Inc., 5353 Parkside Drive Jupiter, Florida 33458, ) , MacConnell, Andrew B. (Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical TB Research/Medi) , Doran, Todd. M. , Ronacher, Katharina , Stanley, Kim , Utset, Ofelia , Walzl, Gerhard , Paegel, Brian M. , Kodadek, Thomas
    ACS chemical biology v.12 no.1 ,pp. 234 - 243 , 2017 , 1554-8929 ,

    초록

    The circulating antibody repertoire encodes a patient’s health status and pathogen exposure history, but identifying antibodies with diagnostic potential usually requires knowledge of the antigen(s). We previously circumvented this problem by screening libraries of bead-displayed small molecules against case and control serum samples to discover “epitope surrogates” (ligands of IgGs enriched in the case sample). Here, we describe an improved version of this technology that employs DNA-encoded libraries and high-throughput FACS-based screening to discover epitope surrogates that differentiate noninfectious/latent (LTB) patients from infectious/active TB (ATB) patients, which is imperative for proper treatment selection and antibiotic stewardship. Normal control/LTB (10 patients each, NCL) and ATB (10 patients) serum pools were screened against a library (5 × 10 6 beads, 448 000 unique compounds) using fluorescent antihuman IgG to label hit compound beads for FACS. Deep sequencing decoded all hit structures and each hit’s occurrence frequencies. ATB hits were pruned of NCL hits and prioritized for resynthesis based on occurrence and homology. Several structurally homologous families were identified and 16/21 resynthesized representative hits validated as selective ligands of ATB serum IgGs ( p E. coli recombinant form) competed with one of the validated ligands for binding to antibodies, suggesting that it mimics a native Ag85B epitope. The use of DNA-encoded libraries and FACS-based screening in epitope surrogate discovery reveals thousands of potential hit structures. Distilling this list down to several consensus chemical structures yielded a diagnostic panel for ATB composed of thermally stable and economically produced small molecule ligands in place of protein antigens. Graphic Abstract ACS Electronic Supporting Info

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

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  2. [해외논문]   Transformation of the Non-Selective Aminocyclohexanol-Based Hsp90 Inhibitor into a Grp94-Seletive Scaffold   SCIE

    Mishra, Sanket J. (Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas, ) , Ghosh, Suman (Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas, ) , Stothert, Andrew R. (Department of Molecular Medicine and Byrd Alzheiemer's Research Institute, University of South Florida, Tampa, Florida 33613, ) , Dickey, Chad A. (Department of Molecular Medicine and Byrd Alzheiemer's Research Institute, University of South Florida, Tampa, Florida 33613, ) , Blagg, Brian S. J. (Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas,)
    ACS chemical biology v.12 no.1 ,pp. 244 - 253 , 2017 , 1554-8929 ,

    초록

    Glucose regulated protein 94 kDa, Grp94, is the endoplasmic reticulum (ER) localized isoform of heat shock protein 90 (Hsp90) that is responsible for the trafficking and maturation of toll-like receptors, immunoglobulins, and integrins. As a result, Grp94 has emerged as a therapeutic target to disrupt cellular communication, adhesion, and tumor proliferation, potentially with fewer side effects compared to pan -inhibitors of all Hsp90 isoforms. Although, the N-terminal ATP binding site is highly conserved among all four Hsp90 isoforms, recent cocrystal structures of Grp94 have revealed subtle differences between Grp94 and other Hsp90 isoforms that has been exploited for the development of Grp94-selective inhibitors. In the current study, a structure-based approach has been applied to a Grp94 nonselective compound, SNX 2112, which led to the development of 8j ( ACO1 ), a Grp94-selective inhibitor that manifests ∼440 nM affinity and >200-fold selectivity against cytosolic Hsp90 isoforms. Graphic Abstract ACS Electronic Supporting Info

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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  3. [해외논문]   LSD1 Substrate Binding and Gene Expression Are Affected by HDAC1-Mediated Deacetylation   SCIE

    Nalawansha, Dhanusha A. , Pflum, Mary Kay H.
    ACS chemical biology v.12 no.1 ,pp. 254 - 264 , 2017 , 1554-8929 ,

    초록

    Lysine Specific Demethylase 1 (LSD1) catalyzes the demethylation of histone 3 to regulate gene expression. With a fundamental role in gene regulation, LSD1 is involved in multiple cellular processes, including embryonic development, cell proliferation, and metastasis. Significantly, LSD1 is overexpressed in multiple cancers and has emerged as a potential anticancer drug target. LSD1 is typically found in association with another epigenetic enzyme, histone deacetylase (HDAC). HDAC and LSD1 inhibitor compounds have been tested as combination anticancer agents. However, the functional link between LSD1 and HDAC has yet to be understood in detail. Here, we used a substrate trapping strategy to identify cellular substrates of HDAC1. Using inactive HDAC1 mutants, we identified LSD1 as an HDAC1 substrate. HDAC1 mediated deacetylation of LSD1 at K374 in the substrate binding lobe, which affected the histone 3 binding and gene expression activity of LSD1. The mechanistic link between HDAC1 and LSD1 established here suggests that HDAC inhibitors influence LSD1 activity, which will ultimately guide drug design targeting epigenetic enzymes. Graphic Abstract ACS Electronic Supporting Info

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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  4. [해외논문]   Lipidomics Characterization of Biosynthetic and Remodeling Pathways of Cardiolipins in Genetically and Nutritionally Manipulated Yeast Cells   SCIE

    Tyurina, Yulia Y. (Department of Biological Sciences, Wayne State University, Detroit, Michigan, ) , Lou, Wenjia (Thomas C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, Maryland, ) , Qu, Feng (Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, ) , Tyurin, Vladimir A (Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan, ) , Mohammadyani, Dariush (Department of Biological Sciences, Wayne State University, Detroit, Michigan,) , Liu, Jenney , Hü , ttemann, Maik , Frasso, Michael A. , Wipf, Peter , Bayir, Hü , lya , Greenberg, Miriam. L. , Kagan, Valerian E.
    ACS chemical biology v.12 no.1 ,pp. 265 - 281 , 2017 , 1554-8929 ,

    초록

    Cardioipins (CLs) are unique tetra-acylated phospholipids of mitochondria and define the bioenergetics and regulatory functions of these organelles. An unresolved paradox is the high uniformity of CL molecular species (tetra-linoleoyl-CL) in the heart, liver, and skeletal musclesin contrast to their high diversification in the brain. Here, we combined liquid chromatography–mass-spectrometry-based phospholipidomics with genetic and nutritional manipulations to explore CLs’ biosynthetic vs postsynthetic remodeling processes in S. cerevisiae yeast cells. By applying the differential phospholipidomics analysis, we evaluated the contribution of Cld1 (CL-specific phospholipase A) and Taz1 (acyl-transferase) as the major regulatory mechanisms of the remodeling process. We further established that nutritional “pressure” by high levels of free fatty acids triggered a massive synthesis of homoacylated molecular species in all classes of phospholipids, resulting in the preponderance of the respective homoacylated CLs. We found that changes in molecular speciation of CLs induced by exogenous C18-fatty acids (C18:1 and C18:2) in wild-type (wt) cells did not occur in any of the remodeling mutant cells, including cld1Δ , taz1Δ , and cld1Δtaz1Δ . Interestingly, molecular speciation of CLs in wt and double mutant cells cld1Δtaz1Δ was markedly different. Given that the bioenergetics functions are preserved in the double mutant, this suggests that the accumulated MLCLrather than the changed CL speciationare the likely major contributors to the mitochondrial dysfunction in taz1Δ mutant cells (also characteristic of Barth syndrome). Biochemical studies of Cld1 specificity and computer modeling confirmed the hydrolytic selectivity of the enzyme toward C16-CL substrates and the preservation of C18:1-containing CL species. Graphic Abstract ACS Electronic Supporting Info

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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  5. [해외논문]   Internal Structure and Preferential Protein Binding of Colloidal Aggregates   SCIE

    Duan, Da (Department of Pharmaceutical Chemistry & Quantitative Biology Institute, University of California, San Francisco, 1700 Fourth Street, San Francisco, California 94158-2550, ) , Torosyan, Hayarpi (Department of Pharmaceutical Chemistry & Quantitative Biology Institute, University of California, San Francisco, 1700 Fourth Street, San Francisco, California 94158-2550, ) , Elnatan, Daniel (Howard Hughes Medical Institute and the Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94158, ) , McLaughlin, Christopher K. (Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario, ) , Logie, Jennifer (Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario, ) , Shoichet, Molly S. (Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario, ) , Agard, David A. (Howard Hughes Medical Institute and the Department of Biochemistry and Biophysics, University of California, San Francisco, San Fr) , Shoichet, Brian K.
    ACS chemical biology v.12 no.1 ,pp. 282 - 290 , 2017 , 1554-8929 ,

    초록

    Colloidal aggregates of small molecules are the most common artifact in early drug discovery, sequestering and inhibiting target proteins without specificity. Understanding their structure and mechanism has been crucial to developing tools to control for, and occasionally even exploit, these particles. Unfortunately, their polydispersity and transient stability have prevented exploration of certain elementary properties, such as how they pack. Dye-stabilized colloidal aggregates exhibit enhanced homogeneity and stability when compared to conventional colloidal aggregates, enabling investigation of some of these properties. By small-angle X-ray scattering and multiangle light scattering, pair distance distribution functions suggest that the dye-stabilized colloids are filled, not hollow, spheres. Stability of the coformulated colloids enabled investigation of their preference for binding DNA, peptides, or folded proteins, and their ability to purify one from the other. The coformulated colloids showed little ability to bind DNA. Correspondingly, the colloids preferentially sequestered protein from even a 1600-fold excess of peptides that are themselves the result of a digest of the same protein. This may reflect the avidity advantage that a protein has in a surface-to-surface interaction with the colloids. For the first time, colloids could be shown to have preferences of up to 90-fold for particular proteins over others. Loaded onto the colloids, bound enzyme could be spun down, resuspended, and released back into buffer, regaining most of its activity. Implications of these observations for colloid mechanisms and utility will be considered. Graphic Abstract ACS Electronic Supporting Info

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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  6. [해외논문]   Engineering Cyclohexanone Monooxygenase for the Production of Methyl Propanoate   SCIE

    van Beek, Hugo L. , Romero, Elvira , Fraaije, Marco W.
    ACS chemical biology v.12 no.1 ,pp. 291 - 299 , 2017 , 1554-8929 ,

    초록

    A previous study showed that cyclohexanone monooxygenase from Acinetobacter calcoaceticus (AcCHMO) catalyzes the Baeyer–Villiger oxidation of 2-butanone, yielding ethyl acetate and methyl propanoate as products. Methyl propanoate is of industrial interest as a precursor of acrylic plastic. Here, various residues near the substrate and NADP + binding sites in AcCHMO were subjected to saturation mutagenesis to enhance both the activity on 2-butanone and the regioselectivity toward methyl propanoate. The resulting libraries were screened using whole cell biotransformations, and headspace gas chromatography–mass spectrometry was used to identify improved AcCHMO variants. This revealed that the I491A AcCHMO mutant exhibits a significant improvement over the wild type enzyme in the desired regioselectivity using 2-butanone as a substrate (40% vs 26% methyl propanoate, respectively). Another interesting mutant is the T56S AcCHMO mutant, which exhibits a higher conversion yield (92%) and k cat (0.5 s –1 ) than wild type AcCHMO (52% and 0.3 s –1 , respectively). Interestingly, the uncoupling rate for the T56S AcCHMO mutant is also significantly lower than that for the wild type enzyme. The T56S/I491A double mutant combined the beneficial effects of both mutations leading to higher conversion and improved regioselectivity. This study shows that even for a relatively small aliphatic substrate (2-butanone), catalytic efficiency and regioselectivity can be tuned by structure-inspired enzyme engineering. Graphic Abstract ACS Electronic Supporting Info

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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  7. [해외논문]   SIRT7 Is an RNA-Activated Protein Lysine Deacylase   SCIE

    Tong, Zhen (Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, ) , Wang, Miao (Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, ) , Wang, Yi (School of Biomedical Sciences, University of Hong Kong, 21 Sassoon Road, Hong Kong, ) , Kim, David D. (Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, ) , Grenier, Jennifer K. (RNA Sequencing Core, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, ) , Cao, Ji (Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, ) , Sadhukhan, Sushabhan (Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, ) , Hao, Quan (School of Biomedical Sciences, University of Hong Kong, 21 Sassoon Road, Hong Kong, ) , Lin, Hening (Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithac)
    ACS chemical biology v.12 no.1 ,pp. 300 - 310 , 2017 , 1554-8929 ,

    초록

    Mammalian SIRT7 is a member of the sirtuin family that regulates multiple biological processes including genome stability, metabolic pathways, stress responses, and tumorigenesis. SIRT7 has been shown to be important for ribosome biogenesis and transcriptional regulation. SIRT7 knockout mice exhibit complications associated with fatty liver and increased aging in hematopoietic stem cells. However, the molecular basis for its biological function remains unclear, in part due to the lack of efficient enzymatic activity in vitro . Previously, we have demonstrated that double-stranded DNA could activate SIRT7’s deacetylase activity in vitro , allowing it to deacetylate H3K18 in the context of chromatin. Here, we show that RNA can increase the catalytic efficiency of SIRT7 even better and that SIRT7 can remove long chain fatty acyl groups more efficiently than removing acetyl groups. Truncation and mutagenesis studies revealed residues at both the amino and carboxyl termini of SIRT7 that are involved in RNA-binding and important for activity. RNA immunoprecipitation-sequencing (RIP-seq) identified ribosomal RNA (rRNA) as the predominant RNA binding partner of SIRT7. The associated RNA was able to effectively activate the deacetylase and defatty-acylase activities of SIRT7. Knockdown of SIRT7 increased the lysine fatty acylation of several nuclear proteins based on metabolic labeling with an alkyne-tagged fatty acid analog, supporting that the defatty-acylase activity of SIRT7 is physiologically relevant. These findings provide important insights into the biological functions of SIRT7, as well as an improved platform to develop SIRT7 modulators. Graphic Abstract ACS Electronic Supporting Info

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

    NDSL에서는 해당 원문을 복사서비스하고 있습니다. 아래의 원문복사신청 또는 장바구니담기를 통하여 원문복사서비스 이용이 가능합니다.

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