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Nature Chemical Biology

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https://www.readbyqxmd.com/read/28192414/selective-in-vivo-metabolic-cell-labeling-mediated-cancer-targeting
#1
Hua Wang, Ruibo Wang, Kaimin Cai, Hua He, Yang Liu, Jonathan Yen, Zhiyu Wang, Ming Xu, Yiwen Sun, Xin Zhou, Qian Yin, Li Tang, Iwona T Dobrucki, Lawrence W Dobrucki, Eric J Chaney, Stephen A Boppart, Timothy M Fan, Stéphane Lezmi, Xuesi Chen, Lichen Yin, Jianjun Cheng
Distinguishing cancer cells from normal cells through surface receptors is vital for cancer diagnosis and targeted therapy. Metabolic glycoengineering of unnatural sugars provides a powerful tool to manually introduce chemical receptors onto the cell surface; however, cancer-selective labeling still remains a great challenge. Herein we report the design of sugars that can selectively label cancer cells both in vitro and in vivo. Specifically, we inhibit the cell-labeling activity of tetraacetyl-N-azidoacetylmannosamine (Ac4ManAz) by converting its anomeric acetyl group to a caged ether bond that can be selectively cleaved by cancer-overexpressed enzymes and thus enables the overexpression of azido groups on the surface of cancer cells...
February 13, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28192413/evolution-of-a-split-rna-polymerase-as-a-versatile-biosensor-platform
#2
Jinyue Pu, Julia Zinkus-Boltz, Bryan C Dickinson
Biosensors that transduce target chemical and biochemical inputs into genetic outputs are essential for bioengineering and synthetic biology. Current biosensor design strategies are often limited by a low signal-to-noise ratio, the extensive optimization required for each new input, and poor performance in mammalian cells. Here we report the development of a proximity-dependent split RNA polymerase (RNAP) as a general platform for biosensor engineering. After discovering that interactions between fused proteins modulate the assembly of a split T7 RNAP, we optimized the split RNAP components for protein-protein interaction detection by phage-assisted continuous evolution (PACE)...
February 13, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28192412/akap-mediated-feedback-control-of-camp-gradients-in-developing-hippocampal-neurons
#3
Kirill Gorshkov, Sohum Mehta, Santosh Ramamurthy, Gabriele V Ronnett, Feng-Quan Zhou, Jin Zhang
Cyclic AMP (cAMP) and protein kinase A (PKA), classical examples of spatially compartmentalized signaling molecules, are critical axon determinants that regulate neuronal polarity and axon formation, yet little is known about micro-compartmentalization of cAMP and PKA signaling and its role in developing neurons. Here, we revealed that cAMP forms a gradient in developing hippocampal neurons, with higher cAMP levels in more distal regions of the axon compared to other regions of the cell. Interestingly, this cAMP gradient changed according to the developmental stage and depended on proper anchoring of PKA by A-kinase anchoring proteins (AKAPs)...
February 13, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28192411/the-glcn6p-cofactor-plays-multiple-catalytic-roles-in-the-glms-ribozyme
#4
Jamie L Bingaman, Sixue Zhang, David R Stevens, Neela H Yennawar, Sharon Hammes-Schiffer, Philip C Bevilacqua
RNA enzymes (ribozymes) have remarkably diverse biological roles despite having limited chemical diversity. Protein enzymes enhance their reactivity through recruitment of cofactors; likewise, the naturally occurring glmS ribozyme uses the glucosamine-6-phosphate (GlcN6P) organic cofactor for phosphodiester bond cleavage. Prior structural and biochemical studies have implicated GlcN6P as the general acid. Here we describe new catalytic roles of GlcN6P through experiments and calculations. Large stereospecific normal thio effects and a lack of metal-ion rescue in the holoribozyme indicate that nucleobases and the cofactor play direct chemical roles and align the active site for self-cleavage...
February 13, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28192410/an-orthogonalized-platform-for-genetic-code-expansion-in-both-bacteria-and-eukaryotes
#5
James S Italia, Partha Sarathi Addy, Chester J J Wrobel, Lisa A Crawford, Marc J Lajoie, Yunan Zheng, Abhishek Chatterjee
In this study, we demonstrate the feasibility of expanding the genetic code of Escherichia coli using its own tryptophanyl-tRNA synthetase and tRNA (TrpRS-tRNA(Trp)) pair. This was made possible by first functionally replacing this endogenous pair with an E. coli-optimized counterpart from Saccharomyces cerevisiae, and then reintroducing the liberated E. coli TrpRS-tRNA(Trp) pair into the resulting strain as a nonsense suppressor, which was then followed by its directed evolution to genetically encode several new unnatural amino acids (UAAs)...
February 13, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28166210/a-water-mediated-allosteric-network-governs-activation-of-aurora-kinase-a
#6
Soreen Cyphers, Emily F Ruff, Julie M Behr, John D Chodera, Nicholas M Levinson
The catalytic activity of many protein kinases is controlled by conformational changes of a conserved Asp-Phe-Gly (DFG) motif. We used an infrared probe to track the DFG motif of the mitotic kinase Aurora A (AurA) and found that allosteric activation by the spindle-associated protein Tpx2 involves an equilibrium shift toward the active DFG-in state. Förster resonance energy transfer experiments show that the activation loop undergoes a nanometer-scale movement that is tightly coupled to the DFG equilibrium...
February 6, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28166209/a-tight-tunable-range-for-ni-ii-sensing-and-buffering-in-cells
#7
Andrew W Foster, Rafael Pernil, Carl J Patterson, Andrew J P Scott, Lars-Olof Pålsson, Robert Pal, Ian Cummins, Peter T Chivers, Ehmke Pohl, Nigel J Robinson
The metal affinities of metal-sensing transcriptional regulators co-vary with cellular metal concentrations over more than 12 orders of magnitude. To understand the cause of this relationship, we determined the structure of the Ni(II) sensor InrS and then created cyanobacteria (Synechocystis PCC 6803) in which transcription of genes encoding a Ni(II) exporter and a Ni(II) importer were controlled by InrS variants with weaker Ni(II) affinities. Variant strains were sensitive to elevated nickel and contained more nickel, but the increase was small compared with the change in Ni(II) affinity...
February 6, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28166208/in-vitro-reconstitution-demonstrates-the-cell-wall-ligase-activity-of-lcp-proteins
#8
Kaitlin Schaefer, Leigh M Matano, Yuan Qiao, Daniel Kahne, Suzanne Walker
Sacculus is a peptidoglycan (PG) matrix that protects bacteria from osmotic lysis. In Gram-positive organisms, the sacculus is densely functionalized with glycopolymers important for survival, but the way in which assembly occurs is not known. In Staphylococcus aureus, three LCP (LytR-CpsA-Psr) family members have been implicated in attaching the major glycopolymer wall teichoic acid (WTA) to PG, but ligase activity has not been demonstrated for these or any other LCP proteins. Using WTA and PG substrates produced chemoenzymatically, we show that all three proteins can transfer WTA precursors to nascent PGs, establishing that LCP proteins are PG-glycopolymer ligases...
February 6, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28166207/structure-and-specificity-of-a-permissive-bacterial-c-prenyltransferase
#9
Sherif I Elshahawi, Hongnan Cao, Khaled A Shaaban, Larissa V Ponomareva, Thangaiah Subramanian, Mark L Farman, H Peter Spielmann, George N Phillips, Jon S Thorson, Shanteri Singh
This study highlights the biochemical and structural characterization of the L-tryptophan C6 C-prenyltransferase (C-PT) PriB from Streptomyces sp. RM-5-8. PriB was found to be uniquely permissive to a diverse array of prenyl donors and acceptors including daptomycin. Two additional PTs also produced novel prenylated daptomycins with improved antibacterial activities over the parent drug.
February 6, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28135238/chromatin-biology-breaking-into-the-prc2-cage
#10
Daniel Holoch, Raphaël Margueron
No abstract text is available yet for this article.
January 30, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28135237/the-eed-protein-protein-interaction-inhibitor-a-395-inactivates-the-prc2-complex
#11
Yupeng He, Sujatha Selvaraju, Michael L Curtin, Clarissa G Jakob, Haizhong Zhu, Kenneth M Comess, Bailin Shaw, Juliana The, Evelyne Lima-Fernandes, Magdalena M Szewczyk, Dong Cheng, Kelly L Klinge, Huan-Qiu Li, Marina Pliushchev, Mikkel A Algire, David Maag, Jun Guo, Justin Dietrich, Sanjay C Panchal, Andrew M Petros, Ramzi F Sweis, Maricel Torrent, Lance J Bigelow, Guillermo Senisterra, Fengling Li, Steven Kennedy, Qin Wu, Donald J Osterling, David J Lindley, Wenqing Gao, Scott Galasinski, Dalia Barsyte-Lovejoy, Masoud Vedadi, Fritz G Buchanan, Cheryl H Arrowsmith, Gary G Chiang, Chaohong Sun, William N Pappano
Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2...
January 30, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28135236/hts-compatible-fret-based-conformational-sensors-clarify-membrane-receptor-activation
#12
Pauline Scholler, David Moreno-Delgado, Nathalie Lecat-Guillet, Etienne Doumazane, Carine Monnier, Fabienne Charrier-Savournin, Ludovic Fabre, Cédric Chouvet, Stéphanie Soldevila, Laurent Lamarque, Geoffrey Donsimoni, Thomas Roux, Jurriaan M Zwier, Eric Trinquet, Philippe Rondard, Jean-Philippe Pin
Cell surface receptors represent a vast majority of drug targets. Efforts have been conducted to develop biosensors reporting their conformational changes in live cells for pharmacological and functional studies. Although Förster resonance energy transfer (FRET) appears to be an ideal approach, its use is limited by the low signal-to-noise ratio. Here we report a toolbox composed of a combination of labeling technologies, specific fluorophores compatible with time-resolved FRET and a novel method to quantify signals...
January 30, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28135235/an-allosteric-prc2-inhibitor-targeting-the-h3k27me3-binding-pocket-of-eed
#13
Wei Qi, Kehao Zhao, Justin Gu, Ying Huang, Youzhen Wang, Hailong Zhang, Man Zhang, Jeff Zhang, Zhengtian Yu, Ling Li, Lin Teng, Shannon Chuai, Chao Zhang, Mengxi Zhao, HoMan Chan, Zijun Chen, Douglas Fang, Qi Fei, Leying Feng, Lijian Feng, Yuan Gao, Hui Ge, Xinjian Ge, Guobin Li, Andreas Lingel, Ying Lin, Yueqin Liu, Fangjun Luo, Minlong Shi, Long Wang, Zhaofu Wang, Yanyan Yu, Jue Zeng, Chenhui Zeng, Lijun Zhang, Qiong Zhang, Shaolian Zhou, Counde Oyang, Peter Atadja, En Li
Polycomb repressive complex 2 (PRC2) consists of three core subunits, EZH2, EED and SUZ12, and plays pivotal roles in transcriptional regulation. The catalytic subunit EZH2 methylates histone H3 lysine 27 (H3K27), and its activity is further enhanced by the binding of EED to trimethylated H3K27 (H3K27me3). Small-molecule inhibitors that compete with the cofactor S-adenosylmethionine (SAM) have been reported. Here we report the discovery of EED226, a potent and selective PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED...
January 30, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28114276/enzyme-catalyzed-cationic-epoxide-rearrangements-in-quinolone-alkaloid-biosynthesis
#14
Yi Zou, Marc Garcia-Borràs, Mancheng C Tang, Yuichiro Hirayama, Dehai H Li, Li Li, Kenji Watanabe, K N Houk, Yi Tang
Epoxides are highly useful synthons and biosynthons for the construction of complex natural products during total synthesis and biosynthesis, respectively. Among enzyme-catalyzed epoxide transformations, a reaction that is notably missing, in regard to the synthetic toolbox, is cationic rearrangement that takes place under strong acid. This is a challenging transformation for enzyme catalysis, as stabilization of the carbocation intermediate upon epoxide cleavage is required. Here, we discovered two Brønsted acid enzymes that can catalyze two unprecedented epoxide transformations in biology...
March 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28114275/redox-regulation-taking-aktion-on-hnes
#15
Eranthie Weerapana
No abstract text is available yet for this article.
March 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28114274/akt3-is-a-privileged-first-responder-in-isozyme-specific-electrophile-response
#16
Marcus J C Long, Saba Parvez, Yi Zhao, Sanjna L Surya, Yiran Wang, Sheng Zhang, Yimon Aye
Isozyme-specific post-translational regulation fine tunes signaling events. However, redundancy in sequence or activity renders links between isozyme-specific modifications and downstream functions uncertain. Methods to study this phenomenon are underdeveloped. Here we use a redox-targeting screen to reveal that Akt3 is a first-responding isozyme sensing native electrophilic lipids. Electrophile modification of Akt3 modulated downstream pathway responses in cells and Danio rerio (zebrafish) and markedly differed from Akt2-specific oxidative regulation...
March 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28114273/the-suv4-20-inhibitor-a-196-verifies-a-role-for-epigenetics-in-genomic-integrity
#17
Kenneth D Bromberg, Taylor R H Mitchell, Anup K Upadhyay, Clarissa G Jakob, Manisha A Jhala, Kenneth M Comess, Loren M Lasko, Conglei Li, Creighton T Tuzon, Yujia Dai, Fengling Li, Mohammad S Eram, Alexander Nuber, Niru B Soni, Vlasios Manaves, Mikkel A Algire, Ramzi F Sweis, Maricel Torrent, Gunnar Schotta, Chaohong Sun, Michael R Michaelides, Alex R Shoemaker, Cheryl H Arrowsmith, Peter J Brown, Vijayaratnam Santhakumar, Alberto Martin, Judd C Rice, Gary G Chiang, Masoud Vedadi, Dalia Barsyte-Lovejoy, William N Pappano
Protein lysine methyltransferases (PKMTs) regulate diverse physiological processes including transcription and the maintenance of genomic integrity. Genetic studies suggest that the PKMTs SUV420H1 and SUV420H2 facilitate proficient nonhomologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation (me2 and me3, respectively) of lysine 20 on histone 4 (H4K20). Here we report the identification of A-196, a potent and selective inhibitor of SUV420H1 and SUV420H2. Biochemical and co-crystallization analyses demonstrate that A-196 is a substrate-competitive inhibitor of both SUV4-20 enzymes...
March 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28092361/designed-cell-consortia-as-fragrance-programmable-analog-to-digital-converters
#18
Marius Müller, Simon Ausländer, Andrea Spinnler, David Ausländer, Julian Sikorski, Marc Folcher, Martin Fussenegger
Synthetic biology advances the rational engineering of mammalian cells to achieve cell-based therapy goals. Synthetic gene networks have nearly reached the complexity of digital electronic circuits and enable single cells to perform programmable arithmetic calculations or to provide dynamic remote control of transgenes through electromagnetic waves. We designed a synthetic multilayered gaseous-fragrance-programmable analog-to-digital converter (ADC) allowing for remote control of digital gene expression with 2-bit AND-, OR- and NOR-gate logic in synchronized cell consortia...
March 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28092360/chemical-proteomics-reveals-adp-ribosylation-of-small-gtpases-during-oxidative-stress
#19
Nathan P Westcott, Joseph P Fernandez, Henrik Molina, Howard C Hang
ADP-ribosylation is a post-translational modification that is known to be involved in cellular homeostasis and stress but has been challenging to analyze biochemically. To facilitate the detection of ADP-ribosylated proteins, we show that an alkyne-adenosine analog, N(6)-propargyl adenosine (N(6)pA), is metabolically incorporated in mammalian cells and enables fluorescence detection and proteomic analysis of ADP-ribosylated proteins. Notably, our analysis of N(6)pA-labeled proteins that are upregulated by oxidative stress revealed differential ADP-ribosylation of small GTPases...
March 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28092359/lysine-relay-mechanism-coordinates-intermediate-transfer-in-vitamin-b6-biosynthesis
#20
Matthew J Rodrigues, Volker Windeisen, Yang Zhang, Gabriela Guédez, Stefan Weber, Marco Strohmeier, Jeremiah W Hanes, Antoine Royant, Gwyndaf Evans, Irmgard Sinning, Steven E Ealick, Tadhg P Begley, Ivo Tews
Substrate channeling has emerged as a common mechanism for enzymatic intermediate transfer. A conspicuous gap in knowledge concerns the use of covalent lysine imines in the transfer of carbonyl-group-containing intermediates, despite their wideuse in enzymatic catalysis. Here we show how imine chemistry operates in the transfer of covalent intermediates in pyridoxal 5'-phosphate biosynthesis by the Arabidopsis thaliana enzyme Pdx1. An initial ribose 5-phosphate lysine imine is converted to the chromophoric I320 intermediate, simultaneously bound to two lysine residues and partially vacating the active site, which creates space for glyceraldehyde 3-phosphate to bind...
March 2017: Nature Chemical Biology
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