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Cell Chemical Biology

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https://www.readbyqxmd.com/read/28625738/mechanisms-of-paradoxical-activation-of-ampk-by-the-kinase-inhibitors-su6656-and-sorafenib
#1
Fiona A Ross, Simon A Hawley, F Romana Auciello, Graeme J Gowans, Abdelmadjid Atrih, Douglas J Lamont, D Grahame Hardie
SU6656, a Src kinase inhibitor, was reported to increase fat oxidation and reduce body weight in mice, with proposed mechanisms involving AMP-activated protein kinase (AMPK) activation via inhibition of phosphorylation of either LKB1 or AMPK by the Src kinase, Fyn. However, we report that AMPK activation by SU6656 is independent of Src kinases or tyrosine phosphorylation of LKB1 or AMPK and is not due to decreased cellular energy status or binding at the ADaM site on AMPK. SU6656 is a potent AMPK inhibitor, yet binding at the catalytic site paradoxically promotes phosphorylation of Thr172 by LKB1...
June 7, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28602761/joining-forces-the-chemical-biology-medicinal-chemistry-continuum
#2
REVIEW
Alleyn T Plowright, Christian Ottmann, Michelle Arkin, Yves P Auberson, Henk Timmerman, Herbert Waldmann
The scientific advances being made across all disciplines are creating ever-increasing opportunities to enhance our knowledge of biological systems and how they relate to human disease. One of the central driving forces in discovering new medicines is medicinal chemistry, where the design and synthesis of novel compounds has led to multiple drugs. Chemical biology, sitting at the interface of many disciplines, has now emerged as a major contributor to the understanding of biological systems and is becoming an integral part of drug discovery...
June 1, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644957/chemical-probes-for-visualizing-intact-animal-and-human-brain-tissue
#3
REVIEW
Hei Ming Lai, Wai-Lung Ng, Steve M Gentleman, Wutian Wu
Newly developed tissue clearing techniques can be used to render intact tissues transparent. When combined with fluorescent labeling technologies and optical sectioning microscopy, this allows visualization of fine structure in three dimensions. Gene-transfection techniques have proved very useful in visualizing cellular structures in animal models, but they are not applicable to human brain tissue. Here, we discuss the characteristics of an ideal chemical fluorescent probe for use in brain and other cleared tissues, and offer a comprehensive overview of currently available chemical probes...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644956/sirt4-is-a-regulator-of-insulin-secretion
#4
Elma Zaganjor, Sejal Vyas, Marcia C Haigis
In a recent issue of Cell Metabolism, Anderson et al. (2017) report that SIRT4 regulates insulin sensitivity in the pancreas via activation of methylcrotonyl-CoA carboxylase 1 (MCCC1) by removal of dicarboxyacyl-lysine modifications. Thus, SIRT4 activates leucine catabolism and causes decreased secretion of insulin from the pancreas.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644955/turning-on-proteasomes
#5
Jan Henrik Krahn, Farnusch Kaschani, Markus Kaiser
While proteasome inhibitors are now well-established research tools and chemotherapeutics, proteasome activators are much less explored. In this issue of Cell Chemical Biology, in a study from the groups of Berkers and Ovaa (Leestemaker et al., 2017), a chemical screen was used to identify a p38 MAPK inhibitor as a proteasome activator. This compound furthermore enhanced clearance of protein aggregates, thereby implicating alternative chemotherapeutic options for treating neurodegenerative diseases.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644954/bacteria-and-the-fate-of-estrogen-in-the-environment
#6
William B Whitman
In this issue of Cell Chemical Biology, Chen et al. (2017) report that 4-hydroxyestrone and pyridinestrone acid are intermediates in the 4,5-seco pathway of aerobic estrogen degradation by the bacterium Sphingomonas. The authors identify a gene for 4-hydroxyestrone 4,5-dioxygenase and find it to be widely distributed in diverse proteobacteria, suggesting that this pathway is environmentally significant.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644953/helping-induced-hpscs-clean-up-their-act
#7
Ho-Chang Jeong, Hyuk-Jin Cha
Inhibition of the tumorigenic potential of human pluripotent stem cells (hPSCs) remains critically important for safe hPSC-based therapy. In this issue of Cell Chemical Biology, Kuang et al. (2017) reveal that the phospho-D-peptide D-3 efficiently induces death of residual hPSCs, but not of differentiated progenies, through high alkaline phosphatase activity in hPSCs.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644952/acsf3-and-mal-onate-adapted-mitochondria
#8
David B Lombard, Yingming Zhao
In this issue of Cell Chemical Biology, Bowman and colleagues show that the mitochondrial enzyme ACSF3 generates malonyl-CoA from malonate, in turn regulating metabolic flux and mitochondrial protein malonylation (Bowman et al., 2017). The study reveals a mechanism to generate mitochondrial malonyl-CoA and how this molecule impacts mitochondrial biology.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28644951/principles-of-chemical-biology-from-sexy-fatty-acids-and-ebv-probes-to-anti-acid-antibiotic-via-post-biotics-and-host-microbe-metabolic-complementarity
#9
(no author information available yet)
This month: The role of fatty acids in sex determination; a probe to monitor and inhibit EBNA1 at the same time; a biological role for post-biotics; what happens when you mix microbes, hosts, and drugs; and an antibiotic that cross-protects with acid.
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28602760/how-to-increase-brightness-of-near-infrared-fluorescent-proteins-in-mammalian-cells
#10
Anton A Shemetov, Olena S Oliinyk, Vladislav V Verkhusha
Numerous near-infrared (NIR) fluorescent proteins (FPs) were recently engineered from bacterial photoreceptors but lack of their systematic comparison makes researcher's choice rather difficult. Here we evaluated side-by-side several modern NIR FPs, such as blue-shifted smURFP and miRFP670, and red-shifted mIFP and miRFP703. We found that among all NIR FPs, miRFP670 had the highest fluorescence intensity in various mammalian cells. For instance, in common HeLa cells miRFP703, mIFP, and smURFP were 2-, 9-, and 53-fold dimmer than miRFP670...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28602759/construction-and-screening-of-a-lentiviral-secretome-library
#11
Tao Liu, Panpan Jia, Huailei Ma, Sean A Reed, Xiaozhou Luo, H Benjamin Larman, Peter G Schultz
Over 2,000 human proteins are predicted to be secreted, but the biological function of the many of these proteins is still unknown. Moreover, a number of these proteins may act as new therapeutic agents or be targets for the development of therapeutic antibodies. To further explore the extracellular proteome, we have developed a secretome-enriched open reading frame (ORF) library that can be readily screened for autocrine activity in cell-based phenotypic or reporter assays. Next-generation sequencing (NGS) and database analysis predict that the library contains approximately 900 ORFs encoding known secreted proteins (accounting for 77...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28579361/triazolopyrimidines-are-microtubule-stabilizing-agents-that-bind-the-vinca-inhibitor-site-of-tubulin
#12
Gonzalo Sáez-Calvo, Ashwani Sharma, Francisco de Asís Balaguer, Isabel Barasoain, Javier Rodríguez-Salarichs, Natacha Olieric, Hugo Muñoz-Hernández, Manuel Álvaro Berbís, Sebastian Wendeborn, Miguel Angel Peñalva, Ruth Matesanz, Ángeles Canales, Andrea Enrico Prota, Jesús Jímenez-Barbero, José Manuel Andreu, Clemens Lamberth, Michel Olivier Steinmetz, José Fernando Díaz
Microtubule-targeting agents (MTAs) are some of the clinically most successful anti-cancer drugs. Unfortunately, instances of multidrug resistances to MTA have been reported, which highlights the need for developing MTAs with different mechanistic properties. One less explored class of MTAs are [1,2,4]triazolo[1,5-a]pyrimidines (TPs). These cytotoxic compounds are microtubule-stabilizing agents that inexplicably bind to vinblastine binding site on tubulin, which is typically targeted by microtubule-destabilizing agents...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28552583/biochemical-mechanisms-and-catabolic-enzymes-involved-in-bacterial-estrogen-degradation-pathways
#13
Yi-Lung Chen, Chang-Ping Yu, Tzong-Huei Lee, King-Siang Goh, Kung-Hui Chu, Po-Hsiang Wang, Wael Ismail, Chao-Jen Shih, Yin-Ru Chiang
Estrogens have been classified as group 1 carcinogens by the World Health Organization and represent a significant concern given that they are found in surface waters worldwide, and long-term exposure to estrogen-contaminated water can disrupt sexual development in animals. To date, the estrogen catabolic enzymes and genes remain unknown. Using a tiered functional genomics approach, we identified three estrogen catabolic gene clusters in Sphingomonas sp. strain KC8. We identified several estrone-derived compounds, including 4-hydroxyestrone, a meta-cleavage product, and pyridinestrone acid...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28552582/proteasome-activation-by-small-molecules
#14
Yves Leestemaker, Annemieke de Jong, Katharina F Witting, Renske Penning, Karianne Schuurman, Boris Rodenko, Esther A Zaal, Bert van de Kooij, Stefan Laufer, Albert J R Heck, Jannie Borst, Wiep Scheper, Celia R Berkers, Huib Ovaa
Drugs that increase 26S proteasome activity have potential therapeutic applications in the treatment of neurodegenerative diseases. A chemical genetics screen of over 2,750 compounds using a proteasome activity probe as a readout in a high-throughput live-cell fluorescence-activated cell sorting-based assay revealed more than ten compounds that increase proteasome activity, with the p38 MAPK inhibitor PD169316 being one of the most potent ones. Genetic and chemical inhibition of either p38 MAPK, its upstream regulators, ASK1 and MKK6, and downstream target, MK2, enhance proteasome activity...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28552581/single-virus-droplet-microfluidics-for-high-throughput-screening-of-neutralizing-epitopes-on-hiv-particles
#15
Chawaree Chaipan, Anna Pryszlak, Hansi Dean, Pascal Poignard, Vladimir Benes, Andrew D Griffiths, Christoph A Merten
Analyzing surface epitopes of single HIV particles holds great potential for the development of vaccine candidates. However, existing technologies do not allow corresponding screens at high throughput. We present here a single-virus droplet-based microfluidics platform enabling sorting of millions of HIV-1 particles with >99% efficiency, based on the expression of epitopes recognized by broadly neutralizing antibodies. We show that virus particles displaying these epitopes can be identified, sorted, and analyzed by next-generation sequencing: an approximately 1,900-fold enrichment of viral particles displaying neutralizing epitopes could be obtained in a single sort, thus opening the way for screening diverse virus libraries with optimal antigenic features for HIV vaccine candidates...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28552580/engineered-proteins-program-mammalian-cells-to-target-inflammatory-disease-sites
#16
Anam Qudrat, Abdullah Al Mosabbir, Kevin Truong
Disease sites in atherosclerosis and cancer feature cell masses (e.g., plaques/tumors), a low pH extracellular microenvironment, and various pro-inflammatory cytokines such as tumor necrosis factor α (TNFα). The ability to engineer a cell to seek TNFα sources allows for targeted therapeutic delivery. To accomplish this, here we introduced a system of proteins: an engineered TNFα chimeric receptor (named TNFR1chi), a previously engineered Ca(2+)-activated RhoA (named CaRQ), vesicular stomatitis virus glycoprotein G (VSVG), and thymidine kinase...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28529132/efficient-selective-removal-of-human-pluripotent-stem-cells-via-ecto-alkaline-phosphatase-mediated-aggregation-of-synthetic-peptides
#17
Yi Kuang, Kenji Miki, Callum J C Parr, Karin Hayashi, Ikue Takei, Jie Li, Mio Iwasaki, Masato Nakagawa, Yoshinori Yoshida, Hirohide Saito
The incomplete differentiation of human induced pluripotent stem cells (iPSCs) poses a serious safety risk owing to their potential tumorigenicity, hindering their clinical application. Here, we explored the potential of phospho-D-peptides as novel iPSC-eliminating agents. Alkaline phosphatases overexpressed on iPSCs dephosphorylate phospho-D-peptides into hydrophobic peptides that aggregate and induce cell death. We isolated a peptide candidate, D-3, that selectively and rapidly induced toxicity in iPSCs within 1 hr but had little influence on various non-iPSCs, including primary hepatocytes and iPSC-derived cardiomyocytes...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28529131/the-structure-of-the-guanidine-ii-riboswitch
#18
Lin Huang, Jia Wang, David M J Lilley
The guanidine-II (mini-ykkC) riboswitch is the smallest of the guanidine-responsive riboswitches, comprising two stem loops of similar sequence. We have solved high-resolution crystal structures of both stem loops for the riboswitch from Gloeobacter violaceus. The stem loops have a strong propensity to dimerize by intimate loop-loop interaction. The dimerization creates specific binding pockets for two guanidine molecules, explaining their cooperative binding. Within the binding pockets the ligands are hydrogen bonded to a guanine at O6 and N7, and to successive backbone phosphates...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28479296/the-mammalian-malonyl-coa-synthetase-acsf3-is-required-for-mitochondrial-protein-malonylation-and-metabolic-efficiency
#19
Caitlyn E Bowman, Susana Rodriguez, Ebru S Selen Alpergin, Michelle G Acoba, Liang Zhao, Thomas Hartung, Steven M Claypool, Paul A Watkins, Michael J Wolfgang
Malonyl-coenzyme A (malonyl-CoA) is a central metabolite in mammalian fatty acid biochemistry generated and utilized in the cytoplasm; however, little is known about noncanonical organelle-specific malonyl-CoA metabolism. Intramitochondrial malonyl-CoA is generated by a malonyl-CoA synthetase, ACSF3, which produces malonyl-CoA from malonate, an endogenous competitive inhibitor of succinate dehydrogenase. To determine the metabolic requirement for mitochondrial malonyl-CoA, ACSF3 knockout (KO) cells were generated by CRISPR/Cas-mediated genome editing...
June 22, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28525771/return-of-the-ice-age-caspases-safeguard-against-inflammatory-cell-death
#20
Marcin Poreba, Guy Salvesen
In a recent issue of Cell Chemical Biology, Taabazuing et al. (2017) reveal a bidirectional interplay between pathways leading to apoptosis and pyroptosis, two forms of regulated cell death with opposing inflammatory outcomes. The outcome is sealed by differential cleavage of the key pyroptosis execution substrate gasdermin D such that inflammatory caspases activate it but apoptotic caspases prevent its activation.
May 18, 2017: Cell Chemical Biology
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