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ACS Chemical Biology

Douglas D Young, Peter G Schultz
Our understanding of the complex molecular processes of living organisms is growing exponentially. This knowledge, togeth-er with a powerful arsenal of tools for manipulating the structures of biological macromolecules, is allowing chemists to begin to harness and reprogram the remarkable machinery of life. Here we review one such example in which the genetic code itself has been expanded with new building blocks that allow us to probe and manipulate the structures and functions of proteins in ways previously unimaginable...
January 18, 2018: ACS Chemical Biology
Venkatesh J Nemmara, Venkataraman Subramanian, Aaron Muth, Santanu Mondal, Ari J Salinger, Aaron J Maurais, Ronak Tilvawala, Eranthie Weerapana, Paul R Thompson
Citrullination is the post-translational hydrolysis of peptidyl-arginines to form peptidyl-citrulline, a reaction that is catalyzed by the protein arginine deiminases (PADs), a family of calcium-regulated enzymes. Aberrantly increased protein citrullination is associated with a slew of autoimmune diseases (e.g., rheumatoid arthritis (RA), multiple sclerosis, lupus, and ulcerative colitis) and certain cancers. Given the clear link between increased PAD activity and human disease, the PADs are therapeutically relevant targets...
January 17, 2018: ACS Chemical Biology
Carmanah D Hunter, Neha Khanna, Michele R Richards, Reza Rezaei Darestani, Chunxia Zou, John S Klassen, Christopher W Cairo
Recognition of terminal sialic acids is central to many cellular processes, and structural modification of sialic acid can disrupt these interactions. A prominent, naturally occuring, modification of sialic acid is 9-O-acetylation (9-O-Ac). Study of this modification through generation and analysis of 9-O-Ac sialosides is challenging due to the lability of the acetate group. Fundamental questions regarding the role of 9-O-Ac sialic acids remain unanswered, including what effect it may have on recognition and hydrolysis by the human neuraminidase enzymes (hNEU)...
January 17, 2018: ACS Chemical Biology
Zsofia Kutil, Zora Novakova, Marat Meleshin, Jana Mikesova, Mike Schutkowski, Cyril Barinka
Histone deacetylase 11 (HDAC11) is a sole member of the class IV HDAC subfamily with negligible intrinsic deacetylation activity. Here we report in vitro profiling of HDAC11 deacylase activities, and our data unequivocally show that the enzyme efficiently removes acyl moieties spanning 8-18 carbons from the side chain nitrogen of the lysine residue of a peptidic substrate. Additionally, N-linked lipoic acid and biotin are removed by the enzyme, although with lower efficacy. Catalytic efficiencies toward dodecanoylated and myristoylated peptides were 77,700 M-1s-1 and 149,000 M-1s-1, respectively, making HDAC11 the most proficient fatty acid deacylase of the HDAC family...
January 16, 2018: ACS Chemical Biology
Alexander Rittner, Karthik S Paithankar, Khanh Vu Huu, Martin Grininger
Fatty acid synthases (FASs) and polyketide synthases (PKSs) condense acyl compounds to fatty acids and polyketides, respectively. Both, FASs and PKSs, harbor acyltransferases (ATs), which select substrates for condensation by β-ketoacyl synthases (KSs). Here, we present the structural and functional characterization of the polyspecific malonyl/acetyltransferase (MAT) of murine FAS. We assign kinetic constants for the transacylation of the native substrates, acetyl- and malonyl-CoA, and demonstrate the promiscuity of FAS to accept structurally and chemically diverse CoA-esters...
January 12, 2018: ACS Chemical Biology
Kazuo Takayama, Hiroyuki Mizuguchi
Gene therapy is expected to be utilized for the treatment of various diseases. However, the spatiotemporal resolution of current gene therapy technology is not high enough. In this study, we generated a new technology for spatiotemporally controllable gene therapy. We introduced optogenetic and CRISPR/Cas9 techniques into a recombinant adenovirus (Ad) vector, which is widely used in clinical trials and exhibits high gene transfer efficiency, to generate an illumination-dependent spatiotemporally controllable gene regulation system (designated the Opt/Cas-Ad system)...
January 12, 2018: ACS Chemical Biology
Jie-Mei Chu, Tian-Tian Ye, Cheng-Jie Ma, Meng-Dan Lan, Ting Liu, Bi-Feng Yuan, Yu-Qi Feng
The recent discovery of reversible chemical modifications on messenger RNA (mRNA) has opened a new era of post-transcriptional gene regulation in eukaryotes. Among the 15 types of modifications identified in mRNA of eukaryotes, N7-methylguanosine (m7G) is unique ow-ing to its presence in the 5' cap structure. It remains unknown whether m7G is also present in-ternally in mRNA, and this is largely attributed to the lack of an appropriate analytical method to differentiate internal m7G in mRNA from that in the 5' cap...
January 9, 2018: ACS Chemical Biology
Miao Ye, Xiangfang Tang, Ru Yang, Hongfu Zhang, Fangshu Li, Fangzheng Tao, Fei Li, Zaigui Wang
Bacillus velezensis has been investigated and applied more and more widely because it can inhibit fungi and bacteria, and become a potential biocontrol agent recently. In order to provide more clear and comprehensive understanding of B. velezensis for researchers, we collected the recent relevant articles systematically and reviewed the discovery and taxonomy, secondary metabolites, characteristic and application, gene function and molecular research of B. velezensis. This article will give some directions to the research and application of this strain for future...
January 8, 2018: ACS Chemical Biology
Thomas E Speltz, Jeanne M Danes, Joshua D Stender, Jonna Frasor, Terry W Moore
We and others have proposed that coactivator binding inhibitors, which block the interaction of estrogen receptor and steroid receptor coactivators, may represent a potential class of new breast cancer therapeutics. The development of coactivator binding inhibitors has been limited, however, because many of the current molecules which are active in in vitro and biochemical assays are not active in cell-based assays. Our goal in this work was to prepare a coactivator binding inhibitor active in cellular models of breast cancer...
January 8, 2018: ACS Chemical Biology
Jonathan H Shrimp, Carissa Grose, Stephanie R T Widmeyer, Abigail L Thorpe, Ajit Jadhav, Jordan L Meier
Lysine acetyltransferases (KATs) play a critical role in the regulation of transcription and other genomic functions. However, a persistent challenge is the development of assays capable of defining KAT activity directly in living cells. Towards this goal, here we report the application of a previously reported dCas9-p300 fusion as a transcriptional reporter of KAT activity. First we benchmark the activity of dCas9-p300 relative to other dCas9-based transcriptional activators, and demonstrate its compatibility with second generation short guide RNA architectures...
January 8, 2018: ACS Chemical Biology
Chen Zhao, Yue Zhang, Yingze Zhao, Yue Ying, Runna Ai, Jingfang Zhang, Yu Wang
Inducible modulation is often required for precise investigations and manipulations of dynamic biological processes. Transcription activator-like effectors (TALEs) provide a powerful tool for targeted gene editing and transcriptional programming. We designed a series of chemical inducible systems by coupling TALEs with a mutated human estrogen receptor (ERT2), which renders them 4-hydroxyl-tamoxifen (4-OHT) inducible for access of the genome. Chemical inducible genome editing was achieved via fusing two tandem ERT2 domains to customized transcription activator-like effector nuclease (TALEN), which we termed "Hybrid Inducible Technology" (HIT-TALEN)...
January 8, 2018: ACS Chemical Biology
Jiahui Wu, Ahmed S Abdelfattah, Hang Zhou, Araya Ruangkittisakul, Yong Qian, Klaus Ballanyi, Robert E Campbell
Glutamate is one of the 20 common amino acids, and of utmost importance for chemically mediated synaptic transmission in nervous systems. To expand the color palette of genetically encoded indicators for glutamate, we used protein engineering to develop a red intensity-based glutamate-sensing fluorescent reporter (R-iGluSnFR1). Manipulating the topology of R-iGluSnFR1, and a previously reported green fluorescent indicator, led to the development of non-circularly permutated (ncp) variants. R- and Rncp-iGluSnFR1 display glutamate affinities of 11 µM and 0...
January 8, 2018: ACS Chemical Biology
Michelle Fodor, Edmund Price, Ping Wang, Hengyu Lu, Andreea Argintaru, Zhouliang Chen, Meir Glick, Huai-Xiang Hao, Mitsunori Kato, Robert Koenig, Jonathan R LaRochelle, Gang Liu, Eric McNeill, Dyuti Majumdar, Gisele A Nishiguchi, Lawrence B Perez, Gregory Paris, Christopher M Quinn, Timothy Ramsey, Martin Sendzik, Michael David Shultz, Sarah L Williams, Travis Stams, Stephen C Blacklow, Michael G Acker, Matthew J LaMarche
SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell proliferation, differentiation, and survival. Recently we reported an allosteric mechanism of inhibition that stabilizes the auto-inhibited conformation of SHP2. SHP099 (1) was identified and characterized as a moderately potent, orally bioavailable, allosteric small molecule inhibitor, which binds to a tunnel-like pocket formed by the confluence of three domains of SHP2. In this report, we describe further screening strategies that enabled the identification of a second, distinct small molecule allosteric site...
January 5, 2018: ACS Chemical Biology
Manoj Kushwaha, Shreyans K Jain, Nisha Sharma, Vidushi Abrol, Sundeep Jaglan, Ram A Vishwakarma
Targeting the main three networking systems viz. Las, RhI and PQS via natural quenchers is a new ray of hope for combating the persistent behavior of Pseudomonas aeruginosa. In the bacterial chemical vocabulary pyocyanin, N-AHLs and rhamnolipids are the main keywords, which are responsible for the social and nomadic behavior of P. aeruginosa. In the present work LCMS-based real-time qualitative and quantitative analysis of pyocyanin, green phenazine, N-AHLs, and rhamnolipids were performed. The quantitative analysis indicates that the production of pyocyanin and NHSLs increases with time while the production of rhamnolipids discontinued after 16 Hrs...
January 5, 2018: ACS Chemical Biology
Emily C Ulrich, Despina J Bougioukou, Wilfred A van der Donk
Dehydrophos is a tripeptide phosphonate antibiotic produced by Streptomyces luridus. Its biosynthetic pathway involves the use of aminoacyl-tRNA (aa-tRNA) for amide bond formation. The first amide bond during biosynthesis is formed by DhpH-C, a peptidyltransferase that utilizes Leu-tRNALeu. DhpH-C is a member of a burgeoning family of natural product biosynthetic enzymes that make use of aa-tRNA outside of canonical translation activities in the cell. Here we used site-directed mutagenesis of both DhpH-C and tRNALeu to investigate the enzyme mechanism and substrate specificity, respectively, and analyzed the substrate scope for the production of a series of dipeptides...
January 5, 2018: ACS Chemical Biology
Isabel Aparici-Espert, Guillermo Garcia-Lainez, Inmaculada Andreu, Miguel Angel Miranda, Virginie Lhiaubet-Vallet
In this work, the attention is focused on UVA-photosensitized reactions triggered by a DNA chromophore-containing lesion, namely 5-formyluracil. This is a major oxidatively generated lesion that exhibits an enhanced light absorption in the UVB-UVA region. The mechanistic study combining photochemical and photobiological techniques shows that irradiation of 5-formyluracil leads to a triplet excited state capable of sensitizing formation of cyclobutane pyrimidine dimers in DNA via a triplet-triplet energy transfer...
January 4, 2018: ACS Chemical Biology
Franziska Kundel, Suman De, Patrick Flagmeier, Mathew H Horrocks, Magnus Kjaergaard, Sarah L Shammas, Sophie E Jackson, Christopher M Dobson, David Klenerman
As a key player of the protein quality control network of the cell, the molecular chaperone Hsp70 inhibits the aggregation of the amyloid protein tau. To date, the mechanism of this inhibition and the tau species targeted by Hsp70 remain unknown. This is partly due to the inherent difficulty of studying amyloid aggregates because of their heterogeneous and transient nature. Here, we used ensemble and single-molecule fluorescence measurements to dissect how Hsp70 counteracts the self-assembly process of K18 tau with the pathological deletion ∆K280...
January 4, 2018: ACS Chemical Biology
Jason C Klein, Wei Chen, Molly Gasperini, Jay Shendure
Enhancers control the spatiotemporal expression of genes and are essential for encoding differentiation and development. Since their discovery more than three decades ago, researchers have largely studied enhancers removed from their genomic context. The recent adaptation of CRISPR/Cas9 to genome editing in higher organisms now allows researchers to perturb and test these elements in their genomic context, through both mutation and epigenetic modulation. In this perspective, we discuss recent advances in scanning non-coding regions of the genome for enhancer activity using CRISPR-based tools...
January 4, 2018: ACS Chemical Biology
Travis Hardcastle, Irina Novosjolova, Venubabu Kotikam, Samwel K Cheruiyot, Daniel Mutisya, Scott D Kennedy, Martin Egli, Melissa L Kelley, Anja van Brabant Smith, Eriks Rozners
Potential in vivo applications of RNA interference (RNAi) require suppression of various off-target activities. Herein we report that replacement of a single phosphate linkage between the first and second nucleosides of the passenger strand with an amide linkage almost completely abolished its undesired activity and restored the desired activity of guide strands that had been compromised by unfavorable amide modifications. Molecular modelling suggested that the observed effect was most likely due to suppressed loading of the amide-modified strand into Ago2 caused by inability of amide to adopt the conformation required for the backbone twist that docks the first nucleotide of the guide strand in the MID domain of Ago2...
January 3, 2018: ACS Chemical Biology
Masato Niwa, Tasuku Hirayama, Ikumi Oomoto, Dan Ohtan Wang, Hideko Nagasawa
Iron is an essential transition metal species for all living organisms and plays various physiologically important roles on the basis of its redox activity; accordingly, the disruption of iron homeostasis triggers oxidative stress and cellular damage. Therefore, cells have developed a sophisticated iron-uptake machinery to acquire iron while protecting cells from uncontrolled oxidative damage during the uptake process. To examine the detailed mechanism of iron uptake while controlling the redox status, it is necessary to develop useful methods with redox state-selectivity, sensitivity, and organelle-specificity to monitor labile iron, which is weakly bound to subcellular ligands...
January 3, 2018: ACS Chemical Biology
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