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Nature Chemical Biology

Christoph Manz, Andrei Yu Kobitski, Ayan Samanta, Bettina G Keller, Andres Jäschke, G Ulrich Nienhaus
S-adenosyl-L-methionine (SAM) ligand binding induces major structural changes in SAM-I riboswitches, through which gene expression is regulated via transcription termination. Little is known about the conformations and motions governing the function of the full-length Bacillus subtilis yitJ SAM-I riboswitch. Therefore, we have explored its conformational energy landscape as a function of Mg(2+) and SAM ligand concentrations using single-molecule Förster resonance energy transfer (smFRET) microscopy and hidden Markov modeling analysis...
September 18, 2017: Nature Chemical Biology
Jun Chen, Benjamin M Sutter, Lei Shi, Benjamin P Tu
The GATOR1 (SEACIT) complex consisting of Iml1-Npr2-Npr3 inhibits target of rapamycin complex 1 (TORC1) in response to amino acid insufficiency. In glucose medium, Saccharomyces cerevisiae mutants lacking the function of this complex grow poorly in the absence of amino acid supplementation, despite showing hallmarks of increased TORC1 signaling. Such mutants sense that they are amino acid replete and thus repress metabolic activities that are important for achieving this state. We found that npr2Δ mutants have defective mitochondrial tricarboxylic acid (TCA)-cycle activity and retrograde response...
September 18, 2017: Nature Chemical Biology
Tristan de Rond, Parker Stow, Ian Eigl, Rebecca E Johnson, Leanne Jade G Chan, Garima Goyal, Edward E K Baidoo, Nathan J Hillson, Christopher J Petzold, Richmond Sarpong, Jay D Keasling
Prodiginines, which are tripyrrole alkaloids displaying a wide array of bioactivities, occur as linear and cyclic congeners. Identification of an unclustered biosynthetic gene led to the discovery of the enzyme responsible for catalyzing the regiospecific C-H activation and cyclization of prodigiosin to cycloprodigiosin in Pseudoalteromonas rubra. This enzyme is related to alkylglycerol monooxygenase and unrelated to RedG, the Rieske oxygenase that produces cyclized prodiginines in Streptomyces, implying convergent evolution...
September 11, 2017: Nature Chemical Biology
Xingyue He, Jessica Riceberg, Teresa Soucy, Erik Koenig, James Minissale, Melissa Gallery, Hugues Bernard, Xiaofeng Yang, Hua Liao, Claudia Rabino, Pooja Shah, Kristina Xega, Zhong-Hua Yan, Mike Sintchak, John Bradley, He Xu, Matt Duffey, Dylan England, Hirotake Mizutani, Zhigen Hu, Jianping Guo, Ryan Chau, Lawrence R Dick, James E Brownell, John Newcomb, Steve Langston, Eric S Lightcap, Neil Bence, Sai M Pulukuri
Small ubiquitin-like modifier (SUMO) family proteins regulate target-protein functions by post-translational modification. However, a potent and selective inhibitor targeting the SUMO pathway has been lacking. Here we describe ML-792, a mechanism-based SUMO-activating enzyme (SAE) inhibitor with nanomolar potency in cellular assays. ML-792 selectively blocks SAE enzyme activity and total SUMOylation, thus decreasing cancer cell proliferation. Moreover, we found that induction of the MYC oncogene increased the ML-792-mediated viability effect in cancer cells, thus indicating a potential application of SAE inhibitors in treating MYC-amplified tumors...
September 11, 2017: Nature Chemical Biology
Yuhua Fu, Peng Wu, Yuyin Pan, Xiaoli Sun, Huiya Yang, Marian Difiglia, Boxun Lu
Protein misfolding is a common theme in neurodegenerative disorders including Huntington's disease (HD). The HD-causing mutant huntingtin protein (mHTT) has an expanded polyglutamine (polyQ) stretch that may adopt multiple conformations, and the most toxic of these is the one recognized by antibody 3B5H10. Here we show that the 3B5H10-recognized mHTT species has a slower degradation rate due to its resistance to selective autophagy in human cells and brains, revealing mechanisms of its higher toxicity.
September 4, 2017: Nature Chemical Biology
Thomas Thomik, Ilka Wittig, Jun-Yong Choe, Eckhard Boles, Mislav Oreb
Efficient substrate utilization is the first and most important prerequisite for economically viable production of biofuels and chemicals by microbial cell factories. However, production rates and yields are often compromised by low transport rates of substrates across biological membranes and their diversion to competing pathways. This is especially true when common chassis organisms are engineered to utilize nonphysiological feedstocks. Here, we addressed this problem by constructing an artificial complex between an endogenous sugar transporter and a heterologous xylose isomerase in Saccharomyces cerevisiae...
September 4, 2017: Nature Chemical Biology
Bastien Bissaro, Åsmund K Røhr, Gerdt Müller, Piotr Chylenski, Morten Skaugen, Zarah Forsberg, Svein J Horn, Gustav Vaaje-Kolstad, Vincent G H Eijsink
Enzymes currently known as lytic polysaccharide monooxygenases (LPMOs) play an important role in the conversion of recalcitrant polysaccharides, but their mode of action has remained largely enigmatic. It is generally believed that catalysis by LPMOs requires molecular oxygen and a reductant that delivers two electrons per catalytic cycle. Using enzyme assays, mass spectrometry and experiments with labeled oxygen atoms, we show here that H2O2, rather than O2, is the preferred co-substrate of LPMOs. By controlling H2O2 supply, stable reaction kinetics are achieved, the LPMOs work in the absence of O2, and the reductant is consumed in priming rather than in stoichiometric amounts...
October 2017: Nature Chemical Biology
Mikhail Metelev, Ilya A Osterman, Dmitry Ghilarov, Nelli F Khabibullina, Alexander Yakimov, Konstantin Shabalin, Irina Utkina, Dmitry Y Travin, Ekaterina S Komarova, Marina Serebryakova, Tatyana Artamonova, Mikhail Khodorkovskii, Andrey L Konevega, Petr V Sergiev, Konstantin Severinov, Yury S Polikanov
Whereas screening of the small-molecule metabolites produced by most cultivatable microorganisms often results in the rediscovery of known compounds, genome-mining programs allow researchers to harness much greater chemical diversity, and result in the discovery of new molecular scaffolds. Here we report the genome-guided identification of a new antibiotic, klebsazolicin (KLB), from Klebsiella pneumoniae that inhibits the growth of sensitive cells by targeting ribosomes. A ribosomally synthesized post-translationally modified peptide (RiPP), KLB is characterized by the presence of a unique N-terminal amidine ring that is essential for its activity...
October 2017: Nature Chemical Biology
Marie Pancera, Yen-Ting Lai, Tatsiana Bylund, Aliaksandr Druz, Sandeep Narpala, Sijy O'Dell, Arne Schön, Robert T Bailer, Gwo-Yu Chuang, Hui Geng, Mark K Louder, Reda Rawi, Djade I Soumana, Andrés Finzi, Alon Herschhorn, Navid Madani, Joseph Sodroski, Ernesto Freire, David R Langley, John R Mascola, Adrian B McDermott, Peter D Kwong
The HIV-1 envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4- and CCR5-bound) and postfusion states to facilitate HIV-1 entry into cells. Although the prefusion closed conformation is a potential target for inhibition, development of small-molecule leads has been stymied by difficulties in obtaining structural information. Here, we report crystal structures at 3.8-Å resolution of an HIV-1-Env trimer with BMS-378806 and a derivative BMS-626529 for which a prodrug version is currently in Phase III clinical trials...
October 2017: Nature Chemical Biology
Subrata Panja, Boyang Hua, Diego Zegarra, Taekjip Ha, Sarah A Woodson
Twister is a small ribozyme present in almost all kingdoms of life that rapidly self-cleaves in variety of divalent metal ions. We used activity assays, bulk FRET and single-molecule FRET (smFRET) to understand how different metal ions promote folding and self-cleavage of the Oryza sativa twister ribozyme. Although most ribozymes require additional Mg(2+) for catalysis, twister inverts this expectation, requiring 20-30 times less Mg(2+) to self-cleave than to fold. Transition metals such as Co(2+), Ni(2+) and Zn(2+) activate twister more efficiently than Mg(2+) ions...
October 2017: Nature Chemical Biology
Liv Johannessen, Thomas B Sundberg, Daniel J O'Connell, Raivo Kolde, James Berstler, Katelyn J Billings, Bernard Khor, Brinton Seashore-Ludlow, Anne Fassl, Caitlin N Russell, Isabel J Latorre, Baishan Jiang, Daniel B Graham, Jose R Perez, Piotr Sicinski, Andrew J Phillips, Stuart L Schreiber, Nathanael S Gray, Alykhan F Shamji, Ramnik J Xavier
Enhancing production of the anti-inflammatory cytokine interleukin-10 (IL-10) is a promising strategy to suppress pathogenic inflammation. To identify new mechanisms regulating IL-10 production, we conducted a phenotypic screen for small molecules that enhance IL-10 secretion from activated dendritic cells. Mechanism-of-action studies using a prioritized hit from the screen, BRD6989, identified the Mediator-associated kinase CDK8, and its paralog CDK19, as negative regulators of IL-10 production during innate immune activation...
October 2017: Nature Chemical Biology
Huaiying Zhang, Chanat Aonbangkhen, Ekaterina V Tarasovetc, Edward R Ballister, David M Chenoweth, Michael A Lampson
Kinetochores act as hubs for multiple activities during cell division, including microtubule interactions and spindle checkpoint signaling. Each kinetochore can act autonomously, and activities change rapidly as proteins are recruited to, or removed from, kinetochores. Understanding this dynamic system requires tools that can manipulate kinetochores on biologically relevant temporal and spatial scales. Optogenetic approaches have the potential to provide temporal and spatial control with molecular specificity...
October 2017: Nature Chemical Biology
Valentin Cracan, Denis V Titov, Hongying Shen, Zenon Grabarek, Vamsi K Mootha
The redox coenzymes NADH and NADPH are broadly required for energy metabolism, biosynthesis and detoxification. Despite detailed knowledge of specific enzymes and pathways that utilize these coenzymes, a holistic understanding of the regulation and compartmentalization of NADH- and NADPH-dependent pathways is lacking, partly because of a lack of tools with which to investigate these processes in living cells. We have previously reported the use of the naturally occurring Lactobacillus brevis H2O-forming NADH oxidase (LbNOX) as a genetic tool for manipulation of the NAD(+)/NADH ratio in human cells...
October 2017: Nature Chemical Biology
Rob C Oslund, Xiaoyang Su, Michael Haugbro, Jung-Min Kee, Mark Esposito, Yael David, Boyuan Wang, Eva Ge, David H Perlman, Yibin Kang, Tom W Muir, Joshua D Rabinowitz
Lower glycolysis involves a series of reversible reactions, which interconvert intermediates that also feed anabolic pathways. 3-phosphoglycerate (3-PG) is an abundant lower glycolytic intermediate that feeds serine biosynthesis via the enzyme phosphoglycerate dehydrogenase, which is genomically amplified in several cancers. Phosphoglycerate mutase 1 (PGAM1) catalyzes the isomerization of 3-PG into the downstream glycolytic intermediate 2-phosphoglycerate (2-PG). PGAM1 needs to be histidine phosphorylated to become catalytically active...
October 2017: Nature Chemical Biology
Li Zha, Yindi Jiang, Matthew T Henke, Matthew R Wilson, Jennifer X Wang, Neil L Kelleher, Emily P Balskus
Despite containing an α-amino acid, the versatile cofactor S-adenosylmethionine (SAM) is not a known building block for nonribosomal peptide synthetase (NRPS) assembly lines. Here we report an unusual NRPS module from colibactin biosynthesis that uses SAM for amide bond formation and subsequent cyclopropanation. Our findings showcase a new use for SAM and reveal a novel biosynthetic route to a functional group that likely mediates colibactin's genotoxicity.
October 2017: Nature Chemical Biology
David D Shock, Bret D Freudenthal, William A Beard, Samuel H Wilson
DNA polymerases catalyze efficient and high-fidelity DNA synthesis. While this reaction favors nucleotide incorporation, polymerases also catalyze a reverse reaction, pyrophosphorolysis, that removes the DNA primer terminus and generates deoxynucleoside triphosphates. Because pyrophosphorolysis can influence polymerase fidelity and sensitivity to chain-terminating nucleosides, we analyzed pyrophosphorolysis with human DNA polymerase β and found the reaction to be inefficient. The lack of a thio-elemental effect indicated that this reaction was limited by a nonchemical step...
October 2017: Nature Chemical Biology
Takahiro Mori, Taiki Iwabuchi, Shotaro Hoshino, Hang Wang, Yudai Matsuda, Ikuro Abe
Trt14 from Aspergillus terreus is involved in unusual skeletal reconstruction during the biosynthesis of the fungal meroterpenoid terretonin. Detailed in vitro characterization revealed that this novel multifunctional enzyme catalyzes not only the D-ring expansion via intramolecular methoxy rearrangement, but also the hydrolysis of the expanded D-ring. The X-ray crystal structures of Trt14, in complex with substrate or product, and two Trt14 homologs, AusH and PrhC from Aspergillus nidulans and Penicillium brasilianum, respectively, indicated similar overall structures to those of the NTF2-like superfamily of enzymes, despite lacking sequence and functional similarities...
October 2017: Nature Chemical Biology
Ana C Figueiredo, Helder Maiato
No abstract text is available yet for this article.
September 2017: Nature Chemical Biology
Eun-Ik Koh, Anne E Robinson, Nilantha Bandara, Buck E Rogers, Jeffrey P Henderson
Copper plays a dual role as a nutrient and a toxin during bacterial infections. While uropathogenic Escherichia coli (UPEC) strains can use the copper-binding metallophore yersiniabactin (Ybt) to resist copper toxicity, Ybt also converts bioavailable copper to Cu(II)-Ybt in low-copper conditions. Although E. coli have long been considered to lack a copper import pathway, we observed Ybt-mediated copper import in UPEC using canonical Fe(III)-Ybt transport proteins. UPEC removed copper from Cu(II)-Ybt with subsequent re-export of metal-free Ybt to the extracellular space...
September 2017: Nature Chemical Biology
Elwood A Mullins, Rongxin Shi, Brandt F Eichman
Yatakemycin (YTM) is an extraordinarily toxic DNA alkylating agent with potent antimicrobial and antitumor properties and is the most recent addition to the CC-1065 and duocarmycin family of natural products. Though bulky DNA lesions the size of those produced by YTM are normally removed from the genome by the nucleotide-excision repair (NER) pathway, YTM adducts are also a substrate for the bacterial DNA glycosylases AlkD and YtkR2, unexpectedly implicating base-excision repair (BER) in their elimination. The reason for the extreme toxicity of these lesions and the molecular basis for the way they are eliminated by BER have been unclear...
September 2017: Nature Chemical Biology
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