A multi-step peptidolytic cascade for amino acid recovery in chloroplasts

October 31st, 2016 by Pedro F Teixeira

Nature Chemical Biology 13, 15 (2017). doi:10.1038/nchembio.2227

Authors: Pedro F Teixeira, Beata Kmiec, Rui M M Branca, Monika W Murcha, Anna Byzia, Aneta Ivanova, James Whelan, Marcin Drag, Janne Lehtiö & Elzbieta Glaser

Plastids (including chloroplasts) are subcellular sites for a plethora of proteolytic reactions, required in functions ranging from protein biogenesis to quality control. Here we show that peptides generated from pre-protein maturation within chloroplasts of Arabidopsis thaliana are degraded to amino acids by a multi-step peptidolytic cascade consisting of oligopeptidases and aminopeptidases, effectively allowing the recovery of single amino acids within these organelles.

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Design and characterization of bivalent BET inhibitors

October 24th, 2016 by Minoru Tanaka

Nature Chemical Biology 12, 1089 (2016). doi:10.1038/nchembio.2209

Authors: Minoru Tanaka, Justin M Roberts, Hyuk-Soo Seo, Amanda Souza, Joshiawa Paulk, Thomas G Scott, Stephen L DeAngelo, Sirano Dhe-Paganon & James E Bradner

Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2

October 24th, 2016 by Xiaozhe Xiong

Nature Chemical Biology 12, 1111 (2016). doi:10.1038/nchembio.2218

Authors: Xiaozhe Xiong, Tatyana Panchenko, Shuang Yang, Shuai Zhao, Peiqiang Yan, Wenhao Zhang, Wei Xie, Yuanyuan Li, Yingming Zhao, C David Allis & Haitao Li

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Small-molecule factor D inhibitors targeting the alternative complement pathway

October 24th, 2016 by Jürgen Maibaum

Nature Chemical Biology 12, 1105 (2016). doi:10.1038/nchembio.2208

Authors: Jürgen Maibaum, Sha-Mei Liao, Anna Vulpetti, Nils Ostermann, Stefan Randl, Simon Rüdisser, Edwige Lorthiois, Paul Erbel, Bernd Kinzel, Fabrice A Kolb, Samuel Barbieri, Julia Wagner, Corinne Durand, Kamal Fettis, Solene Dussauge, Nicola Hughes, Omar Delgado, Ulrich Hommel, Ty Gould, Aengus Mac Sweeney, Bernd Gerhartz, Frederic Cumin, Stefanie Flohr, Anna Schubart, Bruce Jaffee, Richard Harrison, Antonio Maria Risitano, Jörg Eder & Karen Anderson

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Potent and selective bivalent inhibitors of BET bromodomains

October 24th, 2016 by Michael J Waring

Nature Chemical Biology 12, 1097 (2016). doi:10.1038/nchembio.2210

Authors: Michael J Waring, Huawei Chen, Alfred A Rabow, Graeme Walker, Romel Bobby, Scott Boiko, Rob H Bradbury, Rowena Callis, Edwin Clark, Ian Dale, Danette L Daniels, Austin Dulak, Liz Flavell, Geoff Holdgate, Thomas A Jowitt, Alexey Kikhney, Mark McAlister, Jacqui Méndez, Derek Ogg, Joe Patel, Philip Petteruti, Graeme R Robb, Matthew B Robers, Sakina Saif, Natalie Stratton, Dmitri I Svergun, Wenxian Wang, David Whittaker, David M Wilson & Yi Yao

Necroptosis-like neuronal cell death caused by cellular cholesterol accumulation [Neurobiology]

October 18th, 2016 by Funakoshi, T., Aki, T., Tajiri, M., Unuma, K., Uemura, K.

Aberrant cellular accumulation of cholesterol is associated with neuronal lysosomal storage disorders such as Niemann-Pick disease Type C (NPC). We have shown previously that l-norephedrine (l-Nor), a sympathomimetic amine, induces necrotic cell death associated with massive cytoplasmic vacuolation in SH-SY5Y human neuroblastoma cells. To reveal the molecular mechanism underling necrotic neuronal cell death caused by l-Nor, we examined alterations in the gene expression profile of cells during l-Nor exposure. DNA microarray analysis revealed that the gene levels for cholesterol transport (LDL receptor and NPC2) as well as cholesterol biosynthesis (mevalonate pathway enzymes) are increased after exposure to 3 mM l-Nor for ~6 hours. Concomitant with this observation, the master transcriptional regulator of cholesterol homeostasis, SREBP-2, is activated by l-Nor. The increase in cholesterol uptake as well as biosynthesis is not accompanied by an increase in cholesterol in the plasma membrane, but rather by aberrant accumulation in cytoplasmic compartments. We also found that cell death by l-Nor can be suppressed by nec-1s, an inhibitor of a regulated form of necrosis, necroptosis. Abrogation of SREBP-2 activation by the small molecule inhibitor betulin or by overexpression of dominant negative SREBP-2 efficiently reduces cell death by l-Nor. The mobilization of cellular cholesterol in the presence cyclodextrin (CD) also suppresses cell death. These results were also observed in primary culture of striatum neurons. Taken together, our results indicate that the excessive uptake as well as synthesis of cholesterol should underlie neuronal cell death by l-Nor exposure, and suggest a possible link between lysosomal cholesterol storage disorders and the regulated form of necrosis in neuronal cells.

Metabolic engineering: Biosensors get the green light

October 18th, 2016 by Sarah K Hammer

Nature Chemical Biology 12, 894 (2016). doi:10.1038/nchembio.2214

Authors: Sarah K Hammer & José L Avalos

A novel approach recruits the largest prokaryotic family of ligand-induced transcriptional regulators to develop a new class of biosensors in yeast based on transcriptional activation, vastly expanding the repertoire of biosensors that could function in eukaryotic hosts.

Enzyme mechanisms: Sugary shears

October 18th, 2016 by Ethan D Goddard-Borger

Nature Chemical Biology 12, 892 (2016). doi:10.1038/nchembio.2216

Author: Ethan D Goddard-Borger

Proteolytic maturation of an important transcriptional regulator is performed by a glycosyltransferase. The reaction involves glycosylation of a glutamate residue and conversion of the γ-glycosyl ester product into an N-acyl pyroglutamate, which undergoes spontaneous hydrolysis to effect peptide backbone fission.

Antibiotics: New recipe for targeting resistance

October 18th, 2016 by Balázs Papp

Nature Chemical Biology 12, 891 (2016). doi:10.1038/nchembio.2215

Authors: Balázs Papp & Viktória Lázár

The rapid spread of antibiotic-resistant bacteria demands novel treatment approaches that delay or even reverse the evolution of resistance. A new screening strategy identifies two compounds that select against a common tetracycline-resistance gene in Escherichia coli.

Long non-coding RNAs: Pulsating RNA motifs

October 18th, 2016 by Terry L. Sheppard

Nature Chemical Biology 12, 889 (2016). doi:10.1038/nchembio.2223

Author: Terry L. Sheppard