Polyketide synthase chimeras reveal key role of ketosynthase domain in chain branching

October 19th, 2015 by Srividhya Sundaram

Nature Chemical Biology 11, 949 (2015). doi:10.1038/nchembio.1932

Authors: Srividhya Sundaram, Daniel Heine & Christian Hertweck

Biosynthesis of rhizoxin in Burkholderia rhizoxinica affords an unusual polyketide synthase module with ketosynthase and branching domains that install the δ-lactone, conferring antimitotic activity. To investigate their functions in chain branching, we designed chimeric modules with structurally similar domains from a glutarimide-forming module and a dehydratase. Biochemical, kinetic and mutational analyses reveal a structural role of the accessory domains and multifarious catalytic actions of the ketosynthase.

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Chemical libraries: How dark is HTS dark matter?

October 19th, 2015 by Ricardo Macarron

Nature Chemical Biology 11, 904 (2015). doi:10.1038/nchembio.1937

Author: Ricardo Macarron

Selecting compounds for the chemical library is the foundation of high-throughput screening (HTS). After some years and multiple HTS campaigns, many molecules in the Novartis and NIH Molecular Libraries Program screening collections have never been found to be active. An in-depth exploration of the bioactivity of this 'dark matter' does in fact reveal some compounds of interest.

Dark chemical matter as a promising starting point for drug lead discovery

October 19th, 2015 by Anne Mai Wassermann

Nature Chemical Biology 11, 958 (2015). doi:10.1038/nchembio.1936

Authors: Anne Mai Wassermann, Eugen Lounkine, Dominic Hoepfner, Gaelle Le Goff, Frederick J King, Christian Studer, John M Peltier, Melissa L Grippo, Vivian Prindle, Jianshi Tao, Ansgar Schuffenhauer, Iain M Wallace, Shanni Chen, Philipp Krastel, Amanda Cobos-Correa, Christian N Parker, John W Davies & Meir Glick

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Light-assisted small-molecule screening against protein kinases

October 12th, 2015 by Álvaro Inglés-Prieto

Nature Chemical Biology 11, 952 (2015). doi:10.1038/nchembio.1933

Authors: Álvaro Inglés-Prieto, Eva Reichhart, Markus K Muellner, Matthias Nowak, Sebastian M B Nijman, Michael Grusch & Harald Janovjak

High-throughput live-cell screens are intricate elements of systems biology studies and drug discovery pipelines. Here, we demonstrate an optogenetics-assisted method that avoids the need for chemical activators and reporters, reduces the number of operational steps and increases information content in a cell-based small-molecule screen against human protein kinases, including an orphan receptor tyrosine kinase. This blueprint for all-optical screening can be adapted to many drug targets and cellular processes.

Determinants of amyloid fibril degradation by the PDZ protease HTRA1

October 5th, 2015 by Simon Poepsel

Nature Chemical Biology 11, 862 (2015). doi:10.1038/nchembio.1931

Authors: Simon Poepsel, Andreas Sprengel, Barbara Sacca, Farnusch Kaschani, Markus Kaiser, Christos Gatsogiannis, Stefan Raunser, Tim Clausen & Michael Ehrmann

New IDH1 mutant inhibitors for treatment of acute myeloid leukemia

October 5th, 2015 by Ujunwa C Okoye-Okafor

Nature Chemical Biology 11, 878 (2015). doi:10.1038/nchembio.1930

Authors: Ujunwa C Okoye-Okafor, Boris Bartholdy, Jessy Cartier, Enoch N Gao, Beth Pietrak, Alan R Rendina, Cynthia Rominger, Chad Quinn, Angela Smallwood, Kenneth J Wiggall, Alexander J Reif, Stanley J Schmidt, Hongwei Qi, Huizhen Zhao, Gerard Joberty, Maria Faelth-Savitski, Marcus Bantscheff, Gerard Drewes, Chaya Duraiswami, Pat Brady, Arthur Groy, Swathi-Rao Narayanagari, Iléana Antony-Debre, Kelly Mitchell, Heng Rui Wang, Yun-Ruei Kao, Maximilian Christopeit, Luis Carvajal, Laura Barreyro, Elisabeth Paietta, Hideki Makishima, Britta Will, Nestor Concha, Nicholas D Adams, Benjamin Schwartz, Michael T McCabe, Jaroslav Maciejewski, Amit Verma & Ulrich Steidl

Crystal structure of the Varkud satellite ribozyme

September 28th, 2015 by Nikolai B Suslov

Nature Chemical Biology 11, 840 (2015). doi:10.1038/nchembio.1929

Authors: Nikolai B Suslov, Saurja DasGupta, Hao Huang, James R Fuller, David M J Lilley, Phoebe A Rice & Joseph A Piccirilli

Ribozymes: How RNA catalyzes cyclization

September 28th, 2015 by Zhensheng Zhong

Nature Chemical Biology 11, 830 (2015). doi:10.1038/nchembio.1928

Authors: Zhensheng Zhong & Gang Chen

The long-awaited crystal structure of the Varkud satellite (VS) ribozyme dimer provides atomic-level insights into how the VS ribozyme folds and catalyzes RNA circularization during rolling circle replication, as well as revealing convergent evolution used by RNAs to catalyze an SN2 reaction.

Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism

September 28th, 2015 by Hongjun Yu

Nature Chemical Biology 11, 847 (2015). doi:10.1038/nchembio.1927

Authors: Hongjun Yu, Megumi Takeuchi, Jamie LeBarron, Joshua Kantharia, Erwin London, Hans Bakker, Robert S Haltiwanger, Huilin Li & Hideyuki Takeuchi

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Two cytochromes P450 catalyze S-heterocyclizations in cabbage phytoalexin biosynthesis

September 21st, 2015 by Andrew P Klein

Nature Chemical Biology 11, 837 (2015). doi:10.1038/nchembio.1914

Authors: Andrew P Klein & Elizabeth S Sattely

Phytoalexins are abundant in edible crucifers and have important biological activities, yet no dedicated gene for their biosynthesis is known. Here, we report two new cytochromes P450 from Brassica rapa (Chinese cabbage) that catalyze unprecedented S-heterocyclizations in cyclobrassinin and spirobrassinin biosynthesis. Our results provide genetic and biochemical insights into the biosynthesis of a prominent pair of dietary metabolites and have implications for pathway discovery across >20 recently sequenced crucifers.

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