Volume 8 Issue 3, March 2012

Volume 8 Issue 3

A bioinformatics analysis of untargeted metabolomic data defines N,N-dimethylsphingosine as a chemical trigger for neuropathic pain. This image depicts the metabolomic alignment process as performed by the bioinformatic software XCMS, superimposed on a neural synapse. Cover art by Erin Dewalt, based on an image from Gary Siuzdak and Gary Patti, using artwork with permission from Purdue Pharma L.P. Brief Communication, p232

Research Highlights

News and Views

  • News & Views |

    Metal ions are frequently used in enzyme catalysis. The extension of computational methods to metalloenzyme redesign opens up new ways to construct enzymes with new functions.

    • Birte Höcker
  • News & Views |

    Osmolytes that normally accumulate in cells to equilibrate osmotic stress are also called chemical chaperones because of their ability to stabilize native proteins in vitro. A recent paper shows that various chemical chaperones differently alter the cellular milieu and permit the appearance of osmolyte-specific protein mutant variants during evolution.

    • Paolo De Los Rios
    •  & Pierre Goloubinoff
  • News & Views |

    A combination of genetic and pharmacological approaches using mouse leukemia models show that STAT5 phosphorylation is one of the major drivers of the proliferation of Philadelphia chromosome–positive (BCR-ABL-positive or Ph+) chronic myeloid leukemia. Once BCR-ABL expression has been established, JAK2 is required only for lymphoid cell transformation, not for the maintenance of the lymphoid or myeloid leukemia.

    • Doriano Fabbro

Brief Communications

  • Brief Communication |

    Untargeted metabolomics reveals a dysregulation of sphingolipid production during neuropathic pain exemplified by N,N-dimethylsphingosine, whose upregulation is involved in the generation of pain.

    • Gary J. Patti
    • , Oscar Yanes
    • , Leah P Shriver
    • , Jean-Phillipe Courade
    • , Ralf Tautenhahn
    • , Marianne Manchester
    •  & Gary Siuzdak
  • Brief Communication |

    Selection of clones resistant to drugs in human cells, followed by massively parallel transcriptome sequencing of these clones and bioinformatics analyses to identify genes mutated with high frequency, allow for identification of direct targets and indirect resistance mechanisms of cytotoxic drugs.

    • Sarah A Wacker
    • , Benjamin R Houghtaling
    • , Olivier Elemento
    •  & Tarun M Kapoor

Articles

  • Article |

    Osmolytes act as chemical chaperones capable of directly assisting the folding of destabilizing mutations in proteins in vivo, with different osmolytes having distinct targets and thereby increasing the level of genetic variability.

    • Anannya Bandyopadhyay
    • , Kanika Saxena
    • , Neha Kasturia
    • , Vijit Dalal
    • , Niraj Bhatt
    • , Asher Rajkumar
    • , Shuvadeep Maity
    • , Shantanu Sengupta
    •  & Kausik Chakraborty
  • Article |

    NMR and structural analyses of DHFR complexes with inhibitors of differing affinities define a model for ligand dissociation involving conformational switching and a new excited state that mediates the dissociation.

    • Mary J Carroll
    • , Randall V Mauldin
    • , Anna V Gromova
    • , Scott F Singleton
    • , Edward J Collins
    •  & Andrew L Lee
  • Article |

    Glycosylation is a well-known post-translational modification, but identifying specific roles for the attached glycans is often challenging. The identification and investigation of a new O-GlcNAc site on the transcription factor CREB provides insights into how glycosylation works together with phosphorylation to coordinate neural function.

    • Jessica E Rexach
    • , Peter M Clark
    • , Daniel E Mason
    • , Rachael L Neve
    • , Eric C Peters
    •  & Linda C Hsieh-Wilson
  • Article |

    Semisynthetic constructs of protein kinase CK2 incorporating nonhydrolyzable post-translational modifications now demonstrate the interplay between phosphorylation and glycosylation in regulating CK2 stability, controlling substrate specificity and modifying interactions with regulatory proteins.

    • Mary Katherine Tarrant
    • , Hee-Sool Rho
    • , Zhi Xie
    • , Yu Lin Jiang
    • , Christopher Gross
    • , Jeffrey C Culhane
    • , Gai Yan
    • , Jiang Qian
    • , Yoshitaka Ichikawa
    • , Tatsuji Matsuoka
    • , Natasha Zachara
    • , Felicia A Etzkorn
    • , Gerald W Hart
    • , Jun Seop Jeong
    • , Seth Blackshaw
    • , Heng Zhu
    •  & Philip A Cole
  • Article |

    The combination of a caged morpholino and a photoactivated fluorophore, allowing isolation of targeted cells by FACS, and subsequent transcriptional profiling reveals new and temporally distinct targets for Ntla during notochord development in zebrafish.

    • Ilya A Shestopalov
    • , Cameron L W Pitt
    •  & James K Chen
  • Article |

    MLL fusion genes often encode leukemogenic proteins that depend on interaction with menin, a component of the MLL SET1-like histone methyltransferase complex. MI-2 and MI-3 are the first small molecules that can block menin–MLL fusion protein interaction and their oncogenic effects in cells.

    • Jolanta Grembecka
    • , Shihan He
    • , Aibin Shi
    • , Trupta Purohit
    • , Andrew G Muntean
    • , Roderick J Sorenson
    • , Hollis D Showalter
    • , Marcelo J Murai
    • , Amalia M Belcher
    • , Thomas Hartley
    • , Jay L Hess
    •  & Tomasz Cierpicki
  • Article |

    Although JAK2 inhibitors were proposed to be beneficial in chronic myeloid leukemia, myeloid transformation and STAT5 activation in BCR-ABL–positive leukemias are JAK2 independent. Mechanistic investigations reveal that certain JAK2 inhibitors act via off-target inhibition of BCR-ABL.

    • Oliver Hantschel
    • , Wolfgang Warsch
    • , Eva Eckelhart
    • , Ines Kaupe
    • , Florian Grebien
    • , Kay-Uwe Wagner
    • , Giulio Superti-Furga
    •  & Veronika Sexl
  • Article |

    Metals serve as unique structural and functional elements in biology, providing a wealth of reactivities not available in a wholly proteinogenic active site. The computational redesign and directed evolution of zinc enzymes to create a phosphotriesterase provides insights into how these elements can be utilized in the development of new functions.

    • Sagar D Khare
    • , Yakov Kipnis
    • , Per Jr Greisen
    • , Ryo Takeuchi
    • , Yacov Ashani
    • , Moshe Goldsmith
    • , Yifan Song
    • , Jasmine L Gallaher
    • , Israel Silman
    • , Haim Leader
    • , Joel L Sussman
    • , Barry L Stoddard
    • , Dan S Tawfik
    •  & David Baker
  • Article |

    Identifying DNA sequences that adopt alternative structures within the context of genomic DNA presents a major challenge. Pyridostatin, a G-quadruplex–specific chemical probe, was shown to induce DNA damage at specific genomic sites, including the proto-oncogene SRC, leading to cell cycle arrest in human cancer cells.

    • Raphaël Rodriguez
    • , Kyle M Miller
    • , Josep V Forment
    • , Charles R Bradshaw
    • , Mehran Nikan
    • , Sébastien Britton
    • , Tobias Oelschlaegel
    • , Blerta Xhemalce
    • , Shankar Balasubramanian
    •  & Stephen P Jackson
  • Article |

    Halofuginone was recently shown to inhibit the differentiation of T helper 17 (TH17) cells, which are associated with autoimmune diseases. The demonstration that halofuginone inhibits prolyl-tRNA synthetase activity explains the observed activation of the amino acid response pathway in TH17 cells and identifies amino acid restriction pathways as potential drug targets in inflammatory disease.

    • Tracy L Keller
    • , Davide Zocco
    • , Mark S Sundrud
    • , Margaret Hendrick
    • , Maja Edenius
    • , Jinah Yum
    • , Yeon-Jin Kim
    • , Hak-Kyo Lee
    • , Joseph F Cortese
    • , Dyann F Wirth
    • , John David Dignam
    • , Anjana Rao
    • , Chang-Yeol Yeo
    • , Ralph Mazitschek
    •  & Malcolm Whitman

Corrigenda