Volume 8 Issue 11, November 2012

Volume 8 Issue 11

Cancer mutations lead to a variety of outcomes, including—for isocitrate dehydrogenase—gains of function unique from that of the parent molecule. A new design strategy transplants these activating mutations into a homologous protein to deliver a new enzyme function and a biocatalytic intermediate to the commodity chemical adipic acid. This composite shows the transfer of mutational information from anaplastic oligodendroglioma through to an adipic acid–derived nylon fabric. Cover art by MaryLou Quillen, based on imagery from Zachary Reitman, Steven Conlon and Roger McLendon. Brief Communication, p887; News & Views, p874

Editorial

  • Editorial |

    The ENCODE project provides fundamental insights into the genome and large-scale science, inspiring future collaboration at the genomics–chemical biology interface.

Research Highlights

News and Views

  • News & Views |

    A gain of function in the cancer-associated mutant of isocitrate dehydrogenase inspired protein engineering of Saccharomyces cerevisiae homoisocitrate dehydrogenase to create a 2-hydroxyadipate dehydrogenase. This neoactivity yields chirally pure (R)-2-hydroxyadipic acid, a synthetic precursor to the industrially valuable adipic acid used in pharmaceuticals and synthetic polymers.

    • Lenny Dang
  • News & Views |

    The first direct chemical inhibitor of a key histone-methylating enzyme provides a new tool to alter epigenetic states and genome expression profiles in normal and cancer cells.

    • Jeffrey A Simon
  • News & Views |

    A metabolic route including a RubisCO-like protein links polyamine metabolism with isoprenoid biosynthesis in the photosynthetic bacterium Rhodospirillum rubrum. Methanethiol is released in the pathway but is recaptured in the form of methionine, and thus methylthioadenosine, previously regarded as something of a byproduct of polyamine biosynthesis, is converted to two major cell components.

    • Haruyuki Atomi

Review

Brief Communication

  • Brief Communication |

    A new approach for rational enzyme design uses gain-of-function cancer mutations to guide homologous mutations in homoisocitrate dehydrogenase, yielding a biocatalytic path to (R)-2-hydroxyadipate, a precursor for the major commodity chemical adipic acid.

    • Zachary J Reitman
    • , Bryan D Choi
    • , Ivan Spasojevic
    • , Darell D Bigner
    • , John H Sampson
    •  & Hai Yan

Articles

  • Article |

    EZH2 is a protein methyltransferase component of the polycomb repressive complex 2 (PRC2) that installs the H3K27me3 chromatin mark. EPZ005687 inhibits EZH2 function and H3K27 trimethylation in cells and selectively kills lymphoma cells that require EZH2 for proliferation.

    • Sarah K Knutson
    • , Tim J Wigle
    • , Natalie M Warholic
    • , Christopher J Sneeringer
    • , Christina J Allain
    • , Christine R Klaus
    • , Joelle D Sacks
    • , Alejandra Raimondi
    • , Christina R Majer
    • , Jeffrey Song
    • , Margaret Porter Scott
    • , Lei Jin
    • , Jesse J Smith
    • , Edward J Olhava
    • , Richard Chesworth
    • , Mikel P Moyer
    • , Victoria M Richon
    • , Robert A Copeland
    • , Heike Keilhack
    • , Roy M Pollock
    •  & Kevin W Kuntz
  • Article |

    A small molecule that disrupts interaction between Nur77 and LKB1 leads to LKB1 exit from the nucleus to activate cytoplasmic AMPK and, ultimately, reduces blood glucose and insulin in diabetic mice.

    • Yan-yan Zhan
    • , Yan Chen
    • , Qian Zhang
    • , Jia-jia Zhuang
    • , Min Tian
    • , Hang-zi Chen
    • , Lian-ru Zhang
    • , Hong-kui Zhang
    • , Jian-ping He
    • , Wei-jia Wang
    • , Rong Wu
    • , Yuan Wang
    • , Chunfang Shi
    • , Kai Yang
    • , An-zhong Li
    • , Yong-zhen Xin
    • , Terytty Yang Li
    • , James Y Yang
    • , Zhong-hui Zheng
    • , Chun-dong Yu
    • , Sheng-Cai Lin
    • , Chawnshang Chang
    • , Pei-qiang Huang
    • , Tianwei Lin
    •  & Qiao Wu
  • Article |

    A systems-pharmacology approach reveals that the combined off-target activity of two kinase inhibitors that impedes MAPK signaling to decrease expression of Myc target genes increases apoptosis in CML cells containing gatekeeper mutations in BCR-ABL.

    • Georg E Winter
    • , Uwe Rix
    • , Scott M Carlson
    • , Karoline V Gleixner
    • , Florian Grebien
    • , Manuela Gridling
    • , André C Müller
    • , Florian P Breitwieser
    • , Martin Bilban
    • , Jacques Colinge
    • , Peter Valent
    • , Keiryn L Bennett
    • , Forest M White
    •  & Giulio Superti-Furga
  • Article |

    Mass spectrometric profiling has revealed S-geranylation as a new tRNA modification and identified SelU as the tailoring enzyme in bacterial cells. Nucleotide S-geranylation was found in the anticodon of several tRNAs and regulates translational frameshifting and codon usage.

    • Christoph E Dumelin
    • , Yiyun Chen
    • , Aaron M Leconte
    • , Y Grace Chen
    •  & David R Liu
  • Article |

    A compound derived from a structure-based screen binds to an allosteric site that includes residues of both the helicase and protease domains of HCV NS3, stabilizing an inactive conformation and inhibiting viral replication.

    • Susanne M Saalau-Bethell
    • , Andrew J Woodhead
    • , Gianni Chessari
    • , Maria G Carr
    • , Joseph Coyle
    • , Brent Graham
    • , Steven D Hiscock
    • , Christopher W Murray
    • , Puja Pathuri
    • , Sharna J Rich
    • , Caroline J Richardson
    • , Pamela A Williams
    •  & Harren Jhoti
  • Article |

    Combined omics techniques lead to the functional assignment of four enzymes involved in a new methionine salvage pathway linking polyamine metabolism with isoprenoid biosynthesis. This reaction sequence involves a homolog of nature's most abundant protein, the CO2-fixing enzyme RubisCO.

    • Tobias J Erb
    • , Bradley S Evans
    • , Kyuil Cho
    • , Benjamin P Warlick
    • , Jaya Sriram
    • , B McKay Wood
    • , Heidi J Imker
    • , Jonathan V Sweedler
    • , F Robert Tabita
    •  & John A Gerlt
  • Article |

    The use of abbreviated pathway constructs leads to trapping of a series of cobalamin intermediates, allowing assignment of the full biosynthetic pathway and defining the roles of CobL as a dual-function methyltransferase and CobE as a likely carrier protein, perhaps facilitating metabolic channeling.

    • Evelyne Deery
    • , Susanne Schroeder
    • , Andrew D Lawrence
    • , Samantha L Taylor
    • , Arefeh Seyedarabi
    • , Jitka Waterman
    • , Keith S Wilson
    • , David Brown
    • , Michael A Geeves
    • , Mark J Howard
    • , Richard W Pickersgill
    •  & Martin J Warren
  • Article |

    Ferritin controls iron concentrations by storing Fe(III), but the mechanism by which Fe(II) is bound and trafficked into the protein core after oxidation remains controversial. Spectroscopic methods in combination with labeling and competition assays now define a mechanism conserved from archaea to humans.

    • Kourosh Honarmand Ebrahimi
    • , Eckhard Bill
    • , Peter-Leon Hagedoorn
    •  & Wilfred R Hagen