Volume 8 Issue 4, April 2012

Volume 8 Issue 4

Dissection of an HR-PKS ketoreductase demonstrates substrate length–dependent stereospecificity in enzyme function and identifies motifs responsible for substrate recognition during the biosynthesis of hypothemycin in Hypomyces subiculosus. This image shows a wild mushroom infected by Hypomyces sp. Cover art by Erin Dewalt, based on an image from J.J. Harrison. Brief Communication, p331; News & Views, p322

Research Highlights

News and Views

  • News & Views |

    Selective reduction of keto groups contributes to the structural diversity of polyketide natural products. New research on fungal polyketide synthases reveals unusual biosynthetic programming in which a single ketoreductase domain shows different stereochemical preferences on the basis of substrate-chain length.

    • Ikuro Abe
  • News & Views |

    The activity of the anaphase-promoting complex is regulated by the autoubiquitination of Cdc20. How this autoubiquitination is regulated remains an open question. The pharmacological inhibitor TAME now provides insight into this regulation.

    • Ian T Foe
    •  & David P Toczyski
  • News & Views |

    Owing to population aging, the number of individuals suffering from Alzheimer's disease is rapidly increasing; consequently, finding an effective treatment is becoming an increasingly important goal. The use of O-GlcNAcase inhibitors is emerging as a promising track to prevent and slow disease progression.

    • Tony Lefebvre
  • News & Views |

    The cell wall of tubercle bacilli is targeted by many drugs. A new adamantyl urea compound unveils MmpL3, a member of the resistance, nodulation and division protein family, as the long-sought trehalose monomycolate transporter, essential for translocation of mycolic acids into the cell envelope.

    • Stewart T Cole

Brief Communications

  • Brief Communication |

    X-ray crystallographic analysis of thymine DNA glycosylase (TDG) in complex with DNA containing 5-carboxylcytosine (5caC) analogs reveals that 5caC is a preferred substrate of TDG, providing support for a 5-methylcytosine demethylation pathway involving 5-methylcytosine oxidation and removal by base-excision repair glycosylases.

    • Liang Zhang
    • , Xingyu Lu
    • , Junyan Lu
    • , Haihua Liang
    • , Qing Dai
    • , Guo-Liang Xu
    • , Cheng Luo
    • , Hualiang Jiang
    •  & Chuan He
  • Brief Communication |

    The iterative, highly-reducing polyketide synthases use a single copy of each domain to transform multiple substrates, defying conventional rules regarding enzyme function. Synthetic tool compounds and hybrid constructs now provide insights into the specificity of the ketoreductase in dehydrozearalenol biosynthesis.

    • Hui Zhou
    • , Zhizeng Gao
    • , Kangjian Qiao
    • , Jingjing Wang
    • , John C Vederas
    •  & Yi Tang

Articles

  • Article |

    An adamantyl urea derivative identified as a potent bactericidal compound against Mycobacterium species and multidrug-resistant M. tuberculosis targets a late step in biogenesis of very-long-chain cell wall–bound mycolic acids—by inhibiting the transport of the fatty acids across the bacterial plasma membrane.

    • Anna E Grzegorzewicz
    • , Ha Pham
    • , Vijay A K B Gundi
    • , Michael S Scherman
    • , Elton J North
    • , Tamara Hess
    • , Victoria Jones
    • , Veronica Gruppo
    • , Sarah E M Born
    • , Jana Korduláková
    • , Sivagami Sundaram Chavadi
    • , Christophe Morisseau
    • , Anne J Lenaerts
    • , Richard E Lee
    • , Michael R McNeil
    •  & Mary Jackson
  • Article |

    Optimized negative-staining and cryo–positive staining EM reveals that human cholesteryl ester transfer protein penetrates into HDL and LDL from each distal end and potentially forms a continuous tunnel by connecting its internal series of isolated hydrophobic cavities together for cholesteryl ester transfer.

    • Lei Zhang
    • , Feng Yan
    • , Shengli Zhang
    • , Dongsheng Lei
    • , M Arthur Charles
    • , Giorgio Cavigiolio
    • , Michael Oda
    • , Ronald M Krauss
    • , Karl H Weisgraber
    • , Kerry-Anne Rye
    • , Henry J Pownall
    • , Xiayang Qiu
    •  & Gang Ren
  • Article |

    The unusual crosslinks between cysteine residues and the peptide backbone in the antibiotic peptide subtilosin A are formed by a new member of the radical SAM enzyme superfamily that contains two functionally linked [4Fe-4S] clusters.

    • Leif Flühe
    • , Thomas A Knappe
    • , Michael J Gattner
    • , Antje Schäfer
    • , Olaf Burghaus
    • , Uwe Linne
    •  & Mohamed A Marahiel
  • Article |

    Macrocycles are well represented in natural product structures but have been challenging to access for inclusion in synthetic libraries. A new method uses ring expansion to convert fused small rings into macrolactones and macrolactams that occupy natural product–like chemical space.

    • Felix Kopp
    • , Christopher F Stratton
    • , Lakshmi B Akella
    •  & Derek S Tan
  • Article |

    DNA-templated macrocycles bind the ATP binding pocket of Src kinase, locking it into an inactive conformation. These small-molecule inhibitors compete with both ATP and substrate for binding and inhibit the T338I gatekeeper mutant version of Src.

    • George Georghiou
    • , Ralph E Kleiner
    • , Michael Pulkoski-Gross
    • , David R Liu
    •  & Markus A Seeliger
  • Article |

    Studying specific cellular responses elicited by compartmented cAMP signals in real time has been difficult. A new method called SMICUS overcomes this challenge and reveals a resident pool of nuclear PKA that can convert cAMP signals to rapid responses.

    • Vedangi Sample
    • , Lisa M DiPilato
    • , Jason H Yang
    • , Qiang Ni
    • , Jeffrey J Saucerman
    •  & Jin Zhang
  • Article |

    TAME, an inhibitor of the ubiquitin ligase APC, promotes autoubiquitination and dissociation of Cdc20, an APC activator. In the presence of APC substrate, TAME decreases the catalytic activity of APC-Cdc20 complex and decouples substrate ubiquitination from proteasomal degradation.

    • Xing Zeng
    •  & Randall W King