Volume 8 Issue 6, June 2012

Volume 8 Issue 6

Metabolism is moving beyond flat biochemical charts into three dimensions, where dynamics in time and space lead to distinct biological outcomes and manipulation of metabolic pathways has the potential to address medical and societal needs. This image shows how metabolic blueprints drawn from characterization of enzyme pathways, when shaped by a more comprehensive understanding of flux, regulation and organization, can be used to construct a complete cell. Cover art by Erin Dewalt, based on a KEGG metabolic pathway map used with permission from GenomeNet.

Editorial

  • Editorial |

    Renewed interest in the biological significance and applied outcomes of metabolism is moving the field from static biochemical charts to multidimensional networks.

Commentary

  • Commentary |

    Learning metabolism inevitably involves memorizing pathways. The teacher's challenge is to motivate memorization and to help students progress beyond it. To this end, students should be taught a few fundamental chemical reaction mechanisms and how these are repeatedly used to achieve pathway goals. Pathway knowledge should then be reinforced through quantitative problems that emphasize the relevance of metabolism to bioengineering and medicine.

    • Joshua D Rabinowitz
    •  & Livia Vastag

Research Highlights

News and Views

  • News & Views |

    Crk-like (CrkL) is a key signaling protein that mediates the leukemogenic activity of Bcr-Abl. Structural investigations show that the intramolecular assembly of CrkL is entirely distinct from that of CrkII, shedding light on how CrkL specifically mediates Bcr-Abl signaling.

    • Yoshihiro Kobashigawa
    •  & Fuyuhiko Inagaki
  • News & Views |

    Heterocycles such as thiazoles are introduced into ribosomally synthesized peptide metabolites by post-translational modification. The enzyme that installs those rings has been identified, providing insight into heterocyclization biochemistry and the potential capabilities of an entire protein family.

    • Wendy L Kelly

Reviews

Articles

  • Article |

    Trp-tRNA synthetase (TrpRS) has a well-understood role in translation by facilitating aminoacylation of Trp-tRNAs. The discovery of a nuclear signaling role for TrpRS as a bridging protein for DNA-PK and PARP-1, resulting in p53 activation, explains a previously curious link between interferon-γ signaling and concomitant TrpRS overexpression.

    • Mathew Sajish
    • , Quansheng Zhou
    • , Shuji Kishi
    • , Delgado M Valdez Jr
    • , Mili Kapoor
    • , Min Guo
    • , Sunhee Lee
    • , Sunghoon Kim
    • , Xiang-Lei Yang
    •  & Paul Schimmel
  • Article |

    Antisense oligonucleotides (ASOs) are widely used to modulate gene expression through sequence-specific duplex formation with target RNAs. ASOs containing specific 2′-fluorine substitutions are shown to recruit ILF2/3 to pre-mRNA and induce exon skipping in cells and in mice.

    • Frank Rigo
    • , Yimin Hua
    • , Seung J Chun
    • , Thazha P Prakash
    • , Adrian R Krainer
    •  & C Frank Bennett
  • Article |

    Bacteria must control their metabolism to quickly adapt to changing carbon sources. PEP carboxylase is now shown to be allosterically regulated by fructose-1,6-bisphosphate in an ultrasensitive manner, turning glycolysis on and off almost instantaneously in response to glucose availability.

    • Yi-Fan Xu
    • , Daniel Amador-Noguez
    • , Marshall Louis Reaves
    • , Xiao-Jiang Feng
    •  & Joshua D Rabinowitz
  • Article |

    Cyclodehydrations in thiazole/oxazole-modified microcin biosynthesis are known to require a multiprotein complex, but full details of the reaction were not clear. Substrate analogs and isotopic labeling now show the D protein, thought to serve a scaffolding function, catalyzes ring formation and uses ATP to activate the substrate.

    • Kyle L Dunbar
    • , Joel O Melby
    •  & Douglas A Mitchell
  • Article |

    A chemoproteomic approach adapted for high-throughput screening leads to the identification of a selective PI3Kγ inhibitor. Application of this inhibitor in human and mouse cellular models reveals a role for PI3Kγ in TH17 cell differentiation.

    • Giovanna Bergamini
    • , Kathryn Bell
    • , Satoko Shimamura
    • , Thilo Werner
    • , Andrew Cansfield
    • , Katrin Müller
    • , Jessica Perrin
    • , Christina Rau
    • , Katie Ellard
    • , Carsten Hopf
    • , Carola Doce
    • , Daniel Leggate
    • , Raffaella Mangano
    • , Toby Mathieson
    • , Alison O'Mahony
    • , Ivan Plavec
    • , Faiza Rharbaoui
    • , Friedrich Reinhard
    • , Mikhail M Savitski
    • , Nigel Ramsden
    • , Emilio Hirsch
    • , Gerard Drewes
    • , Oliver Rausch
    • , Marcus Bantscheff
    •  & Gitte Neubauer
  • Article |

    Brassinosteroids (BRs) are plant growth hormones that bind the brassinosteroid receptor (BRI1) and activate its kinase domain. Exploration of BRI1-BR trafficking using a fluorescent brassinosteroid probe alongside chemical and genetic tools reveals that endocytosis pathways are essential for BR signaling attenuation and BRI1 turnover.

    • Niloufer G Irani
    • , Simone Di Rubbo
    • , Evelien Mylle
    • , Jos Van den Begin
    • , Joanna Schneider-Pizoń
    • , Jaroslava Hniliková
    • , Miroslav Šíša
    • , Dieter Buyst
    • , Josep Vilarrasa-Blasi
    • , Anna-Mária Szatmári
    • , Daniël Van Damme
    • , Kiril Mishev
    • , Mirela-Corina Codreanu
    • , Ladislav Kohout
    • , Miroslav Strnad
    • , Ana I Caño-Delgado
    • , Jiří Friml
    • , Annemieke Madder
    •  & Eugenia Russinova
  • Article |

    NMR structures of CrkL, an adaptor protein that mediates Bcr-Abl signaling in CML, reveal domain organization distinct from CrkII that allows constitutive interaction between CrkL and Abl kinase.

    • Wojciech Jankowski
    • , Tamjeed Saleh
    • , Ming-Tao Pai
    • , Ganapathy Sriram
    • , Raymond B Birge
    •  & Charalampos G Kalodimos

Focus

  • Focus |

    Metabolism in 3D

    Metabolism is moving beyond flat biochemical charts into three dimensions, where dynamics in time and space lead to distinct biological outcomes and manipulation of metabolic pathways have the potential to address medical and societal needs. In this focus issue, we feature a collection of commentary and review articles that outline some of the ideas, advances and goals that are laying the foundations for the next era of metabolism research.