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Maruyama C.,Fukui Prefectural University | Toyoda J.,Fukui Prefectural University | Kato Y.,Toyama Prefectural University | Izumikawa M.,Japan Biological Informatics Consortium | And 5 more authors.
Nature Chemical Biology | Year: 2012

The streptothricin (ST) antibiotics, produced by Streptomyces bacteria, contain L-β-lysine ((3S)-3,6-diaminohexanoic acid) oligopeptides as pendant chains. Here we describe three unusual nonribosomal peptide synthetases (NRPSs) involved in ST biosynthesis: ORF 5 (a stand-alone adenylation (A) domain), ORF 18 (containing thiolation (T) and condensation (C) domains) and ORF 19 (a stand-alone A domain). We demonstrate that ST biosynthesis begins with adenylation of L-β-lysine by ORF 5, followed by transfer to the T domain of ORF 18. In contrast, L-β-lysine molecules adenylated by ORF 19 are used to elongate an L-β-lysine peptide chain on ORF 18, a reaction unexpectedly catalyzed by ORF 19 itself. Finally, the C domain of ORF 18 catalyzes the condensation of L-β-lysine oligopeptides covalently bound to ORF 18 with a freely diffusible intermediate to release the ST products. These results highlight an unusual activity for an A domain and unique mechanisms of crosstalk within NRPS machinery. © 2012 Nature America, Inc. All rights reserved. Source


Prokop Z.,Masaryk University | Sato Y.,Tohoku University | Brezovsky J.,Masaryk University | Mozga T.,Masaryk University | And 11 more authors.
Angewandte Chemie - International Edition | Year: 2010

In the loop: Engineering of the surface loop in haloalkane dehalogenases affects their enantiodiscrimination behavior. The temperature dependence of the enantioselectivity (lnE versus 1/T) of β-bromoalkanes by haloalkane dehalogenases is reversed (red data points) by deletion of the surface loop; the selectivity switches back when an additional single-point mutation is made. This behavior is not observed for -bromoesters. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Hashimoto T.,University of Tokyo | Hashimoto J.,Japan Biological Informatics Consortium | Teruya K.,Okinawa Institute of Advanced science | Hirano T.,Okinawa Institute of Advanced science | And 5 more authors.
Journal of the American Chemical Society | Year: 2015

Versipelostatin (VST) is an unusual 17-membered macrocyclic polyketide product that contains a spirotetronate skeleton. In this study, the entire VST biosynthetic gene cluster (vst) spanning 108 kb from Streptomyces versipellis 4083-SVS6 was identified by heterologous expression using a bacterial artificial chromosome vector. Here, we demonstrate that an enzyme, VstJ, catalyzes the stereoselective [4+2]-cycloaddition between the conjugated diene and the exocyclic olefin of a newly identified tetronate-containing intermediate to form the spirotetronate skeleton during VST biosynthesis. © 2014 American Chemical Society. Source


Patent
Kyoto University, Japan Biological Informatics Consortium, Japan National Institute of Advanced Industrial Science and Technology | Date: 2011-02-16

Provided are a method of improving the efficiency of establishment of iPS cells, comprising the step of contacting one or more substances selected from the group consisting of members of the GLIS family (e.g., GLIS1) and nucleic acids that encode the same and one or more substances selected from the group consisting of members of the Klf family and nucleic acids that encode the same, with a somatic cell, an iPS cell comprising an exogenous nucleic acid that encodes a member of the GLIS family or a member of the Klf family, that can be obtained by the method, and a method of producing a somatic cell by inducing the differentiation of the iPS cell.


Tokunaga Y.,Japan Biological Informatics Consortium | Tokunaga Y.,University of Tokyo | Takeuchi K.,Japan National Institute of Advanced Industrial Science and Technology | Takahashi H.,Japan National Institute of Advanced Industrial Science and Technology | And 3 more authors.
Nature Structural and Molecular Biology | Year: 2014

Mitogen-activated protein kinases (MAPKs) are essential to intracellular signal transduction. MAPKs anchor their pathway-specific substrates through so-called 'docking interactions' at locations distal from the active site. Docking interactions ensure efficient substrate recognition, but their contribution to the kinase reaction itself remains unclear. Herein, we use solution NMR to analyze the interaction between dually phosphorylated, active human p38 and the C-terminal fragments of its substrate MK2. p38 phosphorylation and ATP loading collaboratively induce the active conformation; subsequently, p38 accommodates MK2 phosphoacceptor residues in its active site. The docking interaction enhances binding of ATP and the phosphoacceptor to p38, accelerating the phosphotransfer reaction. Thus, the docking interaction enhances p38 's enzymatic activity toward pathway-specific substrates allosterically as well as by the anchor effect. These findings clarify how MAPK cascades are organized in cells, even under ATP-depleted conditions often associated with environmental stress. Source

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