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Functional characterization of ttnd and ttnf, unveiling new insights into tautomycetin biosynthesis

Academic Article
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Overview

authors

  • Luo, Y. G.
  • Li, W. L.
  • Ju, J. H.
  • Yuan, Q. P.
  • Peters, N. R.
  • Hoffmann, F. M.
  • Huang, S. X.
  • Bugni, T. S.
  • Rajski, S.
  • Osada, H.
  • Shen, Ben

publication date

  • May 2010

journal

  • Journal of the American Chemical Society  Journal

abstract

  • The biosynthetic gene cluster for tautomycetin (TTN), a highly potent and selective protein phosphatase (PP) inhibitor isolated from Streptomyces griseochromogenes, has recently been cloned and sequenced. To better understand the transformations responsible for converting the post-polyketide synthase product into the exciting anticancer and immunosuppressive chemotherapeutic candidate TTN, we produced and characterized new analogues resulting from inactivation of two genes, ttnD and ttnF, in S. griseochromogenes. Inactivation of ttnD and ttnF, which encode for putative decarboxylase and dehydratase enzymes, respectively, afforded mutant strains SB13013 and SB13014. The DeltattnD mutant SB13013 accumulated four new TTN analogues, TTN D-1, TTN D-2, TTN D-3, and TTN D-4, whereas the DeltattnF mutant accumulated only one new TTN analogue, TTN F-1. The accumulation of these new TTN analogues defines the function of TtnD and TtnF and the timing of their chemistries in relation to installation of the C5 ketone moiety within TTN. Notably, all new analogues possess a structurally distinguishing carboxylic acid moiety, revealing that TtnD apparently cannot catalyze decarboxylation in the absence of TtnF. Additionally, cytotoxicity and PP inhibition assays reveal the importance of the functional groups installed by TtnDF and, consistent with earlier proposals, the C2''-C5 fragment of TTN to be a critical structural determinant behind the important and unique PP-1 selectivity displayed by TTN.

subject areas

  • Alkenes
  • Antineoplastic Agents
  • Bacterial Proteins
  • Carboxy-Lyases
  • Cell Line, Tumor
  • Enzyme Inhibitors
  • Furans
  • Gene Silencing
  • Humans
  • Hydro-Lyases
  • Inhibitory Concentration 50
  • Lipids
  • Multigene Family
  • Mutation
  • Phosphoprotein Phosphatases
  • Streptomyces
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Identity

PubMed Central ID

  • PMC2876980

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja9082446

PubMed ID

  • 20426415
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Additional Document Info

start page

  • 6663

end page

  • 6671

volume

  • 132

issue

  • 19

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