Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases

  • Nat Chem Biol. 2017 Jul;13(7):709-714. doi: 10.1038/nchembio.2370.
Linda Lauinger  1 ,  Jing Li  2 ,  Anton Shostak  1 ,  Ibrahim Avi Cemel  1 ,  Nati Ha  1 ,  Yaru Zhang  2 ,  Philipp E Merkl  3 ,  Simon Obermeyer  3 ,  Nicolas Stankovic-Valentin  4 ,  Tobias Schafmeier  1 ,  Walter J Wever  5 ,  Albert A Bowers  5 ,  Kyle P Carter  6 ,  Amy E Palmer  6 ,  Herbert Tschochner  3 ,  Frauke Melchior  4 ,  Raymond J Deshaies  2  7 ,  Michael Brunner  1 ,  Axel Diernfellner  1
Affiliations
  • 1. Heidelberg University Biochemistry Center, Heidelberg, Germany.
  • 2. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
  • 3. Lehrstuhl Biochemie III, Biochemie Zentrum Regensburg, Universität Regensburg, Regensburg, Germany.
  • 4. Zentrum Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany.
  • 5. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 6. Department of Chemistry and Biochemistry, BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado, USA.
  • 7. Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA.
PMID: 28459440 DOI: 10.1038/nchembio.2370
Abstract

Thiolutin is a disulfide-containing Antibiotic and anti-angiogenic compound produced by Streptomyces. Its biological targets are not known. We show that reduced thiolutin is a zinc chelator that inhibits the JAB1/MPN/Mov34 (JAMM) domain-containing metalloprotease Rpn11, a deubiquitinating enzyme of the 19S Proteasome. Thiolutin also inhibits the JAMM metalloproteases Csn5, the deneddylase of the COP9 signalosome; AMSH, which regulates ubiquitin-dependent sorting of cell-surface receptors; and BRCC36, a K63-specific Deubiquitinase of the BRCC36-containing isopeptidase complex and the BRCA1-BRCA2-containing complex. We provide evidence that other dithiolopyrrolones also function as inhibitors of JAMM metalloproteases.

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