2. Academic Validation
  3. Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases

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

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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