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

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...

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Published inNature chemical biology Vol. 13; no. 7; pp. 709 - 714
Main Authors Lauinger, Linda, Li, Jing, Shostak, Anton, Cemel, Ibrahim Avi, Ha, Nati, Zhang, Yaru, Merkl, Philipp E, Obermeyer, Simon, Stankovic-Valentin, Nicolas, Schafmeier, Tobias, Wever, Walter J, Bowers, Albert A, Carter, Kyle P, Palmer, Amy E, Tschochner, Herbert, Melchior, Frauke, Deshaies, Raymond J, Brunner, Michael, Diernfellner, Axel
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.07.2017
Subjects
Angiogenesis
Antibiotics
BRCA1 protein
BRCA2 protein
Breast cancer
Cell surface
Chelating Agents - chemistry
Chelating Agents - pharmacology
Dose-Response Relationship, Drug
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
HeLa Cells
Humans
Inhibitors
Ions
Metalloproteases - antagonists & inhibitors
Metalloproteases - metabolism
Metalloproteinase
Molecules
Proteases
Proteasome Endopeptidase Complex - metabolism
Proteasomes
Pyrrolidinones - chemistry
Pyrrolidinones - metabolism
Pyrrolidinones - pharmacology
Receptors
Structure-Activity Relationship
Trans-Activators - antagonists & inhibitors
Trans-Activators - metabolism
Ubiquitin
Zinc
Zinc - chemistry
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Summary: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.
Bibliography:present address: German Cancer Research Center (DKFZ), Applied Bioinformatics, Heidelberg, Germany
present address: University of California Irvine, Department of Biological Chemistry, School of Medicine, 240D Med Sci I, Irvine, CA 92697–1700, USA
present address: Dept. of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
present address: Institute for Diabetes and Cancer IDC Helmholtz Center Munich, Neuherberg, Germany
ISSN:1552-4450
1552-4469
DOI:10.1038/nchembio.2370