1. Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases.
- Author
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Lauinger L, Li J, Shostak A, Cemel IA, Ha N, Zhang Y, Merkl PE, Obermeyer S, Stankovic-Valentin N, Schafmeier T, Wever WJ, Bowers AA, Carter KP, Palmer AE, Tschochner H, Melchior F, Deshaies RJ, Brunner M, and Diernfellner A
- Subjects
- Chelating Agents chemistry, Dose-Response Relationship, Drug, Enzyme Inhibitors chemistry, HeLa Cells, Humans, Metalloproteases metabolism, Proteasome Endopeptidase Complex metabolism, Pyrrolidinones chemistry, Pyrrolidinones metabolism, Pyrrolidinones pharmacology, Structure-Activity Relationship, Trans-Activators metabolism, Chelating Agents pharmacology, Enzyme Inhibitors pharmacology, Metalloproteases antagonists & inhibitors, Trans-Activators antagonists & inhibitors, Zinc chemistry
- 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.
- Published
- 2017
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