Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases
Authors: 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, Diernfellner A
CellNetworks People: Brunner Michael, Melchior Frauke
Journal: Nat Chem Biol. 2017 Jul;13(7):709-714. doi: 10.1038/nchembio.2370.

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.