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.
MeSH terms
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Chelating Agents / chemistry
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Chelating Agents / pharmacology*
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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HeLa Cells
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Humans
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Metalloproteases / antagonists & inhibitors*
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Metalloproteases / metabolism
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Proteasome Endopeptidase Complex / metabolism
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Pyrrolidinones / chemistry
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Pyrrolidinones / metabolism
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Pyrrolidinones / pharmacology
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Structure-Activity Relationship
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / metabolism
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Zinc / chemistry*
Substances
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Chelating Agents
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Enzyme Inhibitors
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PSMD14 protein, human
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Pyrrolidinones
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Trans-Activators
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acetopyrrothine
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Metalloproteases
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Proteasome Endopeptidase Complex
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Zinc
Associated data
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PubChem-Substance/333329529
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PubChem-Substance/333329536
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PubChem-Substance/333329537
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PubChem-Substance/333329538
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PubChem-Substance/333329539
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PubChem-Substance/333329540
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PubChem-Substance/333329541
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PubChem-Substance/333329542
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PubChem-Substance/333329543
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PubChem-Substance/333329530
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PubChem-Substance/333329531
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PubChem-Substance/333329532
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PubChem-Substance/333329533
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PubChem-Substance/333329534
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PubChem-Substance/333329535