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Ion Mobility-Mass Spectrometry Techniques for Determining the Structure and Mechanisms of Metal Ion Recognition and Redox Activity of Metal Binding Oligopeptides
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Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases

Linda Lauinger1, Jing Li2, Anton Shostak1

  • 1Heidelberg University Biochemistry Center, Heidelberg, Germany.

Nature Chemical Biology
|May 2, 2017
PubMed

Insights

Reduced thiolutin acts as a zinc chelator, inhibiting key metalloproteases like Rpn11 in the 19S proteasome. This antibiotic also targets other JAB1/MPN/Mov34 (JAMM) domain metalloproteases, revealing its mechanism of action.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Thiolutin, an antibiotic and anti-angiogenic compound from Streptomyces, has unknown biological targets.
  • Metalloproteases play crucial roles in cellular processes, including protein degradation and signaling.

Purpose of the Study:

  • To identify the biological targets of thiolutin.
  • To elucidate the mechanism of action of thiolutin and related compounds.

Main Methods:

  • Biochemical assays to assess zinc chelation.
  • Enzyme inhibition studies on purified JAMM domain metalloproteases.
  • Testing of other dithiolopyrrolones for inhibitory activity.

Main Results:

  • Reduced thiolutin functions as a zinc chelator.
  • Thiolutin inhibits Rpn11, a deubiquitinating enzyme of the 19S proteasome.
  • Thiolutin also inhibits other JAMM metalloproteases: Csn5, AMSH, and BRCC36.
  • Other dithiolopyrrolones were found to inhibit JAMM metalloproteases.

Conclusions:

  • Thiolutin's anti-angiogenic and antibiotic effects may stem from its inhibition of JAMM metalloproteases.
  • JAMM domain metalloproteases are potential targets for thiolutin and related dithiolopyrrolone compounds.
  • This study identifies novel targets for an existing antibiotic and provides a basis for developing new therapeutic agents.

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