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Structure and function of prodrug-activating peptidases.

José A Velilla1, Grace E Kenney2, Rachelle Gaudet1

  • 1Department of Molecular and Cellular Biology, Harvard University, 52 Oxford St, Cambridge, MA, 02138, USA.

Biochimie
|February 21, 2023
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Summary

Bacteria use prodrug strategies to manage toxic antimicrobial compounds. Specialized enzymes in the periplasm activate these compounds, with transmembrane domains playing key roles in function and transport.

Keywords:
Bacterial toxinBeta-lactamaseMembrane-embedded peptidaseNon-ribosomal peptide synthesisProdrug resistance mechanismSequence similarity network

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Area of Science:

  • Microbiology
  • Biochemistry
  • Structural Biology

Background:

  • Bacteria produce toxic antimicrobial metabolites, necessitating self-protection mechanisms.
  • A key strategy involves assembling non-toxic prodrug precursors in the cytoplasm and activating them in the periplasm via d-amino peptidases.
  • These peptidases possess an S12 hydrolase domain and transmembrane domains (TMDs), with types I and II differing in transporter components.

Purpose of the Study:

  • To review the function, substrate specificity, and assembly of ClbP, a type I peptidase activating colibactin.
  • To extend insights to other prodrug-activating peptidases and ClbP-like proteins using modeling and sequence analyses.
  • To explore potential roles of ClbP-like proteins in natural product biosynthesis/degradation and their interaction with cellular transporters.

Main Methods:

  • Review of existing studies on ClbP function and assembly.
  • Bioinformatic analyses including sequence analysis and protein modeling.
  • Examination of data supporting ClbP-transporter interactions.

Main Results:

  • The TMD is crucial for the function of prodrug-activating peptidases.
  • ClbP-like proteins, outside of resistance clusters, may have diverse roles and substrate specificities.
  • Evidence suggests ClbP interacts with transporters, potentially aiding in natural product export.

Conclusions:

  • Prodrug-activating peptidases and their TMDs are central to bacterial defense against self-produced toxins.
  • ClbP-like proteins represent a broader class with potential roles beyond resistance.
  • Further research on type II peptidases and ClbP-transporter interactions is needed for a complete understanding.