Proteases Involved in Leader Peptide Removal during RiPP Biosynthesis

Sara M. Eslami, Wilfred A. van der Donk

Research output: Contribution to journalReview articlepeer-review

Abstract

Ribosomally synthesized and post-translationally modified peptides (RiPPs) have received much attention in recent years because of their promising bioactivities and the portability of their biosynthetic pathways. Heterologous expression studies of RiPP biosynthetic enzymes identified by genome mining often leave a leader peptide on the final product to prevent toxicity to the host and to allow the attachment of a genetically encoded affinity purification tag. Removal of the leader peptide to produce the mature natural product is then carried out in vitro with either a commercial protease or a protease that fulfills this task in the producing organism. This review covers the advances in characterizing these latter cognate proteases from bacterial RiPPs and their utility as sequence-dependent proteases. The strategies employed for leader peptide removal have been shown to be remarkably diverse. They include one-step removal by a single protease, two-step removal by two dedicated proteases, and endoproteinase activity followed by aminopeptidase activity by the same protease. Similarly, the localization of the proteolytic step varies from cytoplasmic cleavage to leader peptide removal during secretion to extracellular leader peptide removal. Finally, substrate recognition ranges from highly sequence specific with respect to the leader and/or modified core peptide to nonsequence specific mechanisms.

Original languageEnglish (US)
Pages (from-to)20-36
Number of pages17
JournalACS Bio and Med Chem Au
Volume4
Issue number1
Early online dateDec 13 2023
DOIs
StatePublished - Feb 21 2024

Keywords

  • cyclic peptides
  • leader peptide
  • macrocyclase
  • maturation
  • metalloprotease
  • peptidase
  • protease
  • proteolysis
  • RiPP

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery

Fingerprint

Dive into the research topics of 'Proteases Involved in Leader Peptide Removal during RiPP Biosynthesis'. Together they form a unique fingerprint.

Cite this