Macrocyclization and Backbone Modification in RiPP Biosynthesis

Research output: Contribution to journalReview articlepeer-review


The past decade has seen impressive advances in understanding the biosynthesis of ribosomally synthesized and posttranslationally modified peptides (RiPPs). One of the most common modifications found in these natural products is macrocyclization, a strategy also used by medicinal chemists to improve metabolic stability and target affinity and specificity. Another tool of the peptide chemist, modification of the amides in a peptide backbone, has also been observed in RiPPs. This review discusses the molecular mechanisms of biosynthesis of a subset of macrocyclic RiPP families, chosen because of the unusual biochemistry involved: the five classes of lanthipeptides (thioether cyclization by Michael-type addition), sactipeptides and ranthipeptides (thioether cyclization by radical chemistry), thiopeptides (cyclization by 4+2 cycloaddition), and streptide (cyclization by radical C-C bond formation). In addition, the mechanisms of backbone amide methylation, backbone epimerization, and backbone thioamide formation are discussed, as well as an unusual route to small molecules by posttranslational modification.

Original languageEnglish (US)
Pages (from-to)269-294
Number of pages26
JournalAnnual review of biochemistry
StatePublished - 2022


  • Natural product
  • epimerization
  • lanthipeptide
  • radical SAM
  • thioamide
  • thiopeptide

ASJC Scopus subject areas

  • Biochemistry


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