TY - JOUR
T1 - Macrocyclization and Backbone Modification in RiPP Biosynthesis
AU - Lee, Hyunji
AU - Van Der Donk, Wilfred A.
N1 - Publisher Copyright:
© 2022 Annual Reviews Inc.. All rights reserved.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Natural product
KW - epimerization
KW - lanthipeptide
KW - radical SAM
KW - thioamide
KW - thiopeptide
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U2 - 10.1146/annurev-biochem-032620-104956
DO - 10.1146/annurev-biochem-032620-104956
M3 - Review article
C2 - 35303785
AN - SCOPUS:85132454720
SN - 0066-4154
VL - 91
SP - 269
EP - 294
JO - Annual review of biochemistry
JF - Annual review of biochemistry
ER -