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Targeted Rediscovery and Biosynthesis of the Farnesyl‐Transferase Inhibitor Pepticinnamin E
Author(s) -
Santa Maria Kevin C.,
Chan Andrew N.,
O'Neill Erinn M.,
Li Bo
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900025
Subject(s) - biosynthesis , nonribosomal peptide , gene cluster , polyketide , natural product , biochemistry , transferase , moiety , gene , o methyltransferase , methyltransferase , chemistry , amino acid , biology , stereochemistry , enzyme , methylation
The natural product pepticinnamin E potently inhibits protein farnesyl transferases and has potential applications in treating cancer and malaria. Pepticinnamin E contains a rare N‐terminal cinnamoyl moiety as well as several nonproteinogenic amino acids, including the unusual 2‐chloro‐3‐hydroxy‐4‐methoxy‐N‐methyl‐L‐phenylalanine. The biosynthesis of pepticinnamin E has remained uncharacterized because its original producing strain is no longer available. Here we identified a gene cluster ( pcm ) for this natural product in a new producer, Actinobacteria bacterium OK006, by means of a targeted rediscovery strategy. We demonstrated that the pcm cluster is responsible for the biosynthesis of pepticinnamin E, a nonribosomal peptide/polyketide hybrid. We also characterized a key O ‐methyltransferase that modifies 3,4‐dihydroxy‐ l ‐phenylalanine. Our work has identified the gene cluster for pepticinnamins for the first time and sets the stage for elucidating the unique chemistry required for biosynthesis.