Targeted Rediscovery and Biosynthesis of the Farnesyl-Transferase Inhibitor Pepticinnamin?E |
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Authors: | Kevin C Santa?Maria Dr Andrew N Chan Dr Erinn M O'Neill Prof?Dr Bo Li |
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Affiliation: | Department of Chemistry, University of North Carolina at Chapel Hill, CB#3290, Chapel Hill, NC, 27514 USA |
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Abstract: | 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. |
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Keywords: | bioinformatics genome mining natural products nonribosomal peptides transferases |
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