Hybrid nonribosomal peptide-polyketide interfaces in epothilone biosynthesis: Minimal requirements at N and C termini of EpoB for elongation

Fei Liu, Sylvie Garneau, Christopher T. Walsh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

Epothilone (Epo) D, an antitumor agent currently in clinical trials, is a hybrid natural product produced by the combined action of nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS). In the epothilone biosynthetic pathway, EpoB, a 165 kDa NRPS is inserted into an otherwise entirely PKS assembly line, forming two hybrid NRPS-PKS interfaces. In light of the terminal linker effect previously identified in PKS, the N- and C-terminal sequences of EpoB were examined for their roles in propagating the incipient natural product. Eight amino acid residues at EpoB C terminus, in which six are positively charged, were found to be a key component of the C-terminal linker effect. A minimal sequence of 56 residues at EpoB N terminus was required for elongating the acetyl group from the acyl carrier protein (ACP) of EpoA to form methylthiazolyl-S-EpoB.

Original languageEnglish
Pages (from-to)1533-1542
Number of pages10
JournalChemistry and Biology
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 2004
Externally publishedYes

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