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

doi:10.1016/j.chembiol.2004.08.017

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

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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 language	English
Pages (from-to)	1533-1542
Number of pages	10
Journal	Chemistry and Biology
Volume	11
Issue number	11
DOIs	https://doi.org/10.1016/j.chembiol.2004.08.017
State	Published - Nov 2004

Bibliographical note

Funding Information:
Funding for this work was provided by the NIH (GM21643, C.T.W.). F.L. is supported by a National Institutes of Health postdoctoral fellowship (GM66456). Gratitude is extended to Professor Heide for providing a cosmid containing CouN5.

Funding

Funding for this work was provided by the NIH (GM21643, C.T.W.). F.L. is supported by a National Institutes of Health postdoctoral fellowship (GM66456). Gratitude is extended to Professor Heide for providing a cosmid containing CouN5.

Funders	Funder number
National Institutes of Health (NIH)	GM21643
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	F32GM066456

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2004.08.017

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

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.",

author = "Fei Liu and Sylvie Garneau and Walsh, \{Christopher T.\}",

note = "Funding Information: Funding for this work was provided by the NIH (GM21643, C.T.W.). F.L. is supported by a National Institutes of Health postdoctoral fellowship (GM66456). Gratitude is extended to Professor Heide for providing a cosmid containing CouN5.",

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AU - Garneau, Sylvie

AU - Walsh, Christopher T.

N1 - Funding Information: Funding for this work was provided by the NIH (GM21643, C.T.W.). F.L. is supported by a National Institutes of Health postdoctoral fellowship (GM66456). Gratitude is extended to Professor Heide for providing a cosmid containing CouN5.

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

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ASJC Scopus subject areas

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