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Title: A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units

Journal Article · · Nature Communications
DOI:https://doi.org/10.1038/ncomms13609· OSTI ID:1623864
 [1];  [2];  [3];  [1];  [1];  [2];  [3];  [4];  [2];  [1]
  1. University of Warwick (United Kingdom). Dept. of Chemistry
  2. Univ. of California, Irvine, CA (United States). Depts. of Molecular Biology and Biochemistry
  3. RIKEN Center for Sustainable Resource Science (Japan). Chemical Biology Research Group; Saitama University (Japan). Graduate School of Science and Engineering
  4. RIKEN Center for Sustainable Resource Science (Japan). Chemical Biology Research Group
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Type I modular polyketide synthases assemble diverse bioactive natural products. Such multienzymes typically use malonyl and methylmalonyl-CoA building blocks for polyketide chain assembly. However, in several cases more exotic alkylmalonyl-CoA extender units are also known to be incorporated. In all examples studied to date, such unusual extender units are biosynthesized via reductive carboxylation of α, β-unsaturated thioesters catalysed by crotonyl-CoA reductase/carboxylase (CCRC) homologues. Here we show using a chemically-synthesized deuterium-labelled mechanistic probe, and heterologous gene expression experiments that the unusual alkylmalonyl-CoA extender units incorporated into the stambomycin family of polyketide antibiotics are assembled by direct carboxylation of medium chain acyl-CoA thioesters. X-ray crystal structures of the unusual β-subunit of the acyl-CoA carboxylase (YCC) responsible for this reaction, alone and in complex with hexanoyl-CoA, reveal the molecular basis for substrate recognition, inspiring the development of methodology for polyketide bio-orthogonal tagging via incorporation of 6-azidohexanoic acid and 8-nonynoic acid into novel stambomycin analogues.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1623864
Journal Information:
Nature Communications, Vol. 7, Issue 1; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (6)

Armeniaspirol Antibiotic Biosynthesis: Chlorination and Oxidative Dechlorination Steps Affording Spiro[4.4]non‐8‐ene journal January 2019
The biosynthetic pathway to ossamycin, a macrocyclic polyketide bearing a spiroacetal moiety journal April 2019
Structural and functional comparison of Saccharomonospora azurea strains in terms of primycin producing ability journal September 2020
Engineered polyketides: Synergy between protein and host level engineering journal September 2017
Searching for Glycosylated Natural Products in Actinomycetes and Identification of Novel Macrolactams and Angucyclines journal January 2018
Acyltransferases as Tools for Polyketide Synthase Engineering journal July 2018

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