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Metamorphic enzyme assembly in polyketide diversification

Gu, L and Wang, B and Kulkarni, A and Geders, TW and Grindberg, RV and Gerwick, L and Hkansson, K and Wipf, P and Smith, JL and Gerwick, WH and Sherman, DH (2009) Metamorphic enzyme assembly in polyketide diversification. Nature, 459 (7247). 731 - 735. ISSN 0028-0836

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Natural product chemical diversity is fuelled by the emergence and ongoing evolution of biosynthetic pathways in secondary metabolism. However, co-evolution of enzymes for metabolic diversification is not well understood, especially at the biochemical level. Here, two parallel assemblies with an extraordinarily high sequence identity from Lyngbya majuscula form a Β-branched cyclopropane in the curacin A pathway (Cur), and a vinyl chloride group in the jamaicamide pathway (Jam). The components include a halogenase, a 3-hydroxy-3-methylglutaryl enzyme cassette for polyketide Β-branching, and an enoyl reductase domain. The halogenase from CurA, and the dehydratases (ECH"1s), decarboxylases (ECH"2s) and enoyl reductase domains from both Cur and Jam, were assessed biochemically to determine the mechanisms of cyclopropane and vinyl chloride formation. Unexpectedly, the polyketide Β-branching pathway was modified by introduction of a -chlorination step on (S)-3-hydroxy-3-methylglutaryl mediated by Cur halogenase, a non-haem Fe(ii), α-ketoglutarate-dependent enzyme. In a divergent scheme, Cur ECH"2 was found to catalyse formation of the α,Β enoyl thioester, whereas Jam ECH"2 formed a vinyl chloride moiety by selectively generating the corresponding Β, enoyl thioester of the 3-methyl-4-chloroglutaconyl decarboxylation product. Finally, the enoyl reductase domain of CurF specifically catalysed an unprecedented cyclopropanation on the chlorinated product of Cur ECH"2 instead of the canonical α,Β C ≤ C saturation reaction. Thus, the combination of chlorination and polyketide Β-branching, coupled with mechanistic diversification of ECH"2 and enoyl reductase, leads to the formation of cyclopropane and vinyl chloride moieties. These results reveal a parallel interplay of evolutionary events in multienzyme systems leading to functional group diversity in secondary metabolites. © 2009 Macmillan Publishers Limited. All rights reserved.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Gu, L
Wang, B
Kulkarni, A
Geders, TW
Grindberg, RV
Gerwick, L
Hkansson, K
Wipf, Ppwipf@pitt.eduPWIPF
Smith, JL
Gerwick, WH
Sherman, DH
Date: 4 June 2009
Date Type: Publication
Journal or Publication Title: Nature
Volume: 459
Number: 7247
Page Range: 731 - 735
DOI or Unique Handle: 10.1038/nature07870
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0028-0836
MeSH Headings: Cyanobacteria--enzymology; Cyclopropanes--metabolism; Enzymes--biosynthesis; Enzymes--chemistry; Enzymes--metabolism; Evolution, Molecular; Halogenation; Thiazoles--metabolism; Vinyl Chloride--metabolism
Other ID: NLM NIHMS217307, NLM PMC2918389
PubMed Central ID: PMC2918389
PubMed ID: 19494914
Date Deposited: 07 Jun 2013 20:46
Last Modified: 02 Feb 2019 16:56


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