Format

Send to

Choose Destination
See comment in PubMed Commons below
Nature. 2009 Jun 4;459(7247):731-5. doi: 10.1038/nature07870.

Metamorphic enzyme assembly in polyketide diversification.

Author information

1
Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.

Abstract

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 beta-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 beta-branching, and an enoyl reductase domain. The halogenase from CurA, and the dehydratases (ECH(1)s), decarboxylases (ECH(2)s) 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 beta-branching pathway was modified by introduction of a gamma-chlorination step on (S)-3-hydroxy-3-methylglutaryl mediated by Cur halogenase, a non-haem Fe(ii), alpha-ketoglutarate-dependent enzyme. In a divergent scheme, Cur ECH(2) was found to catalyse formation of the alpha,beta enoyl thioester, whereas Jam ECH(2) formed a vinyl chloride moiety by selectively generating the corresponding beta,gamma 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 alpha,beta C = C saturation reaction. Thus, the combination of chlorination and polyketide beta-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.

PMID:
19494914
PMCID:
PMC2918389
DOI:
10.1038/nature07870
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center