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Metamorphic enzyme assembly in polyketide diversification.

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.

SUBMITTER: Gu L

PROVIDER: S-EPMC2918389 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Understanding the stabilization of cratons and how this is related to the onset of plate-tectonics is among the most important questions in geoscience. The assembly of Earth's first supercontinent Columbia represents the first lines of evidence for a global subduction network, when the oldest, deep subduction-related rocks have been reported. We combine the low-, intermediate- and high-T/P global metamorphic record with the two-stage assembly of the Nuna-Columbia supercontinent to address the significance of the oldest "cold" rocks (low-T/P) and the related emergence of bimodal metamorphic belts. For this purpose, we analyse two examples from Laurentia (including Greenland) and Australia between 2.0-1.8 Ga and 1.8-1.6 Ga. Two main observations are: (i) a first-stage (2.0-1.8 Ga) amalgamation of the megacontinent Nuna (precursor to Columbia) is characterized by bimodal metamorphism along major mobile belts suturing the megacontinent's center. In contrast, a second-stage (1.8-1.6 Ga) is dominated by the formation of soft collisional orogens during the final Columbia supercontinent assembly, recording intermediate- to high-T/P metamorphism; (ii) the metamorphic signature of the two assembly stages, featuring low- and intermediate-T/P rocks during Nuna assembly followed by their near absence during Columbia amalgamation, contrasts with the thermobaric ratios recorded by the Phanerozoic Gondwana-Pangea assembly, where intermediate and low-T/P rocks dominated the final stage of Pangea amalgamation. This discrepancy may signify substantial changes in intraplate metamorphism and minor rearrangements during Columbia assembly compared to major continent-continent collisions, such as the Appalachian-Variscan Orogen as well as production and fast exhumation of high- to ultra-high-pressure rocks during the assembly of the supercontinent Pangea. Furthermore, the variation of thermobaric ratios aligns with the concept of a two-stage mega-supercontinent formation, emphasizing differences between the potentially oldest and youngest supercontinent cycles.

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Metamorphic enzyme assembly in polyketide diversification.

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