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Enzyme-catalyzed cationic epoxide rearrangements in quinolone alkaloid biosynthesis

Abstract

Epoxides are highly useful synthons and biosynthons for the construction of complex natural products during total synthesis and biosynthesis, respectively. Among enzyme-catalyzed epoxide transformations, a reaction that is notably missing, in regard to the synthetic toolbox, is cationic rearrangement that takes place under strong acid. This is a challenging transformation for enzyme catalysis, as stabilization of the carbocation intermediate upon epoxide cleavage is required. Here, we discovered two Brønsted acid enzymes that can catalyze two unprecedented epoxide transformations in biology. PenF from the penigequinolone pathway catalyzes a cationic epoxide rearrangement under physiological conditions to generate a quaternary carbon center, while AsqO from the aspoquinolone pathway catalyzes a 3-exo-tet cyclization to forge a cyclopropane–tetrahydrofuran ring system. The discovery of these new epoxide-modifying enzymes further highlights the versatility of epoxides in complexity generation during natural product biosynthesis.

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Figure 1: Versatility of epoxide as a (bio)synthon and the quinolone alkaloid biosynthetic pathways.
Figure 2: In vitro reconstitution of the conversion of 5 to 1.
Figure 3: Proposed reactions catalyzed by PenF and AsqO on the epoxide substrates.
Figure 4: Computational studies on model epoxides.
Figure 5: In vitro reconstitution of activities of asq enzymes and enzymatic synthesis of 2.

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Acknowledgements

We thank C. Hertweck for providing the standard of aspoquinolone A/B (2). This work was supported by NIH 1DP1GM106413 and 1R35GM118056 to Y.T. and NSF CHE-1361104 to K.N.H. Computational resources were provided by the UCLA Institute for Digital Research and Education (IDRE) and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (OCI-1053575). M.G.-B. thanks the Ramo´n Areces Foundation for a postdoctoral fellowship. K.W. thanks the Japan Society for the Promotion of Science (JSPS) Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (No. G2604). We thank M. Jung and N. Garg, as well as L. Hang for helpful discussions.

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Y.Z., M.G.-B., K.N.H. and Y.T. developed the hypothesis and designed the study. Y.Z. performed all in vivo and in vitro experiments, as well as compound isolation and characterization. M.C.T., D.H.L., Y.H. and L.L. performed compound characterization. M.G.-B. and K.N.H. performed the computational experiments. All authors analyzed and discussed the results. Y.Z., M.G.-B., K.W., K.N.H. and Y.T. prepared the manuscript.

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Correspondence to K N Houk or Yi Tang.

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Supplementary Results, Supplementary Tables 1–3 and Supplementary Figures 1–17. (PDF 4331 kb)

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Supplementary compounds NMR data. (PDF 2786 kb)

Supplementary Note 2

Supplementary computational data. (PDF 882 kb)

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Zou, Y., Garcia-Borràs, M., Tang, M. et al. Enzyme-catalyzed cationic epoxide rearrangements in quinolone alkaloid biosynthesis. Nat Chem Biol 13, 325–332 (2017). https://doi.org/10.1038/nchembio.2283

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