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Enzymatic catalysis of anti-Baldwin ring closure in polyether biosynthesis


Polycyclic polyether natural products have fascinated chemists and biologists alike owing to their useful biological activity, highly complex structure and intriguing biosynthetic mechanisms. Following the original proposal for the polyepoxide origin of lasalocid and isolasalocid1 and the experimental determination of the origins of the oxygen and carbon atoms of both lasalocid and monensin, a unified stereochemical model for the biosynthesis of polyether ionophore antibiotics was proposed2. The model was based on a cascade of nucleophilic ring closures of postulated polyepoxide substrates generated by stereospecific oxidation of all-trans polyene polyketide intermediates2. Shortly thereafter, a related model was proposed for the biogenesis of marine ladder toxins, involving a series of nominally disfavoured anti-Baldwin, endo-tet epoxide-ring-opening reactions3,4,5. Recently, we identified Lsd19 from the Streptomyces lasaliensis gene cluster as the epoxide hydrolase responsible for the epoxide-opening cyclization of bisepoxyprelasalocid A6 to form lasalocid A7,8. Here we report the X-ray crystal structure of Lsd19 in complex with its substrate and product analogue9 to provide the first atomic structure—to our knowledge—of a natural enzyme capable of catalysing the disfavoured epoxide-opening cyclic ether formation. On the basis of our structural and computational studies, we propose a general mechanism for the enzymatic catalysis of polyether natural product biosynthesis.

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Figure 1: Polyether natural products and proposed steps in the cyclic ether formation.
Figure 2: Crystal structure of Lsd19.
Figure 3: Computational studies of the Lsd19-catalysed epoxide-opening cyclization reactions.

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The coordinates and structure factors have been deposited with the Protein Data Bank under accession number 3RGA. Reprints and permissions information is available at


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This work was supported by the Royal Commission for the Exhibition of 1851 and Fulbright-AstraZeneca Research Fellowship (R.S.P.), the Japan Society for the Promotion of Science (No. LS103) (K.W.), the National Institutes of Health grant GM075962 (K.N.H.), the MEXT research grant on innovative area 22108002 (H.O.), and the National University of Singapore Life Sciences Institute Young Investigator Award (C.-Y.K.). Data collection was performed at the Stanford Synchrotron Radiation Lightsource. We thank D. W. Christianson, D. Hilvert and C. Khosla for critical reading and discussion of the manuscript.

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A.M. and H.O. prepared the substrate analogue. K.W. cloned and purified Lsd19. X.C. and H.L. purified and crystallized Lsd19. X.C. and I.I.M. collected diffraction data and determined the structure. K.H., X.C. and I.I.M. refined the structure. K.S. provided assistance for crystallography. K.N.H. prepared and analysed models of Lsd19 homologues. R.S.P. and K.N.H. performed the computational study. C.-Y.K. conceived and supervised the project. C.-Y.K. prepared the manuscript with contributions from all co-authors.

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Correspondence to Chu-Young Kim.

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Hotta, K., Chen, X., Paton, R. et al. Enzymatic catalysis of anti-Baldwin ring closure in polyether biosynthesis. Nature 483, 355–358 (2012).

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