Abstract
Iterative highly reducing polyketide synthases from filamentous fungi are the most complex and enigmatic type of polyketide synthase discovered to date. Here we uncover an unusual degree of programming by the hypothemycin highly reducing polyketide synthase, in which a single ketoreductase domain shows stereospecificity that is controlled by substrate length. Mapping of the structural domains responsible for this feature allowed for the biosynthesis of an unnatural diastereomer of the natural product dehydrozearalenol.
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Acknowledgements
This work was supported by US National Institutes of Health grant 1R01GM085128 to Y.T., the Natural Sciences and Engineering Research Council of Canada and the Canada Research Chair in Bioorganic and Medicinal Chemistry to J.C.V. We thank C. Reeves (Amyris Inc.) for the hpm genes.
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H.Z., Y.T. and J.C.V. conceived of the idea and designed the study. Z.G. and H.Z. performed the syntheses of all the thioester substrates in this study. H.Z. designed and performed molecular cloning. H.Z., K.Q. and J.W. performed the heterologous protein expression and purification as well as in vitro and in vivo characterization of the megasynthases. All authors analyzed and discussed the results. H.Z., Y.T. and J.C.V. prepared the manuscript.
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Zhou, H., Gao, Z., Qiao, K. et al. A fungal ketoreductase domain that displays substrate-dependent stereospecificity. Nat Chem Biol 8, 331–333 (2012). https://doi.org/10.1038/nchembio.912
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DOI: https://doi.org/10.1038/nchembio.912
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