Cryptic indole hydroxylation by a non-canonical terpenoid cyclase parallels bacterial xenobiotic detoxification

Susann Kugel, Martin Baunach, Philipp Baer, Mie Ishida-Ito, Srividhya Sundaram, Zhongli Xu, Michael Groll () and Christian Hertweck ()
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Susann Kugel: Leibniz Institute for Natural Product Research and Infection Biology (HKI)
Martin Baunach: Leibniz Institute for Natural Product Research and Infection Biology (HKI)
Philipp Baer: Center for Integrated Protein Science Munich (CIPSM), Technische Universität München
Mie Ishida-Ito: Leibniz Institute for Natural Product Research and Infection Biology (HKI)
Srividhya Sundaram: Leibniz Institute for Natural Product Research and Infection Biology (HKI)
Zhongli Xu: Leibniz Institute for Natural Product Research and Infection Biology (HKI)
Michael Groll: Center for Integrated Protein Science Munich (CIPSM), Technische Universität München
Christian Hertweck: Leibniz Institute for Natural Product Research and Infection Biology (HKI)

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Terpenoid natural products comprise a wide range of molecular architectures that typically result from C–C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report the in vitro reconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated flavoenzyme-reductase (XiaP) that mediates a key step in xiamycin biosynthesis. The crystal structure of XiaF with bound FADH2 (at 2.4 Å resolution) and phylogenetic analyses reveal that XiaF is, surprisingly, most closely related to xenobiotic-degrading enzymes. Biotransformation assays show that XiaF is a designated indole hydroxylase that can be used for the production of indigo and indirubin. We unveil a cryptic hydroxylation step that sets the basis for terpenoid cyclization and suggest that the cyclase has evolved from xenobiotics detoxification enzymes.

Date: 2017
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DOI: 10.1038/ncomms15804

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