Insights into the Dual Activity of a Bifunctional Dehydratase-Cyclase Domain

Angewandte Chemie
Kwang Hoon SungFrank Hahn

Abstract

Oxygen-containing heterocycles are a common structural motif in polyketide natural products and contribute significantly to their biological activity. Here, we report structural and mechanistic investigations on AmbDH3, a polyketide synthase domain with dual activity as dehydratase (DH) and pyran-forming cyclase in ambruticin biosynthesis. AmbDH3 is similar to monofunctional DH domains, using H51 and D215 for dehydration. V173 was confirmed as a diagnostic residue for cyclization activity by a mutational study and enzymatic in vitro experiments. Similar motifs were observed in the seemingly monofunctional AmbDH2, which also shows an unexpected cyclase activity. Our results pave the way for mining of hidden cyclases in biosynthetic pathways. They also open interesting prospects for the generation of novel biocatalysts for chemoenzymatic synthesis and pyran-polyketides by combinatorial biosynthesis.

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Citations

Jun 14, 2018·Angewandte Chemie·Srividhya SundaramChristian Hertweck
Jul 25, 2018·Chembiochem : a European Journal of Chemical Biology·Song MengHai-Xue Pan
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Sep 5, 2018·ACS Chemical Biology·Greg J DodgeJanet L Smith
Feb 27, 2018·ACS Chemical Biology·Drew T WagnerAdrian T Keatinge-Clay
Dec 14, 2017·Biochemistry·Christopher T Walsh, Yi Tang

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