Elsayed Somayah S, van der Heul Helga U, Xiao Xiansha, Nuutila Aleksi, Baars Laura R, Wu Changsheng, Metsä-Ketelä Mikko, van Wezel Gilles P
Department of Molecular Biotechnology, Institute of Biology, Leiden University, Sylviusweg 72, 2333BE, Leiden, The Netherlands.
Department of Structural Biology, Van Andel Institute, Grand Rapids, MI, USA.
Commun Chem. 2023 Dec 18;6(1):281. doi: 10.1038/s42004-023-01059-1.
Angucyclines are type II polyketide natural products, often characterized by unusual structural rearrangements through B- or C-ring cleavage of their tetracyclic backbone. While the enzymes involved in B-ring cleavage have been extensively studied, little is known of the enzymes leading to C-ring cleavage. Here, we unravel the function of the oxygenases involved in the biosynthesis of lugdunomycin, a highly rearranged C-ring cleaved angucycline derivative. Targeted deletion of the oxygenase genes, in combination with molecular networking and structural elucidation, showed that LugOI is essential for C12 oxidation and maintaining a keto group at C6 that is reduced by LugOII, resulting in a key intermediate towards C-ring cleavage. An epoxide group is then inserted by LugOIII, and stabilized by the novel enzyme LugOV for the subsequent cleavage. Thus, for the first time we describe the oxidative enzymatic steps that form the basis for a wide range of rearranged angucycline natural products.
安古环素是II型聚酮类天然产物，其特征通常是通过四环骨架的B环或C环裂解进行不寻常的结构重排。虽然参与B环裂解的酶已得到广泛研究，但对于导致C环裂解的酶却知之甚少。在此，我们揭示了参与鲁格霉素生物合成的加氧酶的功能，鲁格霉素是一种高度重排的C环裂解安古环素衍生物。通过对加氧酶基因进行靶向缺失，并结合分子网络和结构解析，结果表明LugOI对于C12氧化以及维持C6位的酮基至关重要，该酮基会被LugOII还原，从而产生一个通向C环裂解的关键中间体。然后由LugOIII插入一个环氧基团，并由新型酶LugOV使其稳定以便后续裂解。因此，我们首次描述了形成多种重排安古环素天然产物基础的氧化酶促步骤。
