Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis

Somayah S. Elsayed; Helga U. van der Heul; Xiansha Xiao; Aleksi Nuutila; Laura R. Baars; Changsheng Wu; Mikko Metsä-Ketelä; Gilles P. van Wezel

doi:10.1038/s42004-023-01059-1

Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis

Somayah S. Elsayed^*, Helga U. van der Heul, Xiansha Xiao, Aleksi Nuutila, Laura R. Baars, Changsheng Wu, Mikko Metsä-Ketelä, Gilles P. van Wezel^*

^*Corresponding author for this work

NIOO - Microbial Ecology (ME)

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

1 Citation (Scopus)

Abstract

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.

Original language	English
Article number	281
Journal	Communications Chemistry
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/s42004-023-01059-1
Publication status	Published - Dec 2023

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title = "Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis",

abstract = "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.",

author = "Elsayed, {Somayah S.} and {van der Heul}, {Helga U.} and Xiansha Xiao and Aleksi Nuutila and Baars, {Laura R.} and Changsheng Wu and Mikko Mets{\"a}-Ketel{\"a} and {van Wezel}, {Gilles P.}",

note = "Data archiving: no NIOO data",

year = "2023",

month = dec,

doi = "10.1038/s42004-023-01059-1",

language = "English",

volume = "6",

journal = "Communications Chemistry",

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T1 - Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis

AU - Elsayed, Somayah S.

AU - van der Heul, Helga U.

AU - Xiao, Xiansha

AU - Nuutila, Aleksi

AU - Baars, Laura R.

AU - Wu, Changsheng

AU - Metsä-Ketelä, Mikko

AU - van Wezel, Gilles P.

N1 - Data archiving: no NIOO data

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

U2 - 10.1038/s42004-023-01059-1

DO - 10.1038/s42004-023-01059-1

M3 - Article

AN - SCOPUS:85179910331

SN - 2399-3669

VL - 6

JO - Communications Chemistry

JF - Communications Chemistry

IS - 1

M1 - 281

ER -

Unravelling key enzymatic steps in C-ring cleavage during angucycline biosynthesis

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