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

被引:6
作者
Elsayed, Somayah S. [1 ]
van der Heul, Helga U. [1 ]
Xiao, Xiansha [2 ]
Nuutila, Aleksi [3 ]
Baars, Laura R. [4 ]
Wu, Changsheng [5 ]
Metsa-Ketelae, Mikko [3 ]
van Wezel, Gilles P. [1 ,6 ]
机构
[1] Leiden Univ, Inst Biol, Dept Mol Biotechnol, Sylviusweg 72, NL-2333 BE Leiden, Netherlands
[2] Van Andel Inst, Dept Struct Biol, Grand Rapids, MI USA
[3] Univ Turku, Dept Life Technol, Tykistokatu 6, FIN-20014 Turku, Finland
[4] Leiden Univ, Leiden Acad Ctr Drug Res, Dept Syst Pharmacol & Pharm, Einsteinweg 55, NL-2333CC Leiden, Netherlands
[5] Shandong Univ, Inst Microbial Technol, State Key Lab Microbial Technol, Qingdao 266237, Peoples R China
[6] Netherlands Inst Ecol NIOO KNAW, Dept Microbial Ecol, Droevendaalsesteeg 10, NL-6708 PB Wageningen, Netherlands
基金
荷兰研究理事会;
关键词
HETEROLOGOUS EXPRESSION; TAILORING ENZYMES; FUNCTIONAL-ANALYSIS; NATURAL-PRODUCTS; STREPTOMYCES; GENES; GILVOCARCIN; ANTIBIOTICS; URDAMYCIN; PATHWAY;
D O I
10.1038/s42004-023-01059-1
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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. Angucyclines are a class of natural products that harbor unusual structural rearrangements through B- or C-ring cleavage of their tetracyclic backbone, however, the enzymes leading to C-ring cleavage remain poorly understood. Here, the authors use targeted gene deletion and complementation as well as metabolomics to study the function of putative oxygenases involved in lugdunomycin biosynthesis, and reveal their potential roles towards C-ring cleavage.
引用
收藏
页数:16
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