7PCG

BurG (holo) in complex with cyclopropane-1,1-dicarboxylate (7): Biosynthesis of cyclopropanol rings in bacterial toxins

7PCG の概要

• エントリーDOI: 10.2210/pdb7pcg/pdb
• 関連するPDBエントリー: 6AQJ
• 分子名称: Ketol-acid reductoisomerase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: pathogens, natural products, toxins, biosynthesis, catalysis, lyase
• 由来する生物種: Burkholderia thailandensis (strain ATCC 700388 / DSM 13276 / CIP 106301 / E264)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79301.85

構造登録者

Trottmann, F.,Ishida, K.,Ishida, M.,Kries, H.,Groll, M.,Hertweck, C. (登録日: 2021-08-03, 公開日: 2022-08-10, 最終更新日: 2024-01-31)

主引用文献

Trottmann, F.,Ishida, K.,Ishida-Ito, M.,Kries, H.,Groll, M.,Hertweck, C.
Pathogenic bacteria remodel central metabolic enzyme to build a cyclopropanol warhead.
Nat.Chem., 14:884-890, 2022

PubMed Abstract: Bacteria of the Burkholderia pseudomallei (BP) group pose a global health threat, causing the infectious diseases melioidosis, a common cause of pneumonia and sepsis, and glanders, a contagious zoonosis. A trait of BP bacteria is a conserved gene cluster coding for the biosynthesis of polyketides (malleicyprols) with a reactive cyclopropanol unit that is critical for virulence. Enzymes building this warhead represent ideal targets for antivirulence strategies but the biochemical basis of cyclopropanol formation is unknown. Here we describe the formation of the malleicyprol warhead. We show that BurG, an unusual NAD-dependent member of the ketol-acid reductoisomerase family, constructs the strained cyclopropanol ring. Biochemical assays and a suite of eight crystal structures of native and mutated BurG with bound analogues and inhibitors provide snapshots of each step of the complex reaction mechanism, involving a concealed oxidoreduction and a C-S bond cleavage. Our findings illustrate a remarkable case of neofunctionalisation, where a biocatalyst from central metabolism has been evolutionarily repurposed for warhead production in pathogens.

PubMed: 35906404
DOI: 10.1038/s41557-022-01005-z

実験手法

X-RAY DIFFRACTION (1.9 Å)