7PCE

BurG (apo): Biosynthesis of cyclopropanol rings in bacterial toxins

Summary for 7PCE

• Entry DOI: 10.2210/pdb7pce/pdb
• Related: 6AQJ
• Descriptor: Ketol-acid reductoisomerase, ADENOSINE-5'-DIPHOSPHATE, PHOSPHATE ION (3 entities in total)
• Functional Keywords: pathogens, natural products, toxins, biosynthesis, catalysis, lyase
• Biological source: Burkholderia thailandensis (strain ATCC 700388 / DSM 13276 / CIP 106301 / E264)
• Total number of polymer chains: 1
• Total formula weight: 39333.84

Authors

Trottmann, F.,Ishida, K.,Ishida, M.,Kries, H.,Groll, M.,Hertweck, C. (deposition date: 2021-08-03, release date: 2022-08-10, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.9 Å)