7PCO
BurG E232Q mutant (holo) in complex with 2R,3R-2,3-dihydroxy-6-methyl-heptanoate (12): Biosynthesis of cyclopropanol rings in bacterial toxins
Summary for 7PCO
| Entry DOI | 10.2210/pdb7pco/pdb |
| Related | 6AQJ |
| Descriptor | Ketol-acid reductoisomerase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, MAGNESIUM ION, ... (7 entities in total) |
| Functional Keywords | pathogens, natural products, toxins, biosynthesis, catalysis, mutagenesis, lyase |
| Biological source | Burkholderia thailandensis (strain ATCC 700388 / DSM 13276 / CIP 106301 / E264) |
| Total number of polymer chains | 2 |
| Total formula weight | 79323.00 |
| 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 Cited by 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: 35906404DOI: 10.1038/s41557-022-01005-z PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.55 Å) |
Structure validation
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