Download MendeleyPathogenic bacteria remodel central metabolic enzyme to build a cyclopropanol warhead.
Trottmann, F., Ishida, K., Ishida-Ito, M., Kries, H., Groll, M., Hertweck, C.(2022) Nat Chem 14: 884-890
- PubMed: 35906404
- DOI: https://doi.org/10.1038/s41557-022-01005-z
- Primary Citation of Related Structures:
7PCC, 7PCE, 7PCG, 7PCI, 7PCL, 7PCM, 7PCN, 7PCO, 7PCT - 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.
Organizational Affiliation:
Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany.
