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A Multi-Enzyme Machine Polymerizes the Haemophilus influenzae Type b Capsule


J.O. Cifuente, J. Schulze, A. Bethe, V. Di Domenico, C. Litschko, I. Budde, L. Eidenberger, H. Thiesler, I. R. Roth, M. Berger, H. Claus, C. D’Angelo, A. Marina, R. Gerardy-Schahn, M. Schubert, M.E. Guerin &T. Fiebig


Nature Chemical Biology | Volume 19 | July 2023 | 865–877

Bacterial capsules play a critical role in host-pathogen interactions. They provide a protective envelope against host recognition, leading to immune evasion and bacterial survival. Here, we define the capsule biosynthetic pathway of Haemophilus influenzae serotype b (Hib), a Gram-negative bacterium that causes severe infections in infants and children. Reconstitution of this pathway allowed fermentation-free production of Hib vaccine antigens from widely available precursors and detailed characterization of the enzymatic machinery. The X-ray crystal structure of capsule polymerase Bcs3 reveals a multi-enzyme machine that adopts a basket-like shape, providing a protected environment for the synthesis of the complex Hib polymer.
This architecture is commonly used for surface glycan synthesis by both Gram-negative and Gram-positive pathogens. Supported by biochemical studies and comprehensive 2D nuclear magnetic resonance, our data explain how the ribofuranosyltransferase CriT, the phosphatase CrpP, the ribitol phosphate transferase CroT and a polymer-binding domain function as a unique multi-enzyme assembly.

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