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bioRxiv · 10.1101/2024.05.05.592269

Structural Basis for Intermodular Communication in Assembly-Line Polyketide Biosynthesis

Cogan, D. P.·Soohoo, A. M.·Chen, M.·Liu, Y.·Brodsky, K. L.·Khosla, C.
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Abstract

Assembly-line polyketide synthases are large multienzyme systems with considerable potential for genetic reprogramming. To investigate the mechanisms by which reactive biosynthetic intermediates are directionally channeled across a defined sequence of active sites in a naturally occurring assembly line, we employed a bifunctional reagent to crosslink transient domain-domain interfaces of the 6-deoxyerythronolide B synthase. Structural resolution of these crosslinked states by single-particle cryogenic electron microscopy (cryo-EM) together with statistical per-particle image analysis of cryo-EM data revealed ketosynthase - acyl carrier protein (KS-ACP) interactions that discriminate between intra- and inter-modular communication, while reinforcing the relevance of asymmetric conformations during the catalytic cycle. Our findings provide a new foundation for the structure-based design of hybrid polyketide synthases comprised of biosynthetic modules from different assembly lines.

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Cogan, D. P., Soohoo, A. M., Chen, M., Liu, Y., Brodsky, K. L., Khosla, C.. 2024-05-05. Structural Basis for Intermodular Communication in Assembly-Line Polyketide Biosynthesis. https://doi.org/10.1101/2024.05.05.592269

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